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1
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Sekine H, Akaike T, Motohashi H. Oxygen needs sulfur, sulfur needs oxygen: a relationship of interdependence. EMBO J 2025; 44:3307-3326. [PMID: 40394395 DOI: 10.1038/s44318-025-00464-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 04/29/2025] [Accepted: 04/30/2025] [Indexed: 05/22/2025] Open
Abstract
Oxygen and sulfur, both members of the chalcogen group (group 16 elements), play fundamental roles in life. Ancient organisms primarily utilized sulfur for energy metabolism, while the rise in atmospheric oxygen facilitated the evolution of aerobic organisms, enabling highly efficient energy production. Nevertheless, all modern organisms, both aerobes and anaerobes, must protect themselves from oxygen toxicity. Interestingly, aerobes still rely on sulfur for survival. This dependence has been illuminated by the recent discovery of supersulfides, a novel class of biomolecules, made possible through advancements in technology and analytical methods. These breakthroughs are reshaping our understanding of biological processes and emphasizing the intricate interplay between oxygen and sulfur in regulating essential redox reactions. This review summarizes the latest insights into the biological roles of sulfur and oxygen, their interdependence in key processes, and their contributions to adaptive responses to environmental stressors. By exploring these interactions, we aim to provide a comprehensive perspective on how these elements drive survival strategies across diverse life forms, highlighting their indispensable roles in both human health and the sustenance of life.
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Affiliation(s)
- Hiroki Sekine
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Takaaki Akaike
- Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Hozumi Motohashi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
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2
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Froyen EB, Barrantes GP. A Review of the Effects of Flavonoids on NAD(P)H Quinone Oxidoreductase 1 Expression and Activity. J Med Food 2025; 28:407-422. [PMID: 40097203 DOI: 10.1089/jmf.2023.0132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
Cancer is a significant cause of death worldwide. It has been suggested that the consumption of flavonoids decreases the risk for cancer by increasing phase II enzymes, such as Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NAD(P)H) quinone oxidoreductase 1 (NQO1), glutathione S-transferases, and Uridine 5'-diphospho- (UDP)-glucuronosyltransferases that assist in removing carcinogens from the human body. Flavonoids are bioactive compounds found in a variety of dietary sources, including fruits, vegetables, legumes, nuts, and teas. As such, it is important to investigate which flavonoids are involved in the metabolism of carcinogens to help reduce the risk of cancer. Therefore, the objective of this narrative review was to investigate the effects of commonly consumed flavonoids on NQO1 mRNA expression, protein, and activity in human cell and murine models. PubMed was used to search for peer-reviewed journal articles, which demonstrated that selected flavonoids (e.g., quercetin, apigenin, luteolin, genistein, and daidzein) increase NQO1, and therefore, increase the excretion of carcinogens. However, more research is needed regarding the mechanisms by which flavonoids induce NQO1. Furthermore, it is suggested that future efforts focus on providing precise flavonoid recommendations to decrease the risk factors for chronic diseases.
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Affiliation(s)
- Erik B Froyen
- Department of Nutrition and Food Science, Huntley College of Agriculture, California State Polytechnic University, Pomona, California, USA
| | - Gianluis Pimentel Barrantes
- Department of Nutrition and Food Science, Huntley College of Agriculture, California State Polytechnic University, Pomona, California, USA
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3
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Hale OF, Yin M, Behringer MG. Elevated rates and biased spectra of mutations in anaerobically cultured lactic acid bacteria. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.28.639667. [PMID: 40060621 PMCID: PMC11888475 DOI: 10.1101/2025.02.28.639667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
The rate, spectrum, and biases of mutations represent a fundamental force shaping biological evolution. Convention often attributes oxidative DNA damage as a major driver of spontaneous mutations. Yet, despite the contribution of oxygen to mutagenesis and the ecological, industrial, and biomedical importance of anaerobic organisms, relatively little is known about the mutation rates and spectra of anaerobic species. Here, we present the rates and spectra of spontaneous mutations assessed anaerobically over 1000 generations for three fermentative lactic acid bacteria species with varying levels of aerotolerance: Lactobacillus acidophilus, Lactobacillus crispatus, and Lactococcus lactis. Our findings reveal highly elevated mutation rates compared to the average rates observed in aerobically respiring bacteria with mutations strongly biased towards transitions, emphasizing the prevalence of spontaneous deamination in these anaerobic species and highlighting the inherent fragility of purines even under conditions that minimize oxidative stress. Beyond these overarching patterns, we identify several novel mutation dynamics: positional mutation bias around the origin of replication in Lb. acidophilus, a significant disparity between observed and equilibrium GC content in Lc. lactis, and repeated independent deletions of spacer sequences from within the CRISPR locus in Lb. crispatus providing mechanistic insights into the evolution of bacterial adaptive immunity. Overall, our study provides new insights into the mutational landscape of anaerobes, revealing how non-oxygenic factors shape mutation rates and influence genome evolution.
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Affiliation(s)
- Owen F. Hale
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, Tennessee, USA
| | - Michelle Yin
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
- School of Medicine, Tulane University, New Orleans, Louisiana, USA
| | - Megan G. Behringer
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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4
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Elling FJ, Pierrel F, Chobert SC, Abby SS, Evans TW, Reveillard A, Pelosi L, Schnoebelen J, Hemingway JD, Boumendjel A, Becker KW, Blom P, Cordes J, Nathan V, Baymann F, Lücker S, Spieck E, Leadbetter JR, Hinrichs KU, Summons RE, Pearson A. A novel quinone biosynthetic pathway illuminates the evolution of aerobic metabolism. Proc Natl Acad Sci U S A 2025; 122:e2421994122. [PMID: 39977315 PMCID: PMC11874023 DOI: 10.1073/pnas.2421994122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/09/2025] [Indexed: 02/22/2025] Open
Abstract
The dominant organisms in modern oxic ecosystems rely on respiratory quinones with high redox potential (HPQs) for electron transport in aerobic respiration and photosynthesis. The diversification of quinones, from low redox potential (LPQ) in anaerobes to HPQs in aerobes, is assumed to have followed Earth's surface oxygenation ~2.3 billion years ago. However, the evolutionary origins of HPQs remain unresolved. Here, we characterize the structure and biosynthetic pathway of an ancestral HPQ, methyl-plastoquinone (mPQ), that is unique to bacteria of the phylum Nitrospirota. mPQ is structurally related to the two previously known HPQs, plastoquinone from Cyanobacteriota/chloroplasts and ubiquinone from Pseudomonadota/mitochondria, respectively. We demonstrate a common origin of the three HPQ biosynthetic pathways that predates the emergence of Nitrospirota, Cyanobacteriota, and Pseudomonadota. An ancestral HPQ biosynthetic pathway evolved ≥ 3.4 billion years ago in an extinct lineage and was laterally transferred to these three phyla ~2.5 to 3.2 billion years ago. We show that Cyanobacteriota and Pseudomonadota were ancestrally aerobic and thus propose that aerobic metabolism using HPQs significantly predates Earth's surface oxygenation. Two of the three HPQ pathways were later obtained by eukaryotes through endosymbiosis forming chloroplasts and mitochondria, enabling their rise to dominance in modern oxic ecosystems.
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Affiliation(s)
- Felix J. Elling
- Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA02138
- Leibniz-Laboratory for Radiometric Dating and Isotope Research, Christian-Albrecht University of Kiel, Kiel24118, Germany
| | - Fabien Pierrel
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Sophie-Carole Chobert
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Sophie S. Abby
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Thomas W. Evans
- Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA02139
- MARUM—Center for Marine Environmental Sciences and Department of Geosciences, University of Bremen, Bremen28359, Germany
| | - Arthur Reveillard
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Ludovic Pelosi
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Juliette Schnoebelen
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble38000, France
| | - Jordon D. Hemingway
- Department of Earth and Planetary Sciences, Geological Institute, ETH Zürich, Zurich8092, Switzerland
| | | | - Kevin W. Becker
- GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel24148, Germany
| | - Pieter Blom
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen6525 AJ, The Netherlands
| | - Julia Cordes
- MARUM—Center for Marine Environmental Sciences and Department of Geosciences, University of Bremen, Bremen28359, Germany
| | - Vinitra Nathan
- Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA02138
| | - Frauke Baymann
- Laboratoire de Bioénergétique et Ingénierie des Protéines UMR 7281 CNRS/AMU, FR3479, Marseille Cedex 20F-13402, France
| | - Sebastian Lücker
- Department of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen6525 AJ, The Netherlands
| | - Eva Spieck
- Department of Microbiology and Biotechnology, University of Hamburg, Hamburg22609, Germany
| | - Jared R. Leadbetter
- Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA91125
- Division of Engineering and Applied Science, California Institute of Technology, Pasadena, CA91125
| | - Kai-Uwe Hinrichs
- MARUM—Center for Marine Environmental Sciences and Department of Geosciences, University of Bremen, Bremen28359, Germany
| | - Roger E. Summons
- Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Ann Pearson
- Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA02138
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5
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Zheng M, Jiang Y, Ran Z, Liang S, Xiao T, Li X, Ma W. A cyanobacteria-derived intermolecular salt bridge stabilizes photosynthetic NDH-1 and prevents oxidative stress. Commun Biol 2025; 8:172. [PMID: 39905225 PMCID: PMC11794437 DOI: 10.1038/s42003-025-07556-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/15/2025] [Indexed: 02/06/2025] Open
Abstract
Throughout evolution, addition of numerous cyanobacteria-derived subunits to the photosynthetic NDH-1 complex stabilizes the complex and facilitates cyclic electron transfer around photosystem I (PSI CET), a critical antioxidant mechanism for efficient photosynthesis, but its stabilization mechanism remains elusive. Here, a cyanobacteria-derived intermolecular salt bridge is found to form between the two conserved subunits, NdhF1 and NdhD1. Its disruption destabilizes photosynthetic NDH-1 and impairs PSI CET, resulting in the production of more reactive oxygen species under high light conditions. The salt bridge and transmembrane helix 16, both situated at the C-terminus of NdhF1, collaboratively secure the linkage between NdhD1 and NdhB, akin to a cramping mechanism. The linkage is also stabilized by cyanobacteria-derived NdhP and NdhQ subunits, but their stabilization mechanisms are distinctly different. Collectively, to the best of our knowledge, this is the first study to unveil the stabilization mechanism of photosynthetic NDH-1 by incorporating photosynthetic components into its conserved subunits during evolution.
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Affiliation(s)
- Mei Zheng
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Yuanyuan Jiang
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Zhaoxing Ran
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Shengjun Liang
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Tingting Xiao
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Xiafei Li
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China
| | - Weimin Ma
- College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
- Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
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6
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Amritkar K, Cuevas-Zuviría B, Kaçar B. Evolutionary Dynamics of RuBisCO: Emergence of the Small Subunit and its Impact Through Time. Mol Biol Evol 2025; 42:msae268. [PMID: 39776198 PMCID: PMC11707681 DOI: 10.1093/molbev/msae268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/25/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is an ancient protein critical for CO2-fixation and global biogeochemistry. Form-I RuBisCO complexes uniquely harbor small subunits that form a hexadecameric complex together with their large subunits. The small subunit protein is thought to have significantly contributed to RuBisCO's response to the atmospheric rise of O2 ∼2.5 billion years ago, marking a pivotal point in the enzyme's evolutionary history. Here, we performed a comprehensive evolutionary analysis of extant and ancestral RuBisCO sequences and structures to explore the impact of the small subunit's earliest integration on the molecular dynamics of the overall complex. Our simulations suggest that the small subunit restricted the conformational flexibility of the large subunit early in its history, impacting the evolutionary trajectory of the Form-I RuBisCO complex. Molecular dynamics investigations of CO2 and O2 gas distribution around predicted ancient RuBisCO complexes suggest that a proposed "CO2-reservoir" role for the small subunit is not conserved throughout the enzyme's evolutionary history. The evolutionary and biophysical response of RuBisCO to changing atmospheric conditions on ancient Earth showcase multi-level and trackable responses of enzymes to environmental shifts over long timescales.
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Affiliation(s)
- Kaustubh Amritkar
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
- Biophysics Graduate Degree Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Bruno Cuevas-Zuviría
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
- Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid, Madrid, Spain
| | - Betül Kaçar
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA
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7
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Wong W, Bravo P, Yunker PJ, Ratcliff WC, Burnetti AJ. Oxygen-binding proteins aid oxygen diffusion to enhance fitness of a yeast model of multicellularity. PLoS Biol 2025; 23:e3002975. [PMID: 39883703 PMCID: PMC11781632 DOI: 10.1371/journal.pbio.3002975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 12/08/2024] [Indexed: 02/01/2025] Open
Abstract
Oxygen availability is a key factor in the evolution of multicellularity, as larger and more sophisticated organisms often require mechanisms allowing efficient oxygen delivery to their tissues. One such mechanism is the presence of oxygen-binding proteins, such as globins and hemerythrins, which arose in the ancestor of bilaterian animals. Despite their importance, the precise mechanisms by which oxygen-binding proteins influenced the early stages of multicellular evolution under varying environmental oxygen levels are not yet clear. We address this knowledge gap by heterologously expressing the oxygen-binding proteins myoglobin and myohemerythrin in snowflake yeast, a model system of simple, undifferentiated multicellularity. These proteins increased the depth and rate of oxygen diffusion, increasing the fitness of snowflake yeast growing aerobically. Experiments show that, paradoxically, oxygen-binding proteins confer a greater fitness benefit for larger organisms when O2 is least limiting. We show via biophysical modeling that this is because facilitated diffusion is more efficient when oxygen is abundant, transporting a greater quantity of O2 which can be used for metabolism. By alleviating anatomical diffusion limitations to oxygen consumption, the evolution of oxygen-binding proteins in the oxygen-rich Neoproterozoic may have been a key breakthrough enabling the evolution of increasingly large, complex multicellular metazoan lineages.
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Affiliation(s)
- Whitney Wong
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Pablo Bravo
- School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Peter J. Yunker
- School of Physics, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - William C. Ratcliff
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Anthony J. Burnetti
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
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8
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Hengeveld R. Von Uexküll's Umwelt Concept Revived : E. Yong, 2022. An immense world. How animal senses reveal the hidden realms around us. Bodley Head, London, 449 pp; ISBN 978-1-847-92609-8. Acta Biotheor 2024; 72:14. [PMID: 39560780 DOI: 10.1007/s10441-024-09487-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/27/2024] [Indexed: 11/20/2024]
Affiliation(s)
- Rob Hengeveld
- Vrije Universiteit, Amsterdam, The Netherlands.
- , Randwijk, The Netherlands.
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9
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Pfleger A, Arc E, Grings M, Gnaiger E, Roach T. Flavodiiron proteins prevent the Mehler reaction in Chlamydomonas reinhardtii. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2024; 1865:149497. [PMID: 39048034 DOI: 10.1016/j.bbabio.2024.149497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024]
Affiliation(s)
- Ana Pfleger
- Department of Botany, University of Innsbruck, Sternwartestraße 15, Austria
| | - Erwann Arc
- Department of Botany, University of Innsbruck, Sternwartestraße 15, Austria
| | - Mateus Grings
- Oroboros Instruments GmbH, Schöpfstraße 18, 6020 Innsbruck, Austria
| | - Erich Gnaiger
- Oroboros Instruments GmbH, Schöpfstraße 18, 6020 Innsbruck, Austria
| | - Thomas Roach
- Department of Botany, University of Innsbruck, Sternwartestraße 15, Austria.
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10
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Sundar Panja A. The systematic codon usage bias has an important effect on genetic adaption in native species. Gene 2024; 926:148627. [PMID: 38823656 DOI: 10.1016/j.gene.2024.148627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/06/2024] [Accepted: 05/29/2024] [Indexed: 06/03/2024]
Abstract
Random mutations increase genetic variety and natural selection enhances adaption over generations. Codon usage biases (CUB) provide clues about the genome adaptation mechanisms of native species and extremophile species. Significant numbers of gene (CDS) of nine classes of endangered, native species, including extremophiles and mesophiles were utilised to compute CUB. Codon usage patterns differ among the lineages of endangered and extremophiles with native species. Polymorphic usage of nucleotides with codon burial suggests parallelism of native species within relatively confined taxonomic groups. Utilizing the deviation pattern of CUB of endangered and native species, I present a calculation parameter to estimate the extinction risk of endangered species. Species diversity and extinction risk are both positively associated with the propensity of random mutation in CDS (Coding DNA sequence). Codon bias tenet profoundly selected and it governs to adaptive evolution of native species.
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Affiliation(s)
- Anindya Sundar Panja
- Department of Biotechnology, Molecular Informatics Laboratory, Oriental Institute of Science and Technology, Vidyasagar University, Midnapore, West Bengal 721102, India.
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11
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Cottom-Salas W, Becerra A, Lazcano A. RNA or DNA? Revisiting the Chemical Nature of the Cenancestral Genome. J Mol Evol 2024; 92:647-658. [PMID: 39145798 PMCID: PMC11458739 DOI: 10.1007/s00239-024-10194-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024]
Abstract
One of the central issues in the understanding of early cellular evolution is the characterisation of the cenancestor. This includes the description of the chemical nature of its genome. The disagreements on this question comprise several proposals, including the possibility that AlkB-mediated methylation repair of alkylated RNA molecules may be interpreted as evidence of a cenancestral RNA genome. We present here an evolutionary analysis of the cupin-like protein superfamily based on tertiary structure-based phylogenies that includes the oxygen-dependent AlkB and its homologs. Our results suggest that the repair of methylated RNA molecules is the outcome of the enzyme substrate ambiguity, and doesn´t necessarily indicates that the last common ancestor was endowed with an RNA genome.
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Affiliation(s)
- Wolfgang Cottom-Salas
- Posgrado en Ciencias Biológicas, UNAM, Cd. Universitaria, 04510, Mexico City, CDMX, Mexico
- Facultad de Ciencias, UNAM, Cd. Universitaria, Apdo.Postal 70-407, 04510, Mexico City, DF, Mexico
- Escuela Nacional Preparatoria, Plantel 8 Miguel E. Schulz, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Arturo Becerra
- Facultad de Ciencias, UNAM, Cd. Universitaria, Apdo.Postal 70-407, 04510, Mexico City, DF, Mexico
| | - Antonio Lazcano
- Facultad de Ciencias, UNAM, Cd. Universitaria, Apdo.Postal 70-407, 04510, Mexico City, DF, Mexico.
- El Colegio Nacional, Donceles 104, Centro Histórico, 06020, Mexico City, CP, Mexico.
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12
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Li D, Zhang Z, Wang L. Emerging role of tumor microenvironmental nutrients and metabolic molecules in ferroptosis: Mechanisms and clinical implications. Biomed Pharmacother 2024; 179:117406. [PMID: 39255738 DOI: 10.1016/j.biopha.2024.117406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/22/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024] Open
Abstract
In recent years, ferroptosis has gradually attracted increasing attention because of its important role in tumors. Ferroptosis resistance is an important cause of tumor metastasis, recurrence and drug resistance. Exploring the initiating factors and specific mechanisms of ferroptosis has become a key strategy to block tumor progression and improve drug sensitivity. As the external space in direct contact with tumor cells, the tumor microenvironment has a great impact on the biological function of tumor cells. The relationships between abnormal environmental characteristics (hypoxia, lactic acid accumulation, etc.) in the microenvironment and ferroptosis of tumor cells has not been fully characterized. This review focuses on the characteristics of the tumor microenvironment and summarizes the mechanisms of ferroptosis under different environmental factors, aiming to provide new insights for subsequent targeted therapy. Moreover, considering the presence of anticancer drugs in the microenvironment, we further summarize the mechanisms of ferroptosis to provide new strategies for the sensitization of tumor cells to drugs.
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Affiliation(s)
- Dongyu Li
- Department of VIP In-Patient Ward, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zhe Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Lei Wang
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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13
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Laxman S. Biochemical curiosities : Piquing students' interest in biochemistry by exploring evolution's pursuit of the improbable. EMBO Rep 2024; 25:4100-4104. [PMID: 39271772 PMCID: PMC11467204 DOI: 10.1038/s44319-024-00259-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
A teaching course based on seemingly improbable curiosities could attract students’ interest in the magic of biochemical pathways and their evolution.
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Affiliation(s)
- Sunil Laxman
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Post Bellary Road, Bangalore, Karnataka, 560065, India.
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14
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Rose KC, Ferrer EM, Carpenter SR, Crowe SA, Donelan SC, Garçon VC, Grégoire M, Jane SF, Leavitt PR, Levin LA, Oschlies A, Breitburg D. Aquatic deoxygenation as a planetary boundary and key regulator of Earth system stability. Nat Ecol Evol 2024; 8:1400-1406. [PMID: 39009849 DOI: 10.1038/s41559-024-02448-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 05/02/2024] [Indexed: 07/17/2024]
Abstract
Planetary boundaries represent thresholds in major Earth system processes that are sensitive to human activity and control global-scale habitability and stability. These processes are interconnected such that movement of one planetary boundary process can alter the likelihood of crossing other boundaries. Here we argue that the observed deoxygenation of the Earth's freshwater and marine ecosystems represents an additional planetary boundary process that is critical to the integrity of Earth's ecological and social systems, and both regulates and responds to ongoing changes in other planetary boundary processes. Research on the rapid and ongoing deoxygenation of Earth's aquatic habitats indicates that relevant, critical oxygen thresholds are being approached at rates comparable to other planetary boundary processes. Concerted global monitoring, research and policy efforts are needed to address the challenges brought on by rapid deoxygenation, and the expansion of the planetary boundaries framework to include deoxygenation as a boundary helps to focus those efforts.
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Affiliation(s)
- Kevin C Rose
- Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, USA.
- Department of Civil and Environmental Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.
| | - Erica M Ferrer
- Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, Santa Cruz, CA, USA
- Center for Marine Biodiversity and Conservation, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA
| | | | - Sean A Crowe
- Departments of Microbiology and Immunology and Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sarah C Donelan
- Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, MA, USA
| | - Véronique C Garçon
- CNRS-Laboratoire d'Etudes en Géophysique et Océanographie Spatiales, Toulouse, France
- CNRS - Institut de Physique du Globe de Paris, Paris, France
| | - Marilaure Grégoire
- MAST-FOCUS, Department of Astrophysics, Geophysics and Oceanography, University of Liège, Liège, Belgium
| | - Stephen F Jane
- Department of Natural Resources and the Environment, Cornell University, Ithaca, NY, USA
- Cornell Atkinson Center for Sustainability, Cornell University, Ithaca, NY, USA
- Department of Biology, University of Notre Dame, Notre Dame, IN, USA
| | - Peter R Leavitt
- Institute of Environmental Change and Society, University of Regina, Regina, Saskatchewan, Canada
| | - Lisa A Levin
- Center for Marine Biodiversity and Conservation, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA
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15
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Mrnjavac N, Nagies FSP, Wimmer JLE, Kapust N, Knopp MR, Trost K, Modjewski L, Bremer N, Mentel M, Esposti MD, Mizrahi I, Allen JF, Martin WF. The radical impact of oxygen on prokaryotic evolution-enzyme inhibition first, uninhibited essential biosyntheses second, aerobic respiration third. FEBS Lett 2024; 598:1692-1714. [PMID: 38750628 PMCID: PMC7616280 DOI: 10.1002/1873-3468.14906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 07/15/2024]
Abstract
Molecular oxygen is a stable diradical. All O2-dependent enzymes employ a radical mechanism. Generated by cyanobacteria, O2 started accumulating on Earth 2.4 billion years ago. Its evolutionary impact is traditionally sought in respiration and energy yield. We mapped 365 O2-dependent enzymatic reactions of prokaryotes to phylogenies for the corresponding 792 protein families. The main physiological adaptations imparted by O2-dependent enzymes were not energy conservation, but novel organic substrate oxidations and O2-dependent, hence O2-tolerant, alternative pathways for O2-inhibited reactions. Oxygen-dependent enzymes evolved in ancestrally anaerobic pathways for essential cofactor biosynthesis including NAD+, pyridoxal, thiamine, ubiquinone, cobalamin, heme, and chlorophyll. These innovations allowed prokaryotes to synthesize essential cofactors in O2-containing environments, a prerequisite for the later emergence of aerobic respiratory chains.
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Affiliation(s)
- Natalia Mrnjavac
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Falk S P Nagies
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Jessica L E Wimmer
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Nils Kapust
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Michael R Knopp
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Katharina Trost
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Luca Modjewski
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Nico Bremer
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
| | - Marek Mentel
- Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | | | - Itzhak Mizrahi
- Department of Life Sciences, Ben-Gurion University of the Negev and The National Institute for Biotechnology in the Negev, Be'er-Sheva, Israel
| | - John F Allen
- Research Department of Genetics, Evolution and Environment, University College London, UK
| | - William F Martin
- Institute of Molecular Evolution, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Germany
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16
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Fu J, Lin J, Dai Z, Lin B, Zhang J. Hypoxia-associated autophagy flux dysregulation in human cancers. Cancer Lett 2024; 590:216823. [PMID: 38521197 DOI: 10.1016/j.canlet.2024.216823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/09/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024]
Abstract
A general feature of cancer is hypoxia, determined as low oxygen levels. Low oxygen levels may cause cells to alter in ways that contribute to tumor growth and resistance to treatment. Hypoxia leads to variations in cancer cell metabolism, angiogenesis and metastasis. Furthermore, a hypoxic tumor microenvironment might induce immunosuppression. Moreover, hypoxia has the potential to impact cellular processes, such as autophagy. Autophagy refers to the catabolic process by which damaged organelles and toxic macromolecules are broken down. The abnormal activation of autophagy has been extensively recorded in human tumors and it serves as a regulator of cell growth, spread to other parts of the body, and resistance to treatment. There is a correlation between hypoxia and autophagy in human malignancies. Hypoxia can regulate the activity of AMPK, mTOR, Beclin-1, and ATGs to govern autophagy in human malignancies. Furthermore, HIF-1α, serving as an indicator of low oxygen levels, controls the process of autophagy. Hypoxia-induced autophagy has a crucial role in regulating the growth, spread, and resistance to treatment in human malignancies. Hypoxia-induced regulation of autophagy can impact other mechanisms of cell death, such as apoptosis. Chemoresistance and radioresistance have become significant challenges in recent years. Hypoxia-mediated autophagy plays a crucial role in determining the response to these therapeutic treatments.
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Affiliation(s)
- Jiding Fu
- Department of Intensive Care Unit, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Jie Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Zili Dai
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Baisheng Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China
| | - Jian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
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17
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Goldford JE, Smith HB, Longo LM, Wing BA, McGlynn SE. Primitive purine biosynthesis connects ancient geochemistry to modern metabolism. Nat Ecol Evol 2024; 8:999-1009. [PMID: 38519634 DOI: 10.1038/s41559-024-02361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/06/2024] [Indexed: 03/25/2024]
Abstract
An unresolved question in the origin and evolution of life is whether a continuous path from geochemical precursors to the majority of molecules in the biosphere can be reconstructed from modern-day biochemistry. Here we identified a feasible path by simulating the evolution of biosphere-scale metabolism, using only known biochemical reactions and models of primitive coenzymes. We find that purine synthesis constitutes a bottleneck for metabolic expansion, which can be alleviated by non-autocatalytic phosphoryl coupling agents. Early phases of the expansion are enriched with enzymes that are metal dependent and structurally symmetric, supporting models of early biochemical evolution. This expansion trajectory suggests distinct hypotheses regarding the tempo, mode and timing of metabolic pathway evolution, including a late appearance of methane metabolisms and oxygenic photosynthesis consistent with the geochemical record. The concordance between biological and geological analyses suggests that this trajectory provides a plausible evolutionary history for the vast majority of core biochemistry.
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Affiliation(s)
- Joshua E Goldford
- Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA, USA.
- Physics of Living Systems, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Blue Marble Space Institute of Science, Seattle, WA, USA.
| | - Harrison B Smith
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Earth-Life Science Institute, Tokyo Institute of Technology, Tokyo, Japan
| | - Liam M Longo
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Earth-Life Science Institute, Tokyo Institute of Technology, Tokyo, Japan
| | - Boswell A Wing
- Department of Geological Sciences, University of Colorado, Boulder, CO, USA
| | - Shawn Erin McGlynn
- Blue Marble Space Institute of Science, Seattle, WA, USA.
- Earth-Life Science Institute, Tokyo Institute of Technology, Tokyo, Japan.
- Biofunctional Catalyst Research Team, RIKEN Center for Sustainable Resource Science, Wako, Japan.
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18
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Tsekenis G, Cimini G, Kalafatis M, Giacometti A, Gili T, Caldarelli G. Network topology mapping of chemical compounds space. Sci Rep 2024; 14:5266. [PMID: 38438443 PMCID: PMC10912673 DOI: 10.1038/s41598-024-54594-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 02/14/2024] [Indexed: 03/06/2024] Open
Abstract
We define bipartite and monopartite relational networks of chemical elements and compounds using two different datasets of inorganic chemical and material compounds, as well as study their topology. We discover that the connectivity between elements and compounds is distributed exponentially for materials, and with a fat tail for chemicals. Compounds networks show similar distribution of degrees, and feature a highly-connected club due to oxygen . Chemical compounds networks appear more modular than material ones, while the communities detected reveal different dominant elements specific to the topology. We successfully reproduce the connectivity of the empirical chemicals and materials networks by using a family of fitness models, where the fitness values are derived from the abundances of the elements in the aggregate compound data. Our results pave the way towards a relational network-based understanding of the inherent complexity of the vast chemical knowledge atlas, and our methodology can be applied to other systems with the ingredient-composite structure.
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Affiliation(s)
- Georgios Tsekenis
- Institute for Complex Systems, National Research Council, Rome, Italy.
- Department of Molecular Sciences and Nanosystems (DMSN), "Ca' Foscari" University of Venice, Venice, Italy.
| | - Giulio Cimini
- Physics Department and INFN, University of Rome Tor Vergata, Rome, Italy
| | - Marinos Kalafatis
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Achille Giacometti
- Department of Molecular Sciences and Nanosystems (DMSN), "Ca' Foscari" University of Venice, Venice, Italy
- European Centre of Living Technologies (ECLT), "Ca' Foscari" University of Venice, Venice, Italy
| | - Tommaso Gili
- Networks Unit, IMT School for Advanced Studies Lucca, 55100, Lucca, Italy
| | - Guido Caldarelli
- Institute for Complex Systems, National Research Council, Rome, Italy
- Department of Molecular Sciences and Nanosystems (DMSN), "Ca' Foscari" University of Venice, Venice, Italy
- European Centre of Living Technologies (ECLT), "Ca' Foscari" University of Venice, Venice, Italy
- Rara Foundation - Sustainable Materials and Technologies ETS, 30171, Venice, Italy
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19
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Bae T, Hallis SP, Kwak MK. Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer. Exp Mol Med 2024; 56:501-514. [PMID: 38424190 PMCID: PMC10985007 DOI: 10.1038/s12276-024-01180-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 03/02/2024] Open
Abstract
Oxygen is crucial for life and acts as the final electron acceptor in mitochondrial energy production. Cells adapt to varying oxygen levels through intricate response systems. Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response, activating genes to increase the oxygen supply and reduce expenditure. Under conditions of excess oxygen and resulting oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) activates hundreds of genes for oxidant removal and adaptive cell survival. Hypoxia and oxidative stress are core hallmarks of solid tumors and activated HIFs and NRF2 play pivotal roles in tumor growth and progression. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of intricacy to the HIF and NRF2 signaling systems. This review aimed to elucidate the dynamic changes and functions of the HIF and NRF2 signaling pathways in response to conditions of hypoxia and oxidative stress, emphasizing their implications within the tumor milieu. Additionally, this review explored the elaborate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies.
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Affiliation(s)
- Taegeun Bae
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea
| | - Steffanus Pranoto Hallis
- Department of Pharmacy, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea
| | - Mi-Kyoung Kwak
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
- Department of Pharmacy, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
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20
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Demoulin CF, Sforna MC, Lara YJ, Cornet Y, Somogyi A, Medjoubi K, Grolimund D, Sanchez DF, Tachoueres RT, Addad A, Fadel A, Compère P, Javaux EJ. Polysphaeroides filiformis, a proterozoic cyanobacterial microfossil and implications for cyanobacteria evolution. iScience 2024; 27:108865. [PMID: 38313056 PMCID: PMC10837632 DOI: 10.1016/j.isci.2024.108865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/29/2023] [Accepted: 01/08/2024] [Indexed: 02/06/2024] Open
Abstract
Deciphering the fossil record of cyanobacteria is crucial to understand their role in the chemical and biological evolution of the early Earth. They profoundly modified the redox conditions of early ecosystems more than 2.4 Ga ago, the age of the Great Oxidation Event (GOE), and provided the ancestor of the chloroplast by endosymbiosis, leading the diversification of photosynthetic eukaryotes. Here, we analyze the morphology, ultrastructure, chemical composition, and metals distribution of Polysphaeroides filiformis from the 1040-1006 Ma Mbuji-Mayi Supergroup (DR Congo). We evidence trilaminar and bilayered ultrastructures for the sheath and the cell wall, respectively, and the preservation of Ni-tetrapyrrole moieties derived from chlorophyll in intracellular inclusions. This approach allows an unambiguous interpretation of P. filiformis as a branched and multiseriate photosynthetic cyanobacterium belonging to the family of Stigonemataceae. It also provides a possible minimum age for the emergence of multiseriate true branching nitrogen-fixing and probably heterocytous cyanobacteria.
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Affiliation(s)
- Catherine F Demoulin
- Early Life Traces & Evolution-Astrobiology, UR Astrobiology, University of Liège, 4000 Liège, Belgium
| | - Marie Catherine Sforna
- Early Life Traces & Evolution-Astrobiology, UR Astrobiology, University of Liège, 4000 Liège, Belgium
- Centre de Biophysique Moléculaire, (UPR CNRS 4301), 45071 Orléans, France
| | - Yannick J Lara
- Early Life Traces & Evolution-Astrobiology, UR Astrobiology, University of Liège, 4000 Liège, Belgium
| | - Yohan Cornet
- Early Life Traces & Evolution-Astrobiology, UR Astrobiology, University of Liège, 4000 Liège, Belgium
| | | | | | - Daniel Grolimund
- Paul Scherrer Institut, Swiss Light Source, 5232 Villigen PSI, Switzerland
| | | | | | - Ahmed Addad
- Unité Matériaux et Transformations (UMR CNRS 8207), Université Lille 1 - Sciences et Technologies, 59650 Villeneuve d'Ascq, France
| | - Alexandre Fadel
- Unité Matériaux et Transformations (UMR CNRS 8207), Université Lille 1 - Sciences et Technologies, 59650 Villeneuve d'Ascq, France
| | - Philippe Compère
- Functional and Evolutive Morphology, UR FOCUS, and Center for Applied Research and Education in Microscopy (CAREM-ULiege), University of Liège, 4000 Liège, Belgium
| | - Emmanuelle J Javaux
- Early Life Traces & Evolution-Astrobiology, UR Astrobiology, University of Liège, 4000 Liège, Belgium
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21
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Timson RC, Khan A, Uygur B, Saad M, Yeh HW, DelGaudio NL, Weber R, Alwaseem H, Gao J, Yang C, Birsoy K. Development of a mouse model expressing a bifunctional glutathione-synthesizing enzyme to study glutathione limitation in vivo. J Biol Chem 2024; 300:105645. [PMID: 38218225 PMCID: PMC10869265 DOI: 10.1016/j.jbc.2024.105645] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/17/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024] Open
Abstract
Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer, and neurodegenerative disorders, studying the limiting role of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus thermophilus (GshF), which possesses both glutamate-cysteine ligase and glutathione synthase activities. GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis induction, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes further revealed genes required for cell proliferation under cellular and mitochondrial GSH depletion. Among these, we identified the glutamate-cysteine ligase modifier subunit, GCLM, as a requirement for cellular sensitivity to buthionine sulfoximine, a glutathione synthesis inhibitor. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the limiting role of GSH in physiology and disease.
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Affiliation(s)
- Rebecca C Timson
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
| | - Artem Khan
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
| | - Beste Uygur
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
| | - Marwa Saad
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York, USA
| | - Hsi-Wen Yeh
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
| | - Nicole L DelGaudio
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
| | - Ross Weber
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Hanan Alwaseem
- The Proteomics Resource Center, The Rockefeller University, New York, New York, USA
| | - Jing Gao
- The CRISPR & Genome Editing Center, The Rockefeller University, New York, New York, USA
| | - Chingwen Yang
- The CRISPR & Genome Editing Center, The Rockefeller University, New York, New York, USA
| | - Kıvanç Birsoy
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA.
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22
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Yang S, Chen N, Qi J, Salam A, Khan AR, Azhar W, Yang C, Xu N, Wu J, Liu Y, Liu B, Gan Y. OsUGE2 Regulates Plant Growth through Affecting ROS Homeostasis and Iron Level in Rice. RICE (NEW YORK, N.Y.) 2024; 17:6. [PMID: 38212485 PMCID: PMC10784444 DOI: 10.1186/s12284-024-00685-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/04/2024] [Indexed: 01/13/2024]
Abstract
BACKGROUND The growth and development of rice (Oryza sativa L.) are affected by multiple factors, such as ROS homeostasis and utilization of iron. Here, we demonstrate that OsUGE2, a gene encoding a UDP-glucose 4-epimerase, controls growth and development by regulating reactive oxygen species (ROS) and iron (Fe) level in rice. Knockout of this gene resulted in impaired growth, such as dwarf phenotype, weakened root growth and pale yellow leaves. Biochemical analysis showed that loss of function of OsUGE2 significantly altered the proportion and content of UDP-Glucose (UDP-Glc) and UDP-Galactose (UDP-Gal). Cellular observation indicates that the impaired growth may result from decreased cell length. More importantly, RNA-sequencing analysis showed that knockout of OsUGE2 significantly influenced the expression of genes related to oxidoreductase process and iron ion homeostasis. Consistently, the content of ROS and Fe are significantly decreased in OsUGE2 knockout mutant. Furthermore, knockout mutants of OsUGE2 are insensitive to both Fe deficiency and hydrogen peroxide (H2O2) treatment, which further confirmed that OsUGE2 control rice growth possibly through Fe and H2O2 signal. Collectively, these results reveal a new pathway that OsUGE2 could affect growth and development via influencing ROS homeostasis and Fe level in rice.
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Affiliation(s)
- Shuaiqi Yang
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Nana Chen
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Jiaxuan Qi
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Abdul Salam
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Ali Raza Khan
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Wardah Azhar
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Chunyan Yang
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Nuo Xu
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Junyu Wu
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China
| | - Yihua Liu
- College of Agriculture and Forestry Sciences, Linyi University, Linyi, 276000, Shandong, China
| | - Bohan Liu
- College of Agriculture, Hunan Agricultural University, Changsha, 410128, China
| | - Yinbo Gan
- Zhejiang Key Lab of Crop Germplasm, Department of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310000, China.
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23
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Timson RC, Khan A, Uygur B, Saad M, Yeh HW, DelGaudio N, Weber R, Alwaseem H, Gao J, Yang C, Birsoy K. A mouse model to study glutathione limitation in vivo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574722. [PMID: 38260639 PMCID: PMC10802487 DOI: 10.1101/2024.01.08.574722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus Thermophilus (GshF). GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes revealed metabolic liabilities under compartmentalized GSH depletion. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the role of GSH availability in physiology and disease.
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24
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Wong W, Bravo P, Yunker PJ, Ratcliff WC, Burnetti AJ. Examining the role of oxygen-binding proteins on the early evolution of multicellularity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.01.569647. [PMID: 38106219 PMCID: PMC10723371 DOI: 10.1101/2023.12.01.569647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Oxygen availability is a key factor in the evolution of multicellularity, as larger and more sophisticated organisms often require mechanisms allowing efficient oxygen delivery to their tissues. One such mechanism is the presence of oxygen-binding proteins, such as globins and hemerythrins, which arose in the ancestor of bilaterian animals. Despite their importance, the precise mechanisms by which oxygen-binding proteins influenced the early stages of multicellular evolution under varying environmental oxygen levels are not yet clear. We addressed this knowledge gap by heterologously expressing the oxygen binding proteins myoglobin and myohemerythrin in snowflake yeast, a model system of simple, undifferentiated multicellularity. These proteins increased the depth and rate of oxygen diffusion, increasing the fitness of snowflake yeast growing aerobically. Experiments show that, paradoxically, oxygen-binding proteins confer a greater fitness benefit for larger organisms under high, not low, O2 conditions. We show via biophysical modeling that this is because facilitated diffusion is more efficient when oxygen is abundant, transporting a greater quantity of O2 which can be used for metabolism. By alleviating anatomical diffusion limitations to oxygen consumption, the evolution of O2-binding proteins in the oxygen-rich Neoproterozoic may have been a key breakthrough enabling the evolution of increasingly large, complex multicellular metazoan lineages.
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Affiliation(s)
- Whitney Wong
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Pablo Bravo
- School of Physics, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Peter J Yunker
- School of Physics, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - William C Ratcliff
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Anthony J Burnetti
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA
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25
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Li L, Liu Z, Meng D, Liu Y, Liu T, Jiang C, Yin H. Sequence similarity network and protein structure prediction offer insights into the evolution of microbial pathways for ferrous iron oxidation. mSystems 2023; 8:e0072023. [PMID: 37768051 PMCID: PMC10654088 DOI: 10.1128/msystems.00720-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 08/09/2023] [Indexed: 09/29/2023] Open
Abstract
IMPORTANCE Microbial Fe(II) oxidation is a crucial process that harnesses and converts the energy available in Fe, contributing significantly to global element cycling. However, there are still many aspects of this process that remain unexplored. In this study, we utilized a combination of comparative genomics, sequence similarity network analysis, and artificial intelligence-driven structure modeling methods to address the lack of structural information on Fe(II) oxidation proteins and offer a comprehensive perspective on the evolution of Fe(II) oxidation pathways. Our findings suggest that several microbial Fe(II) oxidation pathways currently known may have originated within classes Gammaproteobacteria and Betaproteobacteria.
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Affiliation(s)
- Liangzhi Li
- School of Minerals Processing and Bioengineering, Central South University, Changsha, China
- Key Laboratory of Biometallurgy of Ministry of Education, Central South University, Changsha, China
| | - Zhenghua Liu
- School of Minerals Processing and Bioengineering, Central South University, Changsha, China
- Key Laboratory of Biometallurgy of Ministry of Education, Central South University, Changsha, China
| | - Delong Meng
- School of Minerals Processing and Bioengineering, Central South University, Changsha, China
- Key Laboratory of Biometallurgy of Ministry of Education, Central South University, Changsha, China
| | - Yongjun Liu
- Hunan Tobacco Science Institute, Changsha, China
| | - Tianbo Liu
- Hunan Tobacco Science Institute, Changsha, China
| | - Chengying Jiang
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Huaqun Yin
- School of Minerals Processing and Bioengineering, Central South University, Changsha, China
- Key Laboratory of Biometallurgy of Ministry of Education, Central South University, Changsha, China
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26
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Marchetti M, Ronda L, Cozzi M, Bettati S, Bruno S. Genetically Encoded Biosensors for the Fluorescence Detection of O 2 and Reactive O 2 Species. SENSORS (BASEL, SWITZERLAND) 2023; 23:8517. [PMID: 37896609 PMCID: PMC10611200 DOI: 10.3390/s23208517] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/07/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023]
Abstract
The intracellular concentrations of oxygen and reactive oxygen species (ROS) in living cells represent critical information for investigating physiological and pathological conditions. Real-time measurement often relies on genetically encoded proteins that are responsive to fluctuations in either oxygen or ROS concentrations. The direct binding or chemical reactions that occur in their presence either directly alter the fluorescence properties of the binding protein or alter the fluorescence properties of fusion partners, mostly consisting of variants of the green fluorescent protein. Oxygen sensing takes advantage of several mechanisms, including (i) the oxygen-dependent hydroxylation of a domain of the hypoxia-inducible factor-1, which, in turn, promotes its cellular degradation along with fluorescent fusion partners; (ii) the naturally oxygen-dependent maturation of the fluorophore of green fluorescent protein variants; and (iii) direct oxygen binding by proteins, including heme proteins, expressed in fusion with fluorescent partners, resulting in changes in fluorescence due to conformational alterations or fluorescence resonance energy transfer. ROS encompass a group of highly reactive chemicals that can interconvert through various chemical reactions within biological systems, posing challenges for their selective detection through genetically encoded sensors. However, their general reactivity, and particularly that of the relatively stable oxygen peroxide, can be exploited for ROS sensing through different mechanisms, including (i) the ROS-induced formation of disulfide bonds in engineered fluorescent proteins or fusion partners of fluorescent proteins, ultimately leading to fluorescence changes; and (ii) conformational changes of naturally occurring ROS-sensing domains, affecting the fluorescence properties of fusion partners. In this review, we will offer an overview of these genetically encoded biosensors.
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Affiliation(s)
- Marialaura Marchetti
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy; (M.M.); (L.R.); (M.C.)
| | - Luca Ronda
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy; (M.M.); (L.R.); (M.C.)
- Institute of Biophysics, Italian National Research Council (CNR), 56124 Pisa, Italy
| | - Monica Cozzi
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy; (M.M.); (L.R.); (M.C.)
| | - Stefano Bettati
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy; (M.M.); (L.R.); (M.C.)
- Institute of Biophysics, Italian National Research Council (CNR), 56124 Pisa, Italy
| | - Stefano Bruno
- Department of Food and Drug, University of Parma, 43124 Parma, Italy;
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27
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Puerner C, Vellanki S, Strauch JL, Cramer RA. Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression. Annu Rev Microbiol 2023; 77:403-425. [PMID: 37713457 PMCID: PMC11034785 DOI: 10.1146/annurev-micro-032521-021745] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.
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Affiliation(s)
- Charles Puerner
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA;
| | - Sandeep Vellanki
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA;
| | - Julianne L Strauch
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA;
- Department of Biology, Dartmouth College, Hanover, New Hampshire, USA
| | - Robert A Cramer
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA;
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28
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Gulay A, Fournier G, Smets BF, Girguis PR. Proterozoic Acquisition of Archaeal Genes for Extracellular Electron Transfer: A Metabolic Adaptation of Aerobic Ammonia-Oxidizing Bacteria to Oxygen Limitation. Mol Biol Evol 2023; 40:msad161. [PMID: 37440531 PMCID: PMC10415592 DOI: 10.1093/molbev/msad161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/09/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023] Open
Abstract
Many aerobic microbes can utilize alternative electron acceptors under oxygen-limited conditions. In some cases, this is mediated by extracellular electron transfer (or EET), wherein electrons are transferred to extracellular oxidants such as iron oxide and manganese oxide minerals. Here, we show that an ammonia-oxidizer previously known to be strictly aerobic, Nitrosomonas communis, may have been able to utilize a poised electrode to maintain metabolic activity in anoxic conditions. The presence and activity of multiheme cytochromes in N. communis further suggest a capacity for EET. Molecular clock analysis shows that the ancestors of β-proteobacterial ammonia oxidizers appeared after Earth's atmospheric oxygenation when the oxygen levels were >10-4pO2 (present atmospheric level [PAL]), consistent with aerobic origins. Equally important, phylogenetic reconciliations of gene and species trees show that the multiheme c-type EET proteins in Nitrosomonas and Nitrosospira lineages were likely acquired by gene transfer from γ-proteobacteria when the oxygen levels were between 0.1 and 1 pO2 (PAL). These results suggest that β-proteobacterial EET evolved during the Proterozoic when oxygen limitation was widespread, but oxidized minerals were abundant.
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Affiliation(s)
- Arda Gulay
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA
- Department of Environmental and Resource Engineering, Technical University of Denmark, Lyngby, Denmark
| | - Greg Fournier
- Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Barth F Smets
- Department of Environmental and Resource Engineering, Technical University of Denmark, Lyngby, Denmark
| | - Peter R Girguis
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA
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29
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Bozdag GO, Zamani-Dahaj SA, Day TC, Kahn PC, Burnetti AJ, Lac DT, Tong K, Conlin PL, Balwani AH, Dyer EL, Yunker PJ, Ratcliff WC. De novo evolution of macroscopic multicellularity. Nature 2023; 617:747-754. [PMID: 37165189 PMCID: PMC10425966 DOI: 10.1038/s41586-023-06052-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 04/05/2023] [Indexed: 05/12/2023]
Abstract
While early multicellular lineages necessarily started out as relatively simple groups of cells, little is known about how they became Darwinian entities capable of sustained multicellular evolution1-3. Here we investigate this with a multicellularity long-term evolution experiment, selecting for larger group size in the snowflake yeast (Saccharomyces cerevisiae) model system. Given the historical importance of oxygen limitation4, our ongoing experiment consists of three metabolic treatments5-anaerobic, obligately aerobic and mixotrophic yeast. After 600 rounds of selection, snowflake yeast in the anaerobic treatment group evolved to be macroscopic, becoming around 2 × 104 times larger (approximately mm scale) and about 104-fold more biophysically tough, while retaining a clonal multicellular life cycle. This occurred through biophysical adaptation-evolution of increasingly elongate cells that initially reduced the strain of cellular packing and then facilitated branch entanglements that enabled groups of cells to stay together even after many cellular bonds fracture. By contrast, snowflake yeast competing for low oxygen5 remained microscopic, evolving to be only around sixfold larger, underscoring the critical role of oxygen levels in the evolution of multicellular size. Together, this research provides unique insights into an ongoing evolutionary transition in individuality, showing how simple groups of cells overcome fundamental biophysical limitations through gradual, yet sustained, multicellular evolution.
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Affiliation(s)
- G Ozan Bozdag
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
| | - Seyed Alireza Zamani-Dahaj
- Interdisciplinary Graduate Program in Quantitative Biosciences, Georgia Institute of Technology, Atlanta, GA, USA
- School of Physics, Georgia Institute of Technology, Atlanta, GA, USA
| | - Thomas C Day
- School of Physics, Georgia Institute of Technology, Atlanta, GA, USA
| | - Penelope C Kahn
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
- Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Anthony J Burnetti
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Dung T Lac
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Kai Tong
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
- Interdisciplinary Graduate Program in Quantitative Biosciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Peter L Conlin
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Aishwarya H Balwani
- School of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Eva L Dyer
- School of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Peter J Yunker
- Interdisciplinary Graduate Program in Quantitative Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
| | - William C Ratcliff
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
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30
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Li J, He X, Gao S, Liang Y, Qi Z, Xi Q, Zuo Y, Xing Y. The Metal-binding Protein Atlas (MbPA): an integrated database for curating metalloproteins in all aspects. J Mol Biol 2023:168117. [PMID: 37086947 DOI: 10.1016/j.jmb.2023.168117] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 04/14/2023] [Accepted: 04/17/2023] [Indexed: 04/24/2023]
Abstract
Metal-binding proteins are essential for the vital activities and engage in their roles by acting in concert with metal cations. MbPA (The Metal-binding Protein Atlas) is the most comprehensive resource up to now dedicated to curating metal-binding proteins. Currently, it contains 106373 entries and 440187 sites related to 54 metals and 8169 species. Users can view all metal-binding proteins and species-specific proteins in MbPA. There are also metal-proteomics data that quantitatively describes protein expression in different tissues and organs. By analyzing the data of the amino acid residues at the metal-binding site, it is found that about 80% of the metal ions tend to bind to cysteine, aspartic acid, glutamic acid, and histidine. Moreover, we use Diversity Measure to confirm that the diversity of metal-binding is specific in different area of periodic table, and further elucidate the binding modes of 19 transition metals on 20 amino acids. In addition, MbPA also embraces 6855 potential pathogenic mutations related to metalloprotein. The resource is freely available at http://bioinfor.imu.edu.cn/mbpa.
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Affiliation(s)
- Jinzhao Li
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Xiang He
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Shuang Gao
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Yuchao Liang
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Zhi Qi
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China; Key Laboratory of Forage and Endemic Crop Biotechnology, Ministry of Education, School of Life Sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Qilemuge Xi
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China
| | - Yongchun Zuo
- The Key Laboratory of Mammalian Reproductive Biology and Biotechnology of the Ministry of Education, College of life sciences, Inner Mongolia University, Hohhot, 010021, China.
| | - Yongqiang Xing
- The Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China.
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31
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Cheng W, Hwang S, Guo Q, Qian L, Liu W, Yu Y, Liu L, Tao Y, Cao H. The Special and General Mechanism of Cyanobacterial Harmful Algal Blooms. Microorganisms 2023; 11:microorganisms11040987. [PMID: 37110410 PMCID: PMC10144548 DOI: 10.3390/microorganisms11040987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
Cyanobacterial harmful algal blooms (CyanoHABs) are longstanding aquatic hazards worldwide, of which the mechanism is not yet fully understood, i.e., the process in which cyanobacteria establish dominance over coexisting algae in the same eutrophic waters. The dominance of CyanoHABs represents a deviation from their low abundance under conventional evolution in the oligotrophic state, which has been the case since the origin of cyanobacteria on early Earth. To piece together a comprehensive mechanism of CyanoHABs, we revisit the origin and adaptive radiation of cyanobacteria in oligotrophic Earth, demonstrating ubiquitous adaptive radiation enabled by corresponding biological functions under various oligotrophic conditions. Next, we summarize the biological functions (ecophysiology) which drive CyanoHABs and ecological evidence to synthesize a working mechanism at the population level (the special mechanism) for CyanoHABs: CyanoHABs are the consequence of the synergistic interaction between superior cyanobacterial ecophysiology and elevated nutrients. Interestingly, these biological functions are not a result of positive selection by water eutrophication, but an adaptation to a longstanding oligotrophic state as all the genes in cyanobacteria are under strong negative selection. Last, to address the relative dominance of cyanobacteria over coexisting algae, we postulate a "general" mechanism of CyanoHABs at the community level from an energy and matter perspective: cyanobacteria are simpler life forms and thus have lower per capita nutrient demand for growth than coexisting eukaryotic algae. We prove this by comparing cyanobacteria and eukaryotic algae in cell size and structure, genome size, size of genome-scale metabolic networks, cell content, and finally the golden standard-field studies with nutrient supplementation in the same waters. To sum up, the comprehensive mechanism of CyanoHABs comprises a necessary condition, which is the general mechanism, and a sufficient condition, which is the special mechanism. One prominent prediction based on this tentative comprehensive mechanism is that eukaryotic algal blooms will coexist with or replace CyanoHABs if eutrophication continues and goes over the threshold nutrient levels for eukaryotic algae. This two-fold comprehensive mechanism awaits further theoretic and experimental testing and provides an important guide to control blooms of all algal species.
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Affiliation(s)
- Wenduo Cheng
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Somin Hwang
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Qisen Guo
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Leyuan Qian
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Weile Liu
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Yang Yu
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Li Liu
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
| | - Yi Tao
- Guangdong Provincial Engineering Research Center for Urban Water Recycling and Environmental Safety, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Huansheng Cao
- Division of Natural and Applied Sciences, Duke Kunshan University, 8 Duke Ave, Kunshan 215316, China
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32
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Zhao LL, Liao L, Yan HX, Tang XH, He K, Liu Q, Luo J, Du ZJ, Chen SY, Zhang X, Cheng Z, Yang S. Physiological responses to acute hypoxia in the liver of largemouth bass by alteration of mitochondrial function and Ca 2+ exchange. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 256:106436. [PMID: 36822139 DOI: 10.1016/j.aquatox.2023.106436] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 12/23/2022] [Accepted: 02/16/2023] [Indexed: 06/18/2023]
Abstract
Oxygen is a critical factor for most organisms and this is especially true for aquatic animals. Unfortunately, high-density aquaculture farming practices and environmental degradation will inevitably lead to hypoxic stress in fishes such as largemouth bass (Micropterus salmoides). Thus, characterizing the physiological responses during acute hypoxia exposure is extremely important for understanding the adaptation mechanisms of largemouth bass to hypoxia. The present study aimed to investigate mitochondrial function and Ca2+ exchange in largemouth bass under hypoxic conditions. Largemouth bass were subjected to hypoxia (1.2 ± 0.2 mg/L) for 24 h Liver mitochondria and endoplasmic reticulum (ER) parameters were analyzed. We used Liquid chromatography-mass spectrometry (LC-MS) to further elucidate the pattern of energy metabolism. Changes of Ca2+ concentrations were observed in primary hepatocytes of largemouth bass under hypoxic conditions. Our results indicate that the morphology and function of the mitochondria and ER were altered under hypoxia. First, the occurrence of autophagy was accompanied by reactive oxygen species (ROS) generation and electron transport chain (ETC) activity modulation under hypoxia. Second, hypoxia enhanced mitochondrial fusion and fission, mitochondrial biosynthesis, and ER quality control in the early stages of hypoxic stress (before 8 h). Third, hypoxia modulated tricarboxylic acid (TCA) cycle flux and caused the accumulation of TCA intermediate metabolites (citric acid and oxoglutaric acid). Additionally, Ca2+ efflux in the ER was observed., and the genes for Ca2+ transporters presented high expression levels in cellular and mitochondrial membranes. Collectively, the above physiological responses of the mitochondria and ER contributed to maintaining energy production to withstand the hypoxic stress in largemouth bass. These results provide novel insights into the physiological and metabolic changes in largemouth bass under hypoxic conditions.
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Affiliation(s)
- Liu Lan Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Lei Liao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hao Xiao Yan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xiao Hong Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Kuo He
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Qiao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Jie Luo
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Zong Jun Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Shi Yi Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xin Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Zhang Cheng
- College of Environment, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Song Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
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33
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Semenza GL. Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations. Annu Rev Med 2023; 74:307-319. [PMID: 35773226 DOI: 10.1146/annurev-med-042921-102602] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.
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Affiliation(s)
- Gregg L Semenza
- McKusick-Nathans Department of Genetic Medicine and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
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34
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Boyd ES, Spietz RL, Kour M, Colman DR. A naturalist perspective of microbiology: Examples from methanogenic archaea. Environ Microbiol 2023; 25:184-198. [PMID: 36367391 DOI: 10.1111/1462-2920.16285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
Storytelling has been the primary means of knowledge transfer over human history. The effectiveness and reach of stories are improved when the message is appropriate for the target audience. Oftentimes, the stories that are most well received and recounted are those that have a clear purpose and that are told from a variety of perspectives that touch on the varied interests of the target audience. Whether scientists realize or not, they are accustomed to telling stories of their own scientific discoveries through the preparation of manuscripts, presentations, and lectures. Perhaps less frequently, scientists prepare review articles or book chapters that summarize a body of knowledge on a given subject matter, meant to be more holistic recounts of a body of literature. Yet, by necessity, such summaries are often still narrow in their scope and are told from the perspective of a particular discipline. In other words, interdisciplinary reviews or book chapters tend to be the rarity rather than the norm. Here, we advocate for and highlight the benefits of interdisciplinary perspectives on microbiological subjects.
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Affiliation(s)
- Eric S Boyd
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Rachel L Spietz
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Manjinder Kour
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
| | - Daniel R Colman
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, USA
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35
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A genetically encoded system for oxygen generation in living cells. Proc Natl Acad Sci U S A 2022; 119:e2207955119. [PMID: 36215519 DOI: 10.1073/pnas.2207955119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Oxygen plays a key role in supporting life on our planet. It is particularly important in higher eukaryotes where it boosts bioenergetics as a thermodynamically favorable terminal electron acceptor and has important roles in cell signaling and development. Many human diseases stem from either insufficient or excessive oxygen. Despite its fundamental importance, we lack methods with which to manipulate the supply of oxygen with high spatiotemporal resolution in cells and in organisms. Here, we introduce a genetic system, SupplemeNtal Oxygen Released from ChLorite (SNORCL), for on-demand local generation of molecular oxygen in living cells, by harnessing prokaryotic chlorite O2-lyase (Cld) enzymes that convert chlorite (ClO2-) into molecular oxygen (O2) and chloride (Cl-). We show that active Cld enzymes can be targeted to either the cytosol or mitochondria of human cells, and that coexpressing a chlorite transporter results in molecular oxygen production inside cells in response to externally added chlorite. This first-generation system allows fine temporal and spatial control of oxygen production, with immediate research applications. In the future, we anticipate that technologies based on SNORCL will have additional widespread applications in research, biotechnology, and medicine.
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36
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Redox Status Is the Mainstay of SARS-CoV-2 and Host for Producing Therapeutic Opportunities. Antioxidants (Basel) 2022; 11:antiox11102061. [PMID: 36290783 PMCID: PMC9598460 DOI: 10.3390/antiox11102061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/17/2022] Open
Abstract
Over hundreds of years, humans have faced multiple pandemics and have overcome many of them with scientific advancements. However, the recent coronavirus disease (COVID-19) has challenged the physical, mental, and socioeconomic aspects of human life, which has introduced a general sense of uncertainty among everyone. Although several risk profiles, such as the severity of the disease, infection rate, and treatment strategy, have been investigated, new variants from different parts of the world put humans at risk and require multiple strategies simultaneously to control the spread. Understanding the entire system with respect to the commonly involved or essential mechanisms may be an effective strategy for successful treatment, particularly for COVID-19. Any treatment for COVID-19 may alter the redox profile, which can be an effective complementary method for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and further replication. Indeed, redox profiles are one of the main barriers that suddenly shift the immune response in favor of COVID-19. Fortunately, several redox components exhibit antiviral and anti-inflammatory activities. However, access to these components as support elements against COVID-19 is limited. Therefore, understanding redox-derived species and their nodes as a common interactome in the system will facilitate the treatment of COVID-19. This review discusses the redox-based perspectives of the entire system during COVID-19 infection, including how redox-based molecules impact the accessibility of SARS-CoV-2 to the host and further replication. Additionally, to demonstrate its feasibility as a viable approach, we discuss the current challenges in redox-based treatment options for COVID-19.
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Fu S, Lian S, Angelidaki I, Guo R. Micro-aeration: an attractive strategy to facilitate anaerobic digestion. Trends Biotechnol 2022; 41:714-726. [PMID: 36216713 DOI: 10.1016/j.tibtech.2022.09.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/13/2022] [Accepted: 09/19/2022] [Indexed: 01/11/2023]
Abstract
Micro-aeration can facilitate anaerobic digestion (AD) by regulating microbial communities and promoting the growth of facultative taxa, thereby increasing methane yield and stabilizing the AD process. Additionally, micro-aeration contributes to hydrogen sulfide stripping by oxidization to produce molecular sulfur or sulfuric acid. Although micro-aeration can positively affect AD, it must be strictly regulated to maintain an overall anaerobic environment that permits anaerobic microorganisms to thrive. Even so, obligate anaerobes, especially methanogens, could suffer from oxidative stress during micro-aeration. This review describes the applications of micro-aeration in AD and examines the cutting-edge advances in how methanogens survive under oxygen stress. Moreover, barriers and corresponding solutions are proposed to move micro-aeration technology closer to application at scale.
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Valenti R, Jabłońska J, Tawfik DS. Characterization of ancestral Fe/Mn superoxide dismutases indicates their cambialistic origin. Protein Sci 2022; 31:e4423. [PMID: 36173172 PMCID: PMC9490801 DOI: 10.1002/pro.4423] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/29/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022]
Abstract
Superoxide dismutases (SODs) are critical metalloenzymes mitigating the damages of the modern oxygenated world. However, the emergence of one family of SODs, the Fe/Mn SOD, has been recurrently proposed to predate the great oxygenation event (GOE). This ancient family lacks metal binding selectivity, but displays strong catalytic selectivity. Therefore, some homologues would only be active when bound to Fe or Mn, although others, dubbed cambialistic, would function when loaded with either ion. This posed the longstanding question about the identity of the cognate metal ion of the first SODs to emerge. In this work, we utilize ancestral sequence reconstruction techniques to infer the earliest SODs. We show that the "ancestors" are active in vivo and in vitro. Further, we test their metal specificity and demonstrate that they are cambialistic in nature. Our findings shed light on how the predicted Last Common Universal Ancestor was capable of dealing with decomposition of the superoxide anion, and the early relationship between life, oxygen, and metal ion availability.
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Affiliation(s)
- Rosario Valenti
- Department of Biomolecular SciencesWeizmann Institute of ScienceRehovotIsrael
| | - Jagoda Jabłońska
- Department of Biomolecular SciencesWeizmann Institute of ScienceRehovotIsrael
| | - Dan S. Tawfik
- Department of Biomolecular SciencesWeizmann Institute of ScienceRehovotIsrael
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Rauckhorst AJ, Borcherding N, Pape DJ, Kraus AS, Scerbo DA, Taylor EB. Mouse tissue harvest-induced hypoxia rapidly alters the in vivo metabolome, between-genotype metabolite level differences, and 13C-tracing enrichments. Mol Metab 2022; 66:101596. [PMID: 36100179 PMCID: PMC9589196 DOI: 10.1016/j.molmet.2022.101596] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/17/2022] [Accepted: 09/06/2022] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Metabolomics as an approach to solve biological problems is exponentially increasing in use. Thus, this a pivotal time for the adoption of best practices. It is well known that disrupted tissue oxygen supply rapidly alters cellular energy charge. However, the speed and extent to which delayed mouse tissue freezing after dissection alters the broad metabolome is not well described. Furthermore, how tissue genotype may modulate such metabolomic drift and the degree to which traced 13C-isotopologue distributions may change have not been addressed. METHODS By combined liquid chromatography (LC)- and gas chromatography (GC)-mass spectrometry (MS), we measured how levels of 255 mouse liver metabolites changed following 30-second, 1-minute, 3-minute, and 10-minute freezing delays. We then performed test-of-concept delay-to-freeze experiments evaluating broad metabolomic drift in mouse heart and skeletal muscle, differential metabolomic change between wildtype (WT) and mitochondrial pyruvate carrier (MPC) knockout mouse livers, and shifts in 13C-isotopologue abundances and enrichments traced from 13C-labled glucose into mouse liver. RESULTS Our data demonstrate that delayed mouse tissue freezing after dissection leads to rapid hypoxia-driven remodeling of the broad metabolome, induction of both false-negative and false-positive between-genotype differences, and restructuring of 13C-isotopologue distributions. Notably, we show that increased purine nucleotide degradation products are an especially high dynamic range marker of delayed liver and heart freezing. CONCLUSIONS Our findings provide a previously absent, systematic illustration of the extensive, multi-domain metabolomic changes occurring within the early minutes of delayed tissue freezing. They also provide a novel, detailed resource of mouse liver ex vivo, hypoxic metabolomic remodeling.
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Affiliation(s)
- Adam J Rauckhorst
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; FOEDRC Metabolomics Core Research Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Daniel J Pape
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
| | - Alora S Kraus
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
| | - Diego A Scerbo
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
| | - Eric B Taylor
- Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of Eagles Diabetes Research Center (FOEDRC), University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; FOEDRC Metabolomics Core Research Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
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Wasselin V, Budin-Verneuil A, Rincé I, Léger L, Boukerb AM, Hartke A, Benachour A, Riboulet-Bisson E. The enigmatic physiological roles of AhpCF, Gpx, Npr and Kat in peroxide stress response of Enterococcus faecium. Res Microbiol 2022; 173:103982. [PMID: 35931249 DOI: 10.1016/j.resmic.2022.103982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 06/16/2022] [Accepted: 07/20/2022] [Indexed: 10/16/2022]
Abstract
In this work, the physiological roles of the primary peroxide scavenging activities of Enterococcus faecium AUS0004 strain were analysed. This healthcare-associated pathogen harbours genes encoding putative NADH peroxidase (Npr), alkyl hydroperoxide reductase (AhpCF), glutathione peroxidase (Gpx) and manganese-dependent catalase (Mn-Kat). Gene expression analyses showed that npr and kat genes are especially and significantly induced in cells treated with hydrogen peroxide (H2O2) and cumene hydroperoxide (CuOOH), which suggested an important function of these enzymes to protect E. faecium against peroxide stress. Mutants affected in one or several predicted anti-oxidative activities mentioned above showed that neither the peroxidases nor the catalase are implicated in the defence against peroxide challenges. However, our investigations allowed us to show that Npr is responsible for the degradation of approximately 45% of metabolically derived H2O2 which avoids accumulation of the peroxide to lethal concentrations.
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Affiliation(s)
- Valentin Wasselin
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Aurélie Budin-Verneuil
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Isabelle Rincé
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Loïc Léger
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Amine Mohamed Boukerb
- Normandie Univ, LMSM EA4312-Microbiology Signals and Microenvironment, 27000 Evreux, France.
| | - Axel Hartke
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Abdellah Benachour
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
| | - Eliette Riboulet-Bisson
- Normandie Univ, UNICAEN U2RM-Stress and Virulence, Esplanade de la Paix, 14032 Caen, France.
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Vitamin D in the Context of Evolution. Nutrients 2022; 14:nu14153018. [PMID: 35893872 PMCID: PMC9332464 DOI: 10.3390/nu14153018] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 12/12/2022] Open
Abstract
For at least 1.2 billion years, eukaryotes have been able to synthesize sterols and, therefore, can produce vitamin D when exposed to UV-B. Vitamin D endocrinology was established some 550 million years ago in animals, when the high-affinity nuclear receptor VDR (vitamin D receptor), transport proteins and enzymes for vitamin D metabolism evolved. This enabled vitamin D to regulate, via its target genes, physiological process, the first of which were detoxification and energy metabolism. In this way, vitamin D was enabled to modulate the energy-consuming processes of the innate immune system in its fight against microbes. In the evolving adaptive immune system, vitamin D started to act as a negative regulator of growth, which prevents overboarding reactions of T cells in the context of autoimmune diseases. When, some 400 million years ago, species left the ocean and were exposed to gravitation, vitamin D endocrinology took over the additional role as a major regulator of calcium homeostasis, being important for a stable skeleton. Homo sapiens evolved approximately 300,000 years ago in East Africa and had adapted vitamin D endocrinology to the intensive exposure of the equatorial sun. However, when some 75,000 years ago, when anatomically modern humans started to populate all continents, they also reached regions with seasonally low or no UV-B, i.e., and under these conditions vitamin D became a vitamin.
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Koper K, Han SW, Pastor DC, Yoshikuni Y, Maeda HA. Evolutionary Origin and Functional Diversification of Aminotransferases. J Biol Chem 2022; 298:102122. [PMID: 35697072 PMCID: PMC9309667 DOI: 10.1016/j.jbc.2022.102122] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/30/2022] Open
Abstract
Aminotransferases (ATs) are pyridoxal 5′-phosphate–dependent enzymes that catalyze the transamination reactions between amino acid donor and keto acid acceptor substrates. Modern AT enzymes constitute ∼2% of all classified enzymatic activities, play central roles in nitrogen metabolism, and generate multitude of primary and secondary metabolites. ATs likely diverged into four distinct AT classes before the appearance of the last universal common ancestor and further expanded to a large and diverse enzyme family. Although the AT family underwent an extensive functional specialization, many AT enzymes retained considerable substrate promiscuity and multifunctionality because of their inherent mechanistic, structural, and functional constraints. This review summarizes the evolutionary history, diverse metabolic roles, reaction mechanisms, and structure–function relationships of the AT family enzymes, with a special emphasis on their substrate promiscuity and multifunctionality. Comprehensive characterization of AT substrate specificity is still needed to reveal their true metabolic functions in interconnecting various branches of the nitrogen metabolic network in different organisms.
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Affiliation(s)
- Kaan Koper
- Department of Botany, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Sang-Woo Han
- The US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | | | - Yasuo Yoshikuni
- The US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Global Center for Food, Land, and Water Resources, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Hiroshi A Maeda
- Department of Botany, University of Wisconsin-Madison, Madison, WI, 53706, USA
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Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest 2022; 132:159839. [PMID: 35642641 PMCID: PMC9151701 DOI: 10.1172/jci159839] [Citation(s) in RCA: 299] [Impact Index Per Article: 99.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
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Affiliation(s)
| | - Gregg L Semenza
- Department of Genetic Medicine.,Institute for Cell Engineering, and.,Stanley Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Zhao J, Jiang Y, Tian Y, Mao J, Wei L, Ma W. New insights into the effect of NdhO levels on cyanobacterial cell death triggered by high temperature. FUNCTIONAL PLANT BIOLOGY : FPB 2022; 49:533-541. [PMID: 34428393 DOI: 10.1071/fp21097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/05/2021] [Indexed: 06/13/2023]
Abstract
NdhO, a regulatory oxygenic photosynthesis-specific subunit, is close to the ferredoxin-binding site of cyanobacterial NDH-1, and its levels are negatively associated with the rates of cyclic electron transfer around PSI mediated by NDH-1 (NDH-CET). However, the effect of NdhO levels on cyanobacterial cell death triggered by high temperature remains elusive. Here, our results uncovered a synergistic effect of NdhO levels on the cell death and reactive oxygen species (ROS) accumulation when cyanobacterial cells grown at 30°C for 1 day were transferred to 45°C for 2 days. Such synergistic effect was found to be closely associated with the activities of NDH-CET and CO2 assimilation during high temperature. Collectively, we propose that the effect of NdhO levels on the cyanobacterial cell bleaching and cell death triggered by high temperature is a result of influencing production of ROS by NDH-CET, which is considered to be vital to balance the ATP/NADPH ratio and improve the Calvin-Benson cycle.
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Affiliation(s)
- Jiaohong Zhao
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China
| | - Yuanyuan Jiang
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China
| | - Yuhao Tian
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China
| | - Jun Mao
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China
| | - Lanzhen Wei
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China; and Corresponding author
| | - Weimin Ma
- Shanghai Key laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China; and Corresponding author
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45
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Jabłońska J, Tawfik DS. Innovation and tinkering in the evolution of oxidases. Protein Sci 2022; 31:e4310. [PMID: 35481655 PMCID: PMC9040561 DOI: 10.1002/pro.4310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/25/2022] [Accepted: 04/01/2022] [Indexed: 12/19/2022]
Abstract
Although molecular oxygen is a relative newcomer to the biosphere, it has had a profound impact on metabolism. About 700 oxygen‐dependent enzymatic reactions are known, the vast majority of which emerged only after the appearance of oxygen in the biosphere, circa 3 billion years ago. Oxygen was a major driving force for evolutionary innovation—~60% of all known oxygen‐dependent enzyme families emerged as such; that is, the founding ancestor was an O2‐dependent enzyme. The other 40% seem to have diverged by tinkering from pre‐existing proteins whose function was not related to oxygen. Here, we focus on the latter. We describe transitions from various enzyme classes, as well as from non‐enzymatic proteins, and we explore these transitions in terms of catalytic chemistry, metabolism, and protein structure. These transitions vary from subtle ones, such as simply repurposing oxidoreductases by replacing an electron acceptor such as NAD by O2, to drastic changes in reaction mechanism, such as turning carboxylases and hydrolases into oxidases. The latter is more common and can occur with strikingly minor changes, for example, only one mutation in the active site. We further suggest that engineering enzymes to harness the extraordinary reactivity of oxygen may yield higher catabolic power and versatility.
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Affiliation(s)
- Jagoda Jabłońska
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Dan S Tawfik
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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46
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Wolf D, Muralidharan A, Mohan S. Role of prolyl hydroxylase domain proteins in bone metabolism. Osteoporos Sarcopenia 2022; 8:1-10. [PMID: 35415275 PMCID: PMC8987327 DOI: 10.1016/j.afos.2022.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/12/2022] [Accepted: 03/04/2022] [Indexed: 11/03/2022] Open
Abstract
Cellular metabolism requires dissolved oxygen gas. Because evolutionary refinements have constrained mammalian dissolved oxygen levels, intracellular oxygen sensors are vital for optimizing the bioenergetic and biosynthetic use of dissolved oxygen. Prolyl hydroxylase domain (PHD) homologs 1-3 (PHD1/2/3) are molecular oxygen dependent non-heme dioxygenases whose enzymatic activity is regulated by the concentration of dissolved oxygen. PHD oxygen dependency has evolved into an important intracellular oxygen sensor. The most well studied mechanism of PHD oxygen-sensing is its regulation of the hypoxia-inducible factor (HIF) hypoxia signaling pathway. Heterodimeric HIF transcription factor activity is regulated post-translationally by selective PHD proline hydroxylation of its HIF1α subunit, accelerating HIF1α ubiquitination and proteasomal degradation, preventing HIF heterodimer assembly, nuclear accumulation, and activation of its target oxygen homeostasis genes. Phd2 has been shown to be the key isoform responsible for HIF1α subunit regulation in many cell types and accordingly disruption of the Phd2 gene results in embryonic lethality. In bone cells Phd2 is expressed in high abundance and tightly regulated. Conditional disruption of the Phd1, Phd2 and/or Phd3 gene in various bone cell types using different Cre drivers reveals a major role for PHD2 in skeletal growth and development. In this review, we will summarize the state of current knowledge on the role and mechanism of action of PHD2 as oxygen sensor in regulating bone metabolism.
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Affiliation(s)
- David Wolf
- Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 92357, USA
| | - Aruljothi Muralidharan
- Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 92357, USA
| | - Subburaman Mohan
- Musculoskeletal Disease Center, VA Loma Linda Healthcare System, Loma Linda, CA, 92357, USA
- Department of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA
- Department Biochemistry and Orthopedic Surgery, Loma Linda University, Loma Linda, CA, 92354, USA
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Scaling laws in enzyme function reveal a new kind of biochemical universality. Proc Natl Acad Sci U S A 2022; 119:2106655119. [PMID: 35217602 PMCID: PMC8892295 DOI: 10.1073/pnas.2106655119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2021] [Indexed: 11/21/2022] Open
Abstract
Known examples of life all share the same core biochemistry going back to the last universal common ancestor (LUCA), but whether this feature is universal to other examples, including at the origin of life or alien life, is unknown. We show how a physics-inspired statistical approach identifies universal scaling laws across biochemical reactions that are not defined by common chemical components but instead, as macroscale patterns in the reaction functions used by life. The identified scaling relations can be used to predict statistical features of LUCA, and network analyses reveal some of the functional principles that underlie them. They are, therefore, prime candidates for developing new theory on the “laws of life” that might apply to all possible biochemistries. All life on Earth is unified by its use of a shared set of component chemical compounds and reactions, providing a detailed model for universal biochemistry. However, this notion of universality is specific to known biochemistry and does not allow quantitative predictions about examples not yet observed. Here, we introduce a more generalizable concept of biochemical universality that is more akin to the kind of universality found in physics. Using annotated genomic datasets including an ensemble of 11,955 metagenomes, 1,282 archaea, 11,759 bacteria, and 200 eukaryotic taxa, we show how enzyme functions form universality classes with common scaling behavior in their relative abundances across the datasets. We verify that these scaling laws are not explained by the presence of compounds, reactions, and enzyme functions shared across known examples of life. We demonstrate how these scaling laws can be used as a tool for inferring properties of ancient life by comparing their predictions with a consensus model for the last universal common ancestor (LUCA). We also illustrate how network analyses shed light on the functional principles underlying the observed scaling behaviors. Together, our results establish the existence of a new kind of biochemical universality, independent of the details of life on Earth’s component chemistry, with implications for guiding our search for missing biochemical diversity on Earth or for biochemistries that might deviate from the exact chemical makeup of life as we know it, such as at the origins of life, in alien environments, or in the design of synthetic life.
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48
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Sanders WB. The photoaerogens: algae and plants reunited conceptually. AMERICAN JOURNAL OF BOTANY 2022; 109:363-365. [PMID: 35257370 DOI: 10.1002/ajb2.1828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/16/2021] [Accepted: 12/22/2021] [Indexed: 06/14/2023]
Affiliation(s)
- William B Sanders
- Department of Biological Sciences, Florida Gulf Coast University, Ft. Myers, FL 33965-6565, USA
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49
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Adamovich Y, Dandavate V, Asher G. Circadian clocks' interactions with oxygen sensing and signalling. Acta Physiol (Oxf) 2022; 234:e13770. [PMID: 34984824 DOI: 10.1111/apha.13770] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/14/2021] [Accepted: 01/01/2022] [Indexed: 12/14/2022]
Abstract
In mammals, physiology and metabolism are shaped both by immediate and anticipatory responses to environmental changes through the myriad of molecular mechanisms. Whilst the former is mostly mediated through different acute signalling pathways the latter is primarily orchestrated by the circadian clock. Oxygen is vital for life and as such mammals have evolved different mechanisms to cope with changes in oxygen levels. It is widely accepted that oxygen sensing through the HIF-1 signalling pathway is paramount for the acute response to changes in oxygen levels. Circadian clocks are molecular oscillators that control 24 hours rhythms in various aspects of physiology and behaviour. Evidence emerging in recent years points towards pervasive molecular and functional interactions between these two pathways on multiple levels. Daily oscillations in oxygen levels are circadian clock-controlled and can reset the clock through HIF-1. Furthermore, the circadian clock appears to modulate the hypoxic response. We review herein the literature related to the crosstalk between the circadian clockwork and the oxygen-signalling pathway in mammals at the molecular and physiological level both under normal and pathologic conditions.
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Affiliation(s)
- Yaarit Adamovich
- Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel
| | - Vaishnavi Dandavate
- Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel
| | - Gad Asher
- Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel
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50
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Bromberg Y, Aptekmann AA, Mahlich Y, Cook L, Senn S, Miller M, Nanda V, Ferreiro DU, Falkowski PG. Quantifying structural relationships of metal-binding sites suggests origins of biological electron transfer. SCIENCE ADVANCES 2022; 8:eabj3984. [PMID: 35030025 PMCID: PMC8759750 DOI: 10.1126/sciadv.abj3984] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 11/22/2021] [Indexed: 06/07/2023]
Abstract
Biological redox reactions drive planetary biogeochemical cycles. Using a novel, structure-guided sequence analysis of proteins, we explored the patterns of evolution of enzymes responsible for these reactions. Our analysis reveals that the folds that bind transition metal–containing ligands have similar structural geometry and amino acid sequences across the full diversity of proteins. Similarity across folds reflects the availability of key transition metals over geological time and strongly suggests that transition metal–ligand binding had a small number of common peptide origins. We observe that structures central to our similarity network come primarily from oxidoreductases, suggesting that ancestral peptides may have also facilitated electron transfer reactions. Last, our results reveal that the earliest biologically functional peptides were likely available before the assembly of fully functional protein domains over 3.8 billion years ago.Thus, life is a special, very complex form of motion of matter, but this form did not always exist, and it is not separated from inorganic nature by an impassable abyss; rather, it arose from inorganic nature as a new property in the process of evolution of the world. We must study the history of this evolution if we want to solve the problem of the origin of life. [A. I. Oparin (1)]
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Affiliation(s)
- Yana Bromberg
- Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Dr, New Brunswick, NJ 08873, USA
| | - Ariel A. Aptekmann
- Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Dr, New Brunswick, NJ 08873, USA
| | - Yannick Mahlich
- Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Dr, New Brunswick, NJ 08873, USA
| | - Linda Cook
- Program in Applied and Computational Math, Princeton University, Princeton, NJ 08540, USA
| | - Stefan Senn
- Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Dr, New Brunswick, NJ 08873, USA
| | - Maximillian Miller
- Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Dr, New Brunswick, NJ 08873, USA
| | - Vikas Nanda
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA
| | - Diego U. Ferreiro
- Protein Physiology Lab, Departamento de Química Biológica, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Paul G. Falkowski
- Environmental Biophysics and Molecular Ecology Program, Department of Marine and Coastal Sciences, Rutgers University, New Brunswick, NJ 08901, USA
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