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Simonenko SY, Bogdanova DA, Kuldyushev NA. Emerging Roles of Vitamin B 12 in Aging and Inflammation. Int J Mol Sci 2024; 25:5044. [PMID: 38732262 PMCID: PMC11084641 DOI: 10.3390/ijms25095044] [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: 04/09/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Vitamin B12 (cobalamin) is an essential nutrient for humans and animals. Metabolically active forms of B12-methylcobalamin and 5-deoxyadenosylcobalamin are cofactors for the enzymes methionine synthase and mitochondrial methylmalonyl-CoA mutase. Malfunction of these enzymes due to a scarcity of vitamin B12 leads to disturbance of one-carbon metabolism and impaired mitochondrial function. A significant fraction of the population (up to 20%) is deficient in vitamin B12, with a higher rate of deficiency among elderly people. B12 deficiency is associated with numerous hallmarks of aging at the cellular and organismal levels. Cellular senescence is characterized by high levels of DNA damage by metabolic abnormalities, increased mitochondrial dysfunction, and disturbance of epigenetic regulation. B12 deficiency could be responsible for or play a crucial part in these disorders. In this review, we focus on a comprehensive analysis of molecular mechanisms through which vitamin B12 influences aging. We review new data about how deficiency in vitamin B12 may accelerate cellular aging. Despite indications that vitamin B12 has an important role in health and healthy aging, knowledge of the influence of vitamin B12 on aging is still limited and requires further research.
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Affiliation(s)
- Sergey Yu. Simonenko
- Research Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia;
| | - Daria A. Bogdanova
- Division of Immunobiology and Biomedicine, Center for Genetics and Life Sciences, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Nikita A. Kuldyushev
- Research Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia;
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Milovanovic V, Topic A, Milinkovic N, Lazic Z, Ivosevic A, Radojkovic D, Rankov AD. Association of the methionine sulfoxide reductase A rs10903323 gene polymorphism with functional activity and oxidative modification of alpha-1-antitrypsin in COPD patients. Pulmonology 2024; 30:122-129. [PMID: 34674978 DOI: 10.1016/j.pulmoe.2021.09.003] [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: 06/20/2021] [Revised: 09/16/2021] [Accepted: 09/19/2021] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Chronic obstructive pulmonary disease (COPD) is multi-factorial disorder which results from environmental influences and genetic factors. We aimed to investigate whether methionine sulfoxide reductase A (MSRA) rs10903323 gene polymorphism is associated with COPD development and severity in Serbian adult population. METHODS The study included 155 patients with COPD and 134 healthy volunteers. Genotyping was determined performing home-made polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The difference between the inhibitory activities of normal and oxidized Alpha-1-Antitrypsin (A1AT) against elastase and trypsin was used for determination of Oxidized Alpha-1-Antitrypsin (OxyA1AT) (expressed as % and g/L). Functional activity of A1AT was presented as a specific inhibitor activity to elastase (SIA-Elastase, kU/g). RESULTS Frequencies of the genotypes AA, AG and GG were 80.0%, 20.0%, 0% in COPD patients and 80.5%, 18.5% and 1.5% in the control group, and there was no significant difference in genotype or allele distributions between groups. Serum level of A1AT (g/L) and OxyA1AT was significantly higher in COPD patients than in the control group, but functional activity of A1AT (SIA-Elastase) was significantly lower in COPD patients than in the control group. In COPD group, increased level of OxyA1AT was present in G allele carriers who were smokers relative to G allele carriers who were not smokers. In the smoker group of patients with severe and very severe COPD (GOLD3+4), significant increase in OxyA1AT level was present in G allele carriers compared to AA homozygotes. CONCLUSION These findings suggest that MSRA rs10903323 gene polymorphism is probably not a risk for COPD by itself but could represent a COPD modifier, since minor, G allele, is associated with an increased level of oxidized A1AT, indicating impaired ability of MSRA to repair oxidized A1AT in COPD-smokers, and in severe form of COPD.
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Affiliation(s)
- V Milovanovic
- University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia.
| | - A Topic
- University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia
| | - N Milinkovic
- University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia
| | - Z Lazic
- University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
| | - A Ivosevic
- University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia
| | - D Radojkovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - A Divac Rankov
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
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Tarrago L, Kaya A, Kim HY, Manta B, Lee BC, Gladyshev VN. The selenoprotein methionine sulfoxide reductase B1 (MSRB1). Free Radic Biol Med 2022; 191:228-240. [PMID: 36084791 DOI: 10.1016/j.freeradbiomed.2022.08.043] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/11/2022] [Accepted: 08/31/2022] [Indexed: 11/24/2022]
Abstract
Methionine (Met) can be oxidized to methionine sulfoxide (MetO), which exist as R- and S-diastereomers. Present in all three domains of life, methionine sulfoxide reductases (MSR) are the enzymes that reduce MetO back to Met. Most characterized among them are MSRA and MSRB, which are strictly stereospecific for the S- and R-diastereomers of MetO, respectively. While the majority of MSRs use a catalytic Cys to reduce their substrates, some employ selenocysteine. This is the case of mammalian MSRB1, which was initially discovered as selenoprotein SELR or SELX and later was found to exhibit an MSRB activity. Genomic analyses demonstrated its occurrence in most animal lineages, and biochemical and structural analyses uncovered its catalytic mechanism. The use of transgenic mice and mammalian cell culture revealed its physiological importance in the protection against oxidative stress, maintenance of neuronal cells, cognition, cancer cell proliferation, and the immune response. Coincident with the discovery of Met oxidizing MICAL enzymes, recent findings of MSRB1 regulating the innate immunity response through reversible stereospecific Met-R-oxidation of cytoskeletal actin opened up new avenues for biological importance of MSRB1 and its role in disease. In this review, we discuss the current state of research on MSRB1, compare it with other animal Msrs, and offer a perspective on further understanding of biological functions of this selenoprotein.
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Affiliation(s)
- Lionel Tarrago
- UMR 1163, Biodiversité et Biotechnologie Fongiques, INRAE, Aix-Marseille Université, 13009, Marseille, France.
| | - Alaattin Kaya
- Department of Biology, Virginia Commonwealth University, Richmond, VA, 23284, USA
| | - Hwa-Young Kim
- Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Bruno Manta
- Laboratorio de Genomica Microbiana, Institut Pasteur de Montevideo, Mataojo 2020, 11440, Montevideo, Uruguay; Catedra de Fisiopatología, Facultad de Odontología, Universidad de la República, Las Heras 1925, 11600, Montevideo, Uruguay
| | - Byung-Cheon Lee
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
| | - Vadim N Gladyshev
- Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, USA.
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Kuldyushev N, Schönherr R, Coburger I, Ahmed M, Hussein RA, Wiesel E, Godbole A, Pfirrmann T, Hoshi T, Heinemann SH. A GFP-based ratiometric sensor for cellular methionine oxidation. Talanta 2022; 243:123332. [PMID: 35276500 DOI: 10.1016/j.talanta.2022.123332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022]
Abstract
Methionine oxidation is a reversible post-translational protein modification, affecting protein function, and implicated in aging and degenerative diseases. The detection of accumulating methionine oxidation in living cells or organisms, however, has not been achieved. Here we introduce a genetically encoded probe for methionine oxidation (GEPMO), based on the super-folder green fluorescent protein (sfGFP), as a specific, versatile, and integrating sensor for methionine oxidation. Placed at amino-acid position 147 in an otherwise methionine-less sfGFP, the oxidation of this specific methionine to methionine sulfoxide results in a ratiometric fluorescence change when excited with ∼400 and ∼470 nm light. The strength and homogeneity of the sensor expression is suited for live-cell imaging as well as fluorescence-activated cell sorting (FACS) experiments using standard laser wavelengths (405/488 nm). Expressed in mammalian cells and also in S. cerevisiae, the sensor protein faithfully reports on the status of methionine oxidation in an integrating manner. Variants targeted to membranes and the mitochondria provide subcellular resolution of methionine oxidation, e.g. reporting on site-specific oxidation by illumination of endogenous protoporphyrin IX.
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Affiliation(s)
- Nikita Kuldyushev
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Roland Schönherr
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Ina Coburger
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Marwa Ahmed
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Rama A Hussein
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Eric Wiesel
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Amod Godbole
- Center for Molecular Biomedicine, Institute for Molecular Cell Biology, Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany
| | - Thorsten Pfirrmann
- Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, Hollystr. 1, 06144, Halle/Saale, Germany; Department of Medicine, Health and Medical University, Olympischer Weg 1, 14471 Potsdam, Germany
| | - Toshinori Hoshi
- Department of Physiology, University of Pennsylvania, Philadelphia, PA, 19104-6085, USA
| | - Stefan H Heinemann
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany.
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Indhu MS, Ramamoorthy M, Pandey S, Mathesh K, Mahawar M, Sarkar M, Ghosh SK, Taru Sharma G, Bhure SK. Improved quality and fertilizability of cryopreserved buffalo spermatozoa with the supplementation of methionine sulfoxide reductase A. Andrology 2021; 9:1943-1957. [PMID: 34245495 DOI: 10.1111/andr.13080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/30/2021] [Accepted: 07/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The excessive reactive oxygen species produced during semen-freezing and -thawing damage the macromolecules resulting in impairment of cellular functions. Proteins are the primary targets of oxidative damage, wherein methionine residues are more prone to oxidation and get converted into methionine sulfoxide, thus affecting the protein function. The methionine sulfoxide reductase A (MsrA) catalyzes the conversion of methionine sulfoxide to methionine and restores the functionality of defective proteins. OBJECTIVES To establish the expression of MsrA in male reproductive organs, including semen and its effect on quality of cryopreserved semen upon exogenous supplementation, taking buffalo semen as a model. MATERIALS AND METHODS The expression of MsrA was established by immunohistochemistry, PCR, and Western blots. Further, the effect of recombinant MsrA (rMsrA) supplementation on the quality of cryopreserved spermatozoa was assessed in three treatment groups containing 1.0, 1.5, and 2.0 µg of rMsrA/50 million spermatozoa in egg yolk glycerol extender along with a control group; wherein the post-thaw progressive motility, viability, membrane integrity, and zona binding ability of cryopreserved spermatozoa were studied. RESULTS The MsrA was expressed in buffalo testis, epididymis, accessory sex glands, and spermatozoa except in seminal plasma. In group 2, the supplementation has resulted in a significant (p < 0.05) improvement as compared to the control group in mean progressive motility (47.50 ± 2.50 vs. 36.25 ± 2.63), viability (56.47 ± 1.85 vs. 48.05 ± 2.42), HOST (50.76 ± 1.73 vs. 44.29 ± 1.29), and zona binding ability of spermatozoa (149.50 ± 8.39 vs. 29.50 ± 2.85). DISCUSSION AND CONCLUSION In the absence of native MsrA of seminal plasma, the supplementations of rMsrA may repair the oxidatively damaged seminal plasma proteins and exposed sperm plasma membrane proteins resulting in better quality with a fivefold increase in fertilizability of frozen-thawed spermatozoa. The findings can be extended to other species to improve the semen quality with the variation in the amounts of rMsrA supplementation.
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Affiliation(s)
| | - Muthu Ramamoorthy
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Sriti Pandey
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Karikalan Mathesh
- Wildlife Section, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Manish Mahawar
- Division of Biochemistry, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Mihir Sarkar
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Subrata Kumar Ghosh
- Division of Animal Reproduction, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Guttulu Taru Sharma
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Sanjeev Kumar Bhure
- Division of Biochemistry, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
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Indhu MS, Nanjundappa S, Muttu R, Vikramaditya U, Mahawar M, Sarkar M, Guttula TS, Bhure S. Molecular Expression of Bioactive Recombinant Methionine Sulfoxide Reductase A (MsrA). Protein Pept Lett 2021; 28:11-17. [PMID: 32586239 DOI: 10.2174/0929866527666200625201628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 03/29/2020] [Accepted: 05/08/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND The increase in reactive oxygen species (ROS) production during cryopreservation of semen, leads to oxidation of biomolecules affecting the functionality of spermatozoa. Methionine residues in proteins are highly prone to oxidation and get converted into methionine sulfoxide (MetO). Methionine sulfoxide reductase A (MsrA) can improve the functionality of spermatozoa by reducing the MetO to methionine restoring the lost functionality of the affected proteins. OBJECTIVE The expression of catalytically active recombinant MsrA (rMsrA). METHODS The msrA gene was PCR amplified, cloned and sequenced. Further, the recombinant clone was used for protein expression and purification. The protein was getting precipitated during dialysis in Tris-buffer. Hence, the purified rMsrA was dialyzed at 4°C against the Tris-buffer pH 7.5 containing MgCl2, KCl, NaCl, urea and triton X-100. During dialysis, changes of buffer were done at every 12 h interval with stepwise reduction in the concentrations of NaCl, urea and triton X-100. The final dialysis was done with buffer containing 10 mM MgCl2, 30 mM KCl, and 150 mM NaCl, 25 mM Tris-HCl pH 7.5. The activity of the rMsrA was checked spectrophotometrically. RESULTS The protein BLAST of buffalo MsrA with bovine sequence showed 14 amino acid mismatches. The rMsrA has been purified under denaturing conditions as it was forming inclusion bodies consistently during protein expression. After renaturation, the purified 33 kDa rMsrA was catalytically active by biochemical assay. CONCLUSION The rMsrA expressed in prokaryotic system is catalytically active and can be used for supplementation to semen extender to repair the oxidatively damaged seminal plasma proteins that occur during cryopreservation.
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Affiliation(s)
- M S Indhu
- Division of Biochemistry, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Shruthi Nanjundappa
- Division of Biochemistry, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Ramamoorthy Muttu
- Division of Animal Reproduction, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Upmanyu Vikramaditya
- Division of Biological Standardization, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Manish Mahawar
- Division of Biochemistry, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Mihir Sarkar
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Taru Sharma Guttula
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
| | - Sanjeevkumar Bhure
- Division of Biochemistry, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, U.P., India
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The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models. Molecules 2021; 26:molecules26051372. [PMID: 33806413 PMCID: PMC7961861 DOI: 10.3390/molecules26051372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 11/17/2022] Open
Abstract
MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.
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Reiterer M, Schmidt-Kastner R, Milton SL. Methionine sulfoxide reductase (Msr) dysfunction in human brain disease. Free Radic Res 2019; 53:1144-1154. [PMID: 31775527 DOI: 10.1080/10715762.2019.1662899] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Extensive research has shown that oxidative stress is strongly associated with aging, senescence and several diseases, including neurodegenerative and psychiatric disorders. Oxidative stress is caused by the overproduction of reactive oxygen species (ROS) that can be counteracted by both enzymatic and nonenzymatic antioxidants. One of these antioxidant mechanisms is the widely studied methionine sulfoxide reductase system (Msr). Methionine is one of the most easily oxidized amino acids and Msr can reverse this oxidation and restore protein function, with MsrA and MsrB reducing different stereoisomers. This article focuses on experimental and genetic research performed on Msr and its link to brain diseases. Studies on several model systems as well as genome-wide association studies are compiled to highlight the role of MSRA in schizophrenia, Alzheimer's disease, and Parkinson's disease. Genetic variation of MSRA may also contribute to the risk of psychosis, personality traits, and metabolic factors.
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Affiliation(s)
- Melissa Reiterer
- Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA
| | | | - Sarah L Milton
- Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA
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Ward NP, DeNicola GM. Sulfur metabolism and its contribution to malignancy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 347:39-103. [PMID: 31451216 DOI: 10.1016/bs.ircmb.2019.05.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Metabolic dysregulation is an appreciated hallmark of cancer and a target for therapeutic intervention. Cellular metabolism involves a series of oxidation/reduction (redox) reactions that yield the energy and biomass required for tumor growth. Cells require diverse molecular species with constituent sulfur atoms to facilitate these processes. For humans, this sulfur is derived from the dietary consumption of the proteinogenic amino acids cysteine and methionine, as only lower organisms (e.g., bacteria, fungi, and plants) can synthesize them de novo. In addition to providing the sulfur required to sustain redox chemistry, the metabolism of these sulfur-containing amino acids yield intermediate metabolites that constitute the cellular antioxidant system, mediate inter- and intracellular signaling, and facilitate the epigenetic regulation of gene expression, all of which contribute to tumorigenesis.
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Affiliation(s)
- Nathan P Ward
- Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Gina M DeNicola
- Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
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Keskin O, Farzan N, Birben E, Akel H, Karaaslan C, Maitland-van der Zee AH, Wechsler ME, Vijverberg SJ, Kalayci O. Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review. Clin Transl Allergy 2019; 9:2. [PMID: 30647901 PMCID: PMC6327448 DOI: 10.1186/s13601-018-0239-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
There is wide variability in the response to inhaled corticosteroids (ICS) in asthma. While some of this heterogeneity of response is due to adherence and environmental causes, genetic variation also influences response to treatment and genetic markers may help guide treatment. Over the past years, researchers have investigated the relationship between a large number of genetic variations and response to ICS by performing pharmacogenomic studies. In this systematic review we will provide a summary of recent pharmacogenomic studies on ICS and discuss the latest insight into the potential functional role of identified genetic variants. To date, seven genome wide association studies (GWAS) examining ICS response have been published. There is little overlap between identified variants and methodologies vary largely. However, in vitro and/or in silico analyses provide additional evidence that genes discovered in these GWAS (e.g. GLCCI1, FBXL7, T gene, ALLC, CMTR1) might play a direct or indirect role in asthma/treatment response pathways. Furthermore, more than 30 candidate-gene studies have been performed, mainly attempting to replicate variants discovered in GWAS or candidate genes likely involved in the corticosteroid drug pathway. Single nucleotide polymorphisms located in GLCCI1, NR3C1 and the 17q21 locus were positively replicated in independent populations. Although none of the genetic markers has currently reached clinical practise, these studies might provide novel insights in the complex pathways underlying corticosteroids response in asthmatic patients.
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Affiliation(s)
- Ozlem Keskin
- 1Paediatric Allergy and Immunology Department, School of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Niloufar Farzan
- 2Department of Respiratory Medicine, University of Amsterdam, Amsterdam UMC, Meibergdreef 9, Amsterdam, Netherlands
| | - Esra Birben
- 3Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, 06100 Ankara, Turkey
| | - Hayriye Akel
- 4Department of Molecular Biology, Faculty of Sciences, Hacettepe University, Ankara, Turkey
| | - Cagatay Karaaslan
- 4Department of Molecular Biology, Faculty of Sciences, Hacettepe University, Ankara, Turkey
| | - Anke H Maitland-van der Zee
- 2Department of Respiratory Medicine, University of Amsterdam, Amsterdam UMC, Meibergdreef 9, Amsterdam, Netherlands.,5Department of Pediatric Respiratory Medicine and Allergy, University of Amsterdam, Amsterdam UMC, Meibergdreef 9, Amsterdam, Netherlands
| | | | - Susanne J Vijverberg
- 2Department of Respiratory Medicine, University of Amsterdam, Amsterdam UMC, Meibergdreef 9, Amsterdam, Netherlands
| | - Omer Kalayci
- 3Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, 06100 Ankara, Turkey
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The Oxidized Protein Repair Enzymes Methionine Sulfoxide Reductases and Their Roles in Protecting against Oxidative Stress, in Ageing and in Regulating Protein Function. Antioxidants (Basel) 2018; 7:antiox7120191. [PMID: 30545068 PMCID: PMC6316033 DOI: 10.3390/antiox7120191] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 11/30/2018] [Accepted: 12/01/2018] [Indexed: 12/31/2022] Open
Abstract
Cysteine and methionine residues are the amino acids most sensitive to oxidation by reactive oxygen species. However, in contrast to other amino acids, certain cysteine and methionine oxidation products can be reduced within proteins by dedicated enzymatic repair systems. Oxidation of cysteine first results in either the formation of a disulfide bridge or a sulfenic acid. Sulfenic acid can be converted to disulfide or sulfenamide or further oxidized to sulfinic acid. Disulfide can be easily reversed by different enzymatic systems such as the thioredoxin/thioredoxin reductase and the glutaredoxin/glutathione/glutathione reductase systems. Methionine side chains can also be oxidized by reactive oxygen species. Methionine oxidation, by the addition of an extra oxygen atom, leads to the generation of methionine sulfoxide. Enzymatically catalyzed reduction of methionine sulfoxide is achieved by either methionine sulfoxide reductase A or methionine sulfoxide reductase B, also referred as to the methionine sulfoxide reductases system. This oxidized protein repair system is further described in this review article in terms of its discovery and biologically relevant characteristics, and its important physiological roles in protecting against oxidative stress, in ageing and in regulating protein function.
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12
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Genetic regulation of longevity and age-associated diseases through the methionine sulfoxide reductase system. Biochim Biophys Acta Mol Basis Dis 2018; 1865:1756-1762. [PMID: 30481589 DOI: 10.1016/j.bbadis.2018.11.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 09/25/2018] [Accepted: 11/14/2018] [Indexed: 12/13/2022]
Abstract
Methionine sulfoxide reductase enzymes are a protective system against biological oxidative stress in aerobic organisms. Modifications to this antioxidant system have been shown to impact the lifespan of several model system organisms. In humans, methionine oxidation of critical proteins and deficiencies in the methionine sulfoxide reductase system have been linked to age-related diseases, including cancer and neurodegenerative disease. Substrates for methionine sulfoxide reductases have been reviewed multiple times, and are still an active area of discovery. In contrast, less is known about the genetic regulation of methionine sulfoxide reductases. In this review, we discuss studies on the genetic regulation of the methionine sulfoxide reductase system with relevance to longevity and age-related diseases. A better understanding of genetic regulation for methionine sulfoxide reductases may lead to new therapeutic approaches for age-related diseases in the future.
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Sex-Specific Transcriptome Differences in Substantia Nigra Tissue: A Meta-Analysis of Parkinson's Disease Data. Genes (Basel) 2018; 9:genes9060275. [PMID: 29799491 PMCID: PMC6027313 DOI: 10.3390/genes9060275] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/11/2018] [Accepted: 05/18/2018] [Indexed: 12/26/2022] Open
Abstract
Parkinson’s disease (PD) is one of the most common progressive neurodegenerative diseases. Clinical and epidemiological studies indicate that sex differences, as well as genetic components and ageing, can influence the prevalence, age at onset and symptomatology of PD. This study undertook a systematic meta-analysis of substantia nigra microarray data using the Transcriptome Mapper (TRAM) software to integrate and normalize a total of 10 suitable datasets from multiple sources. Four different analyses were performed according to default parameters, to better define the segments differentially expressed between PD patients and healthy controls, when comparing men and women data sets. The results suggest a possible regulation of specific sex-biased systems in PD susceptibility. TRAM software allowed us to highlight the different activation of some genomic regions and loci involved in molecular pathways related to neurodegeneration and neuroinflammatory mechanisms.
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Luo T, Liu X, Cui Y. A Genome-wide Association Analysis in Four Populations Reveals Strong Genetic Heterogeneity For Birth Weight. Curr Genomics 2017; 17:416-426. [PMID: 28479870 PMCID: PMC5320544 DOI: 10.2174/1389202917666160726152033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 08/24/2015] [Accepted: 08/31/2015] [Indexed: 11/22/2022] Open
Abstract
Low or high birth weight is one of the main causes for neonatal morbidity and mortality. They are also associated with adulthood chronic illness. Birth weight is a complex trait which is affected by baby's genes, maternal environments as well as the complex interactions between them. To understand the genetic basis of birth weight, we reanalyzed a genome-wide association study data set which consists of four populations, namely Thai, Afro-Caribbean, European, and Hispanic population with regular linear models. In addition to fit the data with parametric linear models, we fitted the data with a nonparametric varying-coefficient model to identify variants that are nonlinearly modulated by mother's condition to affect birth weight. For this purpose, we used baby's cord glucose level as the mother's environmental variable. At the 10-5 genome-wide threshold, we identified 33 SNP variants in the Thai population, 26 SNPs in the Afro-Caribbean population, 18 SNPs in the European population, and 7 SNPs in the Hispanic population. Some of the variants are significantly modulated by baby's cord glucose level either linearly or nonlinearly, implying potential interactions between baby's gene and mother's glucose level to affect baby's birth weight. There is no overlap between variants identified in the four populations, indicating strong genetic heterogeneity of birth weight between the four ethnic groups. The findings of this study provide insights into the genetic basis of birth weight and reveal its genetic heterogeneity.
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Affiliation(s)
- Tiane Luo
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Shanxi, 030001, China
| | - Xu Liu
- Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA
| | - Yuehua Cui
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Shanxi, 030001, China.,Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA
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Zhu Q, El-Mergawy RG, Zhou Y, Chen C, Heinemann SH, Schönherr R, Robaa D, Sippl W, Scriba GKE. Stereospecific capillary electrophoresis assays using pentapeptide substrates for the study of Aspergillus nidulans methionine sulfoxide reductase A and mutant enzymes. Electrophoresis 2016; 37:2083-90. [PMID: 27145186 DOI: 10.1002/elps.201600181] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 04/27/2016] [Accepted: 04/27/2016] [Indexed: 12/18/2022]
Abstract
Stereospecific capillary electrophoresis-based methods for the analysis of methionine sulfoxide [Met(O)]-containing pentapeptides were developed in order to investigate the reduction of Met(O)-containing peptide substrates by recombinant Aspergillus nidulans methionine sulfoxide reductase A (MsrA) as well as enzymes carrying mutations in position Glu99 and Asp134. The separation of the diastereomers of the N-acetylated, C-terminally 2,4-dinitrophenyl (Dnp)-labeled pentapeptides ac-Lys-Phe-Met(O)-Lys-Lys-Dnp, ac-Lys-Asp-Met(O)-Asn-Lys-Dnp and ac-Lys-Asn-Met(O)-Asp-Lys-Dnp was achieved in 50 mM Tris-HCl buffers containing sulfated β-CD in fused-silica capillaries, while the diastereomer separation of ac-Lys-Asp-Met(O)-Asp-Lys-Dnp was achieved by sulfated β-CD-mediated MEKC. The methods were validated with regard to range, linearity, accuracy, limits of detection and quantitation as well as precision. Subsequently, the substrates were incubated with wild-type MsrA and three mutants in the presence of dithiothreitol as reductant. Wild-type MsrA displayed the highest activity towards all substrates compared to the mutants. Substitution of Glu99 by Gln resulted in the mutant with the lowest activity towards all substrates except for ac-Lys-Asn-Met(O)-Asp-Lys-Dnp, while replacement Asn for Asp134 lead to a higher activity towards ac-Lys-Asp-Met(O)-Asn-Lys-Dnp compared with the Glu99 mutant. The mutant with Glu instead of Asp134 was the most active among the mutant enzymes. Molecular modeling indicated that the conserved Glu99 residue is buried in the Met-S-(O) groove, which might contribute to the correct placing of substrates and, consequently, to the catalytic activity of MsrA, while Asp134 did not form hydrogen bonds with the substrates but only within the enzyme.
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Affiliation(s)
- Qingfu Zhu
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Jena, Germany
| | - Rabab G El-Mergawy
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany
| | - Yuzhen Zhou
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Jena, Germany
| | - Chunyang Chen
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Jena, Germany
| | - Stefan H Heinemann
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany
| | - Roland Schönherr
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany
| | - Dina Robaa
- Department of Medicinal Chemistry, University of Halle, Halle, Germany
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, University of Halle, Halle, Germany
| | - Gerhard K E Scriba
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Jena, Germany
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Vanhooren V, Navarrete Santos A, Voutetakis K, Petropoulos I, Libert C, Simm A, Gonos ES, Friguet B. Protein modification and maintenance systems as biomarkers of ageing. Mech Ageing Dev 2015; 151:71-84. [PMID: 25846863 DOI: 10.1016/j.mad.2015.03.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 12/22/2022]
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Klutho PJ, Pennington SM, Scott JA, Wilson KM, Gu SX, Doddapattar P, Xie L, Venema AN, Zhu LJ, Chauhan AK, Lentz SR, Grumbach IM. Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling. Arterioscler Thromb Vasc Biol 2015; 35:2594-604. [PMID: 26449752 DOI: 10.1161/atvbaha.115.305857] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 09/28/2015] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Emerging evidence suggests that methionine oxidation can directly affect protein function and may be linked to cardiovascular disease. The objective of this study was to define the role of the methionine sulfoxide reductase A (MsrA) in models of vascular disease and identify its signaling pathways. APPROACH AND RESULTS MsrA was readily identified in all layers of the vascular wall in human and murine arteries. Deletion of the MsrA gene did not affect atherosclerotic lesion area in apolipoprotein E-deficient mice and had no significant effect on susceptibility to experimental thrombosis after photochemical injury. In contrast, the neointimal area after vascular injury caused by complete ligation of the common carotid artery was significantly greater in MsrA-deficient than in control mice. In aortic vascular smooth muscle cells lacking MsrA, cell proliferation was significantly increased because of accelerated G1/S transition. In parallel, cyclin D1 protein and cdk4/cyclin D1 complex formation and activity were increased in MsrA-deficient vascular smooth muscle cell, leading to enhanced retinoblastoma protein phosphorylation and transcription of E2F. Finally, MsrA-deficient vascular smooth muscle cell exhibited greater activation of extracellular signal-regulated kinase 1/2 that was caused by increased activity of the Ras/Raf/mitogen-activated protein kinase signaling pathway. CONCLUSIONS Our findings implicate MsrA as a negative regulator of vascular smooth muscle cell proliferation and neointimal hyperplasia after vascular injury through control of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling pathway.
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Affiliation(s)
- Paula J Klutho
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Steven M Pennington
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Jason A Scott
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Katina M Wilson
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Sean X Gu
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Prakash Doddapattar
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Litao Xie
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Ashlee N Venema
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Linda J Zhu
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Anil K Chauhan
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Steven R Lentz
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa
| | - Isabella M Grumbach
- From the Department of Internal Medicine (P.J.K., S.M.P., J.A.S., K.M.W., S.X.G., P.D., L.X., A.N.V., L.J.Z., A.K.C., S.R.L.) and the Iowa City VA Healthcare System (I.M.G.), University of Iowa.
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Achilli C, Ciana A, Minetti G. The discovery of methionine sulfoxide reductase enzymes: An historical account and future perspectives. Biofactors 2015; 41:135-52. [PMID: 25963551 DOI: 10.1002/biof.1214] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 04/19/2015] [Indexed: 01/26/2023]
Abstract
L-Methionine (L-Met) is the only sulphur-containing proteinogenic amino acid together with cysteine. Its importance is highlighted by it being the initiator amino acid for protein synthesis in all known living organisms. L-Met, free or inserted into proteins, is sensitive to oxidation of its sulfide moiety, with formation of L-Met sulfoxide. The sulfoxide could not be inserted into proteins, and the oxidation of L-Met in proteins often leads to the loss of biological activity of the affected molecule. Key discoveries revealed the existence, in rats, of a metabolic pathway for the reduction of free L-Met sulfoxide and, later, in Escherichia coli, of the enzymatic reduction of L-Met sulfoxide inserted in proteins. Upon oxidation, the sulphur atom becomes a new stereogenic center, and two stable diastereoisomers of L-Met sulfoxide exist. A fundamental discovery revealed the existence of two unrelated families of enzymes, MsrA and MsrB, whose members display opposite stereospecificity of reduction for the two sulfoxides. The importance of Msrs is additionally emphasized by the discovery that one of the only 25 selenoproteins expressed in humans is a Msr. The milestones on the road that led to the discovery and characterization of this group of antioxidant enzymes are recounted in this review.
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Affiliation(s)
- Cesare Achilli
- Laboratories of Biochemistry, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Annarita Ciana
- Laboratories of Biochemistry, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Giampaolo Minetti
- Laboratories of Biochemistry, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
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Moskovitz J, Walss-Bass C, Cruz DA, Thompson PM, Hairston J, Bortolato M. The enzymatic activities of brain catechol-O-methyltransferase (COMT) and methionine sulphoxide reductase are correlated in a COMT Val/Met allele-dependent fashion. Neuropathol Appl Neurobiol 2015; 41:941-51. [PMID: 25640985 DOI: 10.1111/nan.12219] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 01/07/2015] [Indexed: 01/05/2023]
Abstract
AIMS The enzyme catechol-O-methyltransferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulphoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion. METHODS COMT and MSR activities were measured from post-mortem samples of prefrontal cortices, striata and cerebella of 32 subjects by using catechol and dabsyl-Met sulphoxide as substrates, respectively. Allelic discrimination of COMT Val(108/185) Met SNP was performed using the Taqman 5'nuclease assay. RESULTS Our studies revealed that, in homozygous carriers of Met, but not Val alleles, the activity of COMT and MSR was significantly correlated throughout all tested brain regions. CONCLUSION These results suggest that the reduced enzymatic activity of Met-containing COMT may be secondary to Met sulphoxidation and point to MSR as a key molecular determinant for the modulation of COMT activity.
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Affiliation(s)
- Jackob Moskovitz
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, USA
| | - Consuelo Walss-Bass
- Department of Psychiatry and Behavioral Science, School of Medicine, University of Texas Health Science Center, Houston, USA
| | - Dianne A Cruz
- Southwest Brain Bank, Department of Psychiatry, School of Medicine, University of Texas Health Science Center, San Antonio, USA
| | - Peter M Thompson
- Southwest Brain Bank, Department of Psychiatry, School of Medicine, University of Texas Health Science Center, San Antonio, USA
| | - Jenaqua Hairston
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, USA
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, USA
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Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma. THE PHARMACOGENOMICS JOURNAL 2015; 15:422-9. [PMID: 25601762 DOI: 10.1038/tpj.2014.83] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 09/09/2014] [Accepted: 11/07/2014] [Indexed: 12/14/2022]
Abstract
Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.
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Lee MJ, Cho YA, Hwang HJ, Kim JH. Development of in-cell imaging assay systems for MMP-2 and MMP-9 based on trans-localizing molecular beacon proteins. Arch Pharm Res 2015; 38:1099-107. [PMID: 25564338 DOI: 10.1007/s12272-014-0546-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 12/26/2014] [Indexed: 01/23/2023]
Abstract
A sensitive in-cell imaging MMP-2 and MMP-9 detection systems that enables direct fluorescence detection of a target protease and its inhibition inside living cells has been developed. This in-cell imaging system utilizes the concept of fluorescent molecular beacon reporter (MBR) protein comprising a masking protein, a mitochondrial targeting sequence, a protease specific cleavage sequence and a fluorescent marker sequence, green fluorescent protein (GFP). The MBR protein is designed to change its intracellular location upon cleavage by either MMP-2 or MMP-9 from cytosol to mitochondria. Full and partial MMP-2 and MMP-9 were tested for optimal expression and activity in the cell. The activity of MMP-2 and MMP-9 was approximately 65-71%. Among MMP clones, MMP-2 catalytic domain and MMP-9 clone containing pro, catalytic and hemopexin domain were most active. Both MMP-2 and MMP-9 required divalent ions Ca and Zn for its activity and MMP-9 was more active at higher Ca/Zn ratio. With the in-cell imaging assay the protease activity can be measured in cellular environment and cellular toxicity of candidate molecules can be monitored at the same time. These are great advantage when compared to other currently used in vitro biochemical assays. The in-cell imaging assay developed in this study can be modified for other MMPs and can be used in various life science and drug discovery researches including the high throughput screening and high contents screening applications.
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Affiliation(s)
- Min Jun Lee
- Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 130-701, Korea
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Abstract
SIGNIFICANCE Voltage-gated K+ channels are a large family of K+-selective ion channel protein complexes that open on membrane depolarization. These K+ channels are expressed in diverse tissues and their function is vital for numerous physiological processes, in particular of neurons and muscle cells. Potentially reversible oxidative regulation of voltage-gated K+ channels by reactive species such as reactive oxygen species (ROS) represents a contributing mechanism of normal cellular plasticity and may play important roles in diverse pathologies including neurodegenerative diseases. RECENT ADVANCES Studies using various protocols of oxidative modification, site-directed mutagenesis, and structural and kinetic modeling provide a broader phenomenology and emerging mechanistic insights. CRITICAL ISSUES Physicochemical mechanisms of the functional consequences of oxidative modifications of voltage-gated K+ channels are only beginning to be revealed. In vivo documentation of oxidative modifications of specific amino-acid residues of various voltage-gated K+ channel proteins, including the target specificity issue, is largely absent. FUTURE DIRECTIONS High-resolution chemical and proteomic analysis of ion channel proteins with respect to oxidative modification combined with ongoing studies on channel structure and function will provide a better understanding of how the function of voltage-gated K+ channels is tuned by ROS and the corresponding reducing enzymes to meet cellular needs.
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Affiliation(s)
- Nirakar Sahoo
- 1 Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital , Jena, Germany
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23
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Zhu Q, Huo X, Heinemann SH, Schönherr R, El-Mergawy R, Scriba GKE. Experimental design-guided development of a stereospecific capillary electrophoresis assay for methionine sulfoxide reductase enzymes using a diastereomeric pentapeptide substrate. J Chromatogr A 2014; 1359:224-9. [PMID: 25064531 DOI: 10.1016/j.chroma.2014.07.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 06/16/2014] [Accepted: 07/06/2014] [Indexed: 02/05/2023]
Abstract
A capillary electrophoresis method has been developed and validated to evaluate the stereospecific activity of recombinant human methionine sulfoxide reductase enzymes employing the C-terminally dinitrophenyl-labeled N-acetylated pentapeptide ac-KIFM(O)K-Dnp as substrate (M(O)=methionine sulfoxide). The separation of the ac-KIFM(O)K-Dnp diastereomers and the reduced peptide ac-KIFMK-Dnp was optimized using experimental design with regard to the buffer pH, buffer concentration, sulfated β-cyclodextrin and 15-crown-5 concentration as well as capillary temperature and separation voltage. A fractional factorial response IV design was employed for the identification of the significant factors and a five-level circumscribed central composite design for the final method optimization. Resolution of the peptide diastereomers as well as analyte migration time served as responses in both designs. The resulting optimized conditions included 50mM Tris buffer, pH 7.85, containing 5mM 15-crown-5 and 14.3mg/mL sulfated β-cyclodextrin, at an applied voltage of 25kV and a capillary temperature of 21.5°C. The assay was subsequently applied to the determination of the stereospecificity of recombinant human methionine sulfoxide reductases A and B2. The Michaelis-Menten kinetic data were determined. The pentapeptide proved to be a good substrate for both enzymes. Furthermore, the first separation of methionine sulfoxide peptide diastereomers is reported.
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Affiliation(s)
- Qingfu Zhu
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany
| | - Xingyu Huo
- School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, PR China
| | - Stefan H Heinemann
- Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Roland Schönherr
- Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Rabab El-Mergawy
- Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Gerhard K E Scriba
- Department of Pharmaceutical Chemistry, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany.
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Vandermarliere E, Ghesquière B, Jonckheere V, Gevaert K, Martens L. Unraveling the specificities of the different human methionine sulfoxide reductases. Proteomics 2014; 14:1990-8. [PMID: 24737740 DOI: 10.1002/pmic.201300357] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 02/04/2014] [Accepted: 04/08/2014] [Indexed: 01/11/2023]
Abstract
The oxidation of free and protein-bound methionine into methionine sulfoxide is a frequently occurring modification caused by ROS. Most organisms express methionine sulfoxide reductases (MSR enzymes) to repair this potentially damaging modification. Humans express three different MSRB enzymes which reside in different cellular compartments. In this study, we have explored the specificity of the human MSRB enzymes both by in silico modeling and by experiments on oxidized peptides. We found that MSRB1 is the least specific MSRB enzyme, which is in agreement with the observation that MSRB1 is the only MSRB enzyme found in the cytosol and the nucleus, and therefore requires a broad specificity to reduce all possible substrates. MSRB2 and MSRB3, which are both found in mitochondria, are more specific but because of their co-occurrence they can likely repair all possible substrates.
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Affiliation(s)
- Elien Vandermarliere
- Department of Medical Protein Research, VIB, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium
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Influence of DMF-induced oxidative stress on membrane and periplasmic proteins in Paracoccus sp. SKG. Appl Biochem Biotechnol 2014; 173:1263-73. [PMID: 24789337 DOI: 10.1007/s12010-014-0930-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/21/2014] [Indexed: 10/25/2022]
Abstract
The present study describes the N,N-dimethylformamide (DMF)-induced oxidative stress in Paracoccus sp. SKG. The oxidative stress was evaluated by analysing membrane and periplasmic proteins and K+ efflux, as well as by monitoring the activities of antioxidant enzymes like catalase, superoxide dismutase (SOD) and glutathione S-transferase (GST). The exposure of bacterial cells to a higher concentration of DMF resulted in the modification of membrane fatty acid composition which is accompanied by K+ efflux. Further, this oxidative stress resulted in increased periplasmic protein which can be attributed to the induction of GST and methionine sulphoxide reductase (Msr) enzymes under solvent stress. Paracoccus sp. SKG is tolerant to high concentrations of DMF up to 6% (v/v) and its toxic effects. DMF concentration-dependent induction of GST and Msr activities advocates the significant role of these enzymes in the bacterial defence system. The present study provides information which helps us to understand the ROS scavenging machinery in bacteria. The high tolerance of Paracoccus sp. SKG to DMF can be efficiently explored for various bioremediation and biotransformation applications.
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Stereospecific electrophoretically mediated microanalysis assay for methionine sulfoxide reductase enzymes. Anal Bioanal Chem 2014; 406:1723-9. [DOI: 10.1007/s00216-013-7596-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 12/14/2013] [Accepted: 12/19/2013] [Indexed: 12/19/2022]
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Drazic A, Winter J. The physiological role of reversible methionine oxidation. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2014; 1844:1367-82. [PMID: 24418392 DOI: 10.1016/j.bbapap.2014.01.001] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 12/17/2013] [Accepted: 01/02/2014] [Indexed: 01/04/2023]
Abstract
Sulfur-containing amino acids such as cysteine and methionine are particularly vulnerable to oxidation. Oxidation of cysteine and methionine in their free amino acid form renders them unavailable for metabolic processes while their oxidation in the protein-bound state is a common post-translational modification in all organisms and usually alters the function of the protein. In the majority of cases, oxidation causes inactivation of proteins. Yet, an increasing number of examples have been described where reversible cysteine oxidation is part of a sophisticated mechanism to control protein function based on the redox state of the protein. While for methionine the dogma is still that its oxidation inhibits protein function, reversible methionine oxidation is now being recognized as a powerful means of triggering protein activity. This mode of regulation involves oxidation of methionine to methionine sulfoxide leading to activated protein function, and inactivation is accomplished by reduction of methionine sulfoxide back to methionine catalyzed by methionine sulfoxide reductases. Given the similarity to thiol-based redox-regulation of protein function, methionine oxidation is now established as a novel mode of redox-regulation of protein function. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
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Affiliation(s)
- Adrian Drazic
- Center for Integrated Protein Science Munich (CiPS(M)) at the Department Chemie, Technische Universität München, 85747 Garching, Germany
| | - Jeannette Winter
- Center for Integrated Protein Science Munich (CiPS(M)) at the Department Chemie, Technische Universität München, 85747 Garching, Germany.
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Kim HY. The methionine sulfoxide reduction system: selenium utilization and methionine sulfoxide reductase enzymes and their functions. Antioxid Redox Signal 2013; 19. [PMID: 23198996 PMCID: PMC3763222 DOI: 10.1089/ars.2012.5081] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Selenium is utilized in the methionine sulfoxide reduction system that occurs in most organisms. Methionine sulfoxide reductases (Msrs), MsrA and MsrB, are the enzymes responsible for this system. Msrs repair oxidatively damaged proteins, protect against oxidative stress, and regulate protein function, and have also been implicated in the aging process. Selenoprotein forms of Msrs containing selenocysteine (Sec) at the catalytic site are found in bacteria, algae, and animals. RECENT ADVANCES A selenoprotein MsrB1 knockout mouse has been developed. Significant progress in the biochemistry of Msrs has been made, which includes findings of a novel reducing system for Msrs and of an interesting reason for the use of Sec in the Msr system. The effects of mammalian MsrBs, including selenoprotein MsrB1 on fruit fly aging, have been investigated. Furthermore, it is evident that Msrs are involved in methionine metabolism and regulation of the trans-sulfuration pathway. CRITICAL ISSUES This article presents recent progress in the Msr field while focusing on the physiological roles of mammalian Msrs, functions of selenoprotein forms of Msrs, and their biochemistry. FUTURE DIRECTIONS A deeper understanding of the roles of Msrs in redox signaling, the aging process, and metabolism will be achieved. The identity of selenoproteome of Msrs will be sought along with characterization of the identified selenoprotein forms. Exploring new cellular targets and new functions of Msrs is also warranted.
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Affiliation(s)
- Hwa-Young Kim
- Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
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Tong W, Zhang Y, Wang H, Li F, Liu Z, Wang Y, Fang R, Zhao W, Li L. Mulberry (Morus L.) methionine sulfoxide reductase gene cloning, sequence analysis, and expression in plant development and stress response. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2013. [DOI: 10.1134/s1068162013050154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Zhu Q, El-Mergawy RG, Heinemann SH, Schönherr R, Jáč P, Scriba GKE. Stereospecific micellar electrokinetic chromatography assay of methionine sulfoxide reductase activity employing a multiple layer coated capillary. Electrophoresis 2013; 34:2712-7. [DOI: 10.1002/elps.201300147] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 04/18/2013] [Accepted: 04/20/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Qingfu Zhu
- Department of Pharmaceutical Chemistry; Friedrich Schiller University Jena; Jena; Germany
| | - Rabab G. El-Mergawy
- Department of Biophysics; Friedrich Schiller University Jena and Jena University Hospital; Jena; Germany
| | - Stefan H. Heinemann
- Department of Biophysics; Friedrich Schiller University Jena and Jena University Hospital; Jena; Germany
| | - Roland Schönherr
- Department of Biophysics; Friedrich Schiller University Jena and Jena University Hospital; Jena; Germany
| | - Pavel Jáč
- Department of Pharmaceutical Chemistry; Friedrich Schiller University Jena; Jena; Germany
| | - Gerhard K. E. Scriba
- Department of Pharmaceutical Chemistry; Friedrich Schiller University Jena; Jena; Germany
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Hansel A, Jung S, Hoshi T, Heinemann SH. A second human methionine sulfoxide reductase (hMSRB2) reducing methionine-R-sulfoxide displays a tissue expression pattern distinct from hMSRB1. Redox Rep 2013; 8:384-8. [PMID: 14980072 DOI: 10.1179/135100003225003429] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Peptide methionine sulfoxide reductases are important enzymes in the defense against cellular oxidative stress as they reduce methionine sulfoxide, the product of methionine oxidation by physiologically relevant reactive oxygen species. Two distinct enzyme classes, MSRA and MSRB, have evolved for selectively reducing the two epimers, methionine-S-sulfoxide and methionine-R-sulfoxide. A new human MSR enzyme (hMSRB2) specifically reducing methionine-R-sulfoxide, which showed a conversion rate for peptide-bound methionine-S-sulfoxide similar to hMSRB1, was characterized with respect to its tissue expression. As previously found for hMSRB1, expression of hMSRB2 mRNA was weak in brain, but strong in heart and skeletal muscle. In contrast to hMSRB1, its expression was high in smooth muscle-containing organs (digestive system, bladder), lung and aorta, while hMSRB1 displayed a higher expression than hMSRB2 in liver and kidney.
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Affiliation(s)
- Alfred Hansel
- Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Jena, Germany
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32
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Schroeder I, Gazzarrini S, Ferrara G, Thiel G, Hansen UP, Moroni A. Creation of a reactive oxygen species-insensitive Kcv channel. Biochemistry 2013; 52:3130-7. [PMID: 23578303 DOI: 10.1021/bi3016197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The current of the minimal viral K(+) channel Kcv(PCBV-1) heterologously expressed in Xenopus oocytes is strongly inhibited by reactive oxygen species (ROS) like H(2)O(2). Possible targets for the ROS effect are two cysteines (C53 and C79) and four methionines (M1, M15, M23, and M26). The C53A/C79A and M23L/M26L double mutations maintained the same ROS sensitivity as the wild type. However, M15L as a single mutant or in combination with C53A/C79A and/or M23L/M26L caused a complete loss of sensitivity to H(2)O(2). These results indicate a prominent role of M15 at the cytosolic end of the outer transmembrane helix for gating of Kcv(PCBV-1). Furthermore, even though the channel lacks a canonical voltage sensor, it exhibits a weak voltage sensitivity, resulting in a slight activation in the millisecond range after a voltage step to negative potentials. The M15L mutation inverts this kinetics into an inactivation, underlining the critical role of this residue for gating. The negative slope of the I-V curves of M15L is the same as in the wild type, indicating that the selectivity filter is not involved.
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Affiliation(s)
- Indra Schroeder
- Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
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Kim JH, Lee MJ, Hwang I, Hwang HJ. In-cell protease assay systems based on trans-localizing molecular beacon proteins using HCV protease as a model system. PLoS One 2013; 8:e59710. [PMID: 23555756 PMCID: PMC3605327 DOI: 10.1371/journal.pone.0059710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 02/17/2013] [Indexed: 11/30/2022] Open
Abstract
This study describes a sensitive in-cell protease detection system that enables direct fluorescence detection of a target protease and its inhibition inside living cells. This live-cell imaging system provides a fluorescent molecular beacon protein comprised of an intracellular translocation signal sequence, a protease-specific cleavage sequence, and a fluorescent tag sequence(s). The molecular beacon protein is designed to change its intracellular localization upon cleavage by a target protease, i.e., from the cytosol to a subcellular organelle or from a subcellular organelle to the cytosol. Protease activity can be monitored at the single cell level, and accordingly the entire cell population expressing the protease can be accurately enumerated. The clear cellular change in fluorescence pattern makes this system an ideal tool for various life science and drug discovery research, including high throughput and high content screening applications.
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Affiliation(s)
- Jeong Hee Kim
- Department of Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul, Korea
- * E-mail: (JHK); (HJH)
| | - Min Jun Lee
- Department of Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul, Korea
- R&D Center, Ahram Biosystems Inc., Seoul, Korea
| | - Inhwan Hwang
- Department of Life Science, POSTECH, Pohang, Korea
| | - Hyun Jin Hwang
- R&D Center, Ahram Biosystems Inc., Seoul, Korea
- * E-mail: (JHK); (HJH)
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Chondrogianni N, Petropoulos I, Grimm S, Georgila K, Catalgol B, Friguet B, Grune T, Gonos ES. Protein damage, repair and proteolysis. Mol Aspects Med 2012; 35:1-71. [PMID: 23107776 DOI: 10.1016/j.mam.2012.09.001] [Citation(s) in RCA: 179] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 09/26/2012] [Indexed: 01/10/2023]
Abstract
Proteins are continuously affected by various intrinsic and extrinsic factors. Damaged proteins influence several intracellular pathways and result in different disorders and diseases. Aggregation of damaged proteins depends on the balance between their generation and their reversal or elimination by protein repair systems and degradation, respectively. With regard to protein repair, only few repair mechanisms have been evidenced including the reduction of methionine sulfoxide residues by the methionine sulfoxide reductases, the conversion of isoaspartyl residues to L-aspartate by L-isoaspartate methyl transferase and deglycation by phosphorylation of protein-bound fructosamine by fructosamine-3-kinase. Protein degradation is orchestrated by two major proteolytic systems, namely the lysosome and the proteasome. Alteration of the function for both systems has been involved in all aspects of cellular metabolic networks linked to either normal or pathological processes. Given the importance of protein repair and degradation, great effort has recently been made regarding the modulation of these systems in various physiological conditions such as aging, as well as in diseases. Genetic modulation has produced promising results in the area of protein repair enzymes but there are not yet any identified potent inhibitors, and, to our knowledge, only one activating compound has been reported so far. In contrast, different drugs as well as natural compounds that interfere with proteolysis have been identified and/or developed resulting in homeostatic maintenance and/or the delay of disease progression.
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Affiliation(s)
- Niki Chondrogianni
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Helenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece.
| | - Isabelle Petropoulos
- Laboratoire de Biologie Cellulaire du Vieillissement, UR4-UPMC, IFR 83, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France
| | - Stefanie Grimm
- Department of Nutritional Toxicology, Institute of Nutrition, Friedrich-Schiller University, Dornburger Straße 24, 07743 Jena, Germany
| | - Konstantina Georgila
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Helenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece
| | - Betul Catalgol
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center (GEMHAM), Marmara University, Haydarpasa, Istanbul, Turkey
| | - Bertrand Friguet
- Laboratoire de Biologie Cellulaire du Vieillissement, UR4-UPMC, IFR 83, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France
| | - Tilman Grune
- Department of Nutritional Toxicology, Institute of Nutrition, Friedrich-Schiller University, Dornburger Straße 24, 07743 Jena, Germany
| | - Efstathios S Gonos
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Helenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece.
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Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG, Moskovitz J, Knowles MR, Durie PR, Drumm ML, Cutting GR. Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. PLoS Genet 2012; 8:e1002580. [PMID: 22438829 PMCID: PMC3305406 DOI: 10.1371/journal.pgen.1002580] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2011] [Accepted: 01/19/2012] [Indexed: 12/23/2022] Open
Abstract
Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5' to and within the MSRA gene were associated with MI (P = 1.99 × 10(-5) to 1.08 × 10(-6); Bonferroni P = 0.057 to 3.1 × 10(-3)). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53-0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2 × 10(-4)). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr(-/-) and Cftr(-/-)Msra(-/-) mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
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Affiliation(s)
- Lindsay B. Henderson
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Vishal K. Doshi
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Scott M. Blackman
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Kathleen M. Naughton
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Rhonda G. Pace
- Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Jackob Moskovitz
- Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, United States of America
| | - Michael R. Knowles
- Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Peter R. Durie
- Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, Canada
- Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Mitchell L. Drumm
- Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Garry R. Cutting
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- * E-mail:
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Erickson JR, He BJ, Grumbach IM, Anderson ME. CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 2011; 91:889-915. [PMID: 21742790 DOI: 10.1152/physrev.00018.2010] [Citation(s) in RCA: 183] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca(2+)/CaM). Under conditions of sustained exposure to elevated Ca(2+)/CaM, CaMKII transitions into a Ca(2+)/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine-287 in the CaMKII regulatory domain "traps" CaMKII into an open configuration even after Ca(2+)/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca(2+)/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease.
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Affiliation(s)
- Jeffrey R Erickson
- Department of Pharmacology, University of California at Davis, Davis, California 95616, USA.
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Sreekumar PG, Hinton DR, Kannan R. Methionine sulfoxide reductase A: Structure, function and role in ocular pathology. World J Biol Chem 2011; 2:184-92. [PMID: 21909460 PMCID: PMC3163237 DOI: 10.4331/wjbc.v2.i8.184] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 07/27/2011] [Accepted: 08/03/2011] [Indexed: 02/05/2023] Open
Abstract
Methionine is a highly susceptible amino acid that can be oxidized to S and R diastereomeric forms of methionine sulfoxide by many of the reactive oxygen species generated in biological systems. Methionine sulfoxide reductases (Msrs) are thioredoxin-linked enzymes involved in the enzymatic conversion of methionine sulfoxide to methionine. Although MsrA and MsrB have the same function of methionine reduction, they differ in substrate specificity, active site composition, subcellular localization, and evolution. MsrA has been localized in different ocular regions and is abundantly expressed in the retina and in retinal pigment epithelial (RPE) cells. MsrA protects cells from oxidative stress. Overexpression of MsrA increases resistance to cell death, while silencing or knocking down MsrA decreases cell survival; events that are mediated by mitochondria. MsrA participates in protein-protein interaction with several other cellular proteins. The interaction of MsrA with α-crystallins is of utmost importance given the known functions of the latter in protein folding, neuroprotection, and cell survival. Oxidation of methionine residues in α-crystallins results in loss of chaperone function and possibly its antiapoptotic properties. Recent work from our laboratory has shown that MsrA is co-localized with αA and αB crystallins in the retinal samples of patients with age-related macular degeneration. We have also found that chemically induced hypoxia regulates the expression of MsrA and MsrB2 in human RPE cells. Thus, MsrA is a critical enzyme that participates in cell and tissue protection, and its interaction with other proteins/growth factors may provide a target for therapeutic strategies to prevent degenerative diseases.
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Affiliation(s)
- Parameswaran G Sreekumar
- Parameswaran G Sreekumar, David R Hinton, Ram Kannan, Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA 90033, United States
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Ma X, Deng W, Liu X, Li M, Chen Z, He Z, Wang Y, Wang Q, Hu X, Collier DA, Li T. A genome-wide association study for quantitative traits in schizophrenia in China. GENES BRAIN AND BEHAVIOR 2011; 10:734-9. [PMID: 21679298 DOI: 10.1111/j.1601-183x.2011.00712.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Few genome-wide association studies (GWAS) of schizophrenia have included Chinese populations, and verification of positive genetic findings from other ethnic groups is rare in Chinese groups. We used fluid intelligence as the quantitative trait reflecting schizophrenia dysfunction in Chinese populations, and determined the impact of genetic variation on fluid intelligence phenotypic patterns to identify genetic influences in schizophrenia. The study sample comprised 98 patients with schizophrenia and 60 healthy controls. The general fluid intelligence of participants was assessed with Cattell's Culture-Free Intelligence Test (CCFIT). Subjects were genotyped using the Illumina HumanHap 660 beadchip. We identified the methionine sulfoxide reductase A (MSRA) gene on chromosome 8 as having an association with fluid intelligence. However, only CCFIT subtest 1 (series score) demonstrated a significant result for the interaction term using the criteria of the quantitative trait (QT) analysis of 10(-5) for at least three SNPs. There were 15 haplotype blocks of MSRA gene SNPs identified using Haploview 4.2 with solid spine D' > 0.80. The strongest QT interaction was noted in Block 3, with the most common haplotypes being AAACAGCAG and CGCAGAAGA. In conclusion, we report data from a GWAS with quantitative traits design from Chinese first-episode schizophrenia patients and matched controls. Although the gene identified requires confirmation in an independent sample, the MSRA gene located on chromosome 8 was found to be associated with the phenotype of schizophrenia.
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Affiliation(s)
- X Ma
- The Psychiatric Laboratory & The Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China
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Nan C, Li Y, Jean-Charles PY, Chen G, Kreymerman A, Prentice H, Weissbach H, Huang X. Deficiency of methionine sulfoxide reductase A causes cellular dysfunction and mitochondrial damage in cardiac myocytes under physical and oxidative stresses. Biochem Biophys Res Commun 2010; 402:608-13. [DOI: 10.1016/j.bbrc.2010.10.064] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 10/17/2010] [Indexed: 01/18/2023]
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40
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Methionine sulfoxide reductase A down-regulation in human breast cancer cells results in a more aggressive phenotype. Proc Natl Acad Sci U S A 2010; 107:18628-33. [PMID: 20937881 DOI: 10.1073/pnas.1010171107] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is one of the most frequent of human malignancies, and it is therefore fundamental to identify the underlying molecular mechanisms leading to cancer transformation. Among other causative agents in the development of breast cancers, an important role for reactive oxygen species (ROS) has emerged. However, most studies on the role of ROS in cancer have not reached specific conclusions, and many issues remain controversial. In the present study, we show that methionine sulfoxide reductase A (MsrA), which is known to protect proteins from oxidation and which acts as a ROS scavenger, is down-regulated in a number of breast cancers. Moreover, levels of MsrA correlate with advanced tumor grade. We therefore investigated the functional role of MsrA in breast cancer cells. Our data show that reduction of MsrA levels results in increased cell proliferation and extracellular matrix degradation, and consequently in a more aggressive cellular phenotype, both in vivo and in vitro. We also show that the underlying molecular mechanisms involve increased ROS levels, resulting in reduction of phosphatase and tensin homolog deleted on chromosome ten protein (PTEN), and activation of the phosphoinositide 3-kinase pathway. In addition, MsrA down-regulation results in up-regulation of VEGF, providing additional support for tumor growth in vivo.
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Cao G, Lee KP, van der Wijst J, de Graaf M, van der Kemp A, Bindels RJM, Hoenderop JGJ. Methionine sulfoxide reductase B1 (MsrB1) recovers TRPM6 channel activity during oxidative stress. J Biol Chem 2010; 285:26081-7. [PMID: 20584906 DOI: 10.1074/jbc.m110.103655] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Mg(2+) is an essential ion for many cellular processes, including protein synthesis, nucleic acid stability, and numerous enzymatic reactions. Mg(2+) homeostasis in mammals depends on the equilibrium between intestinal absorption, renal excretion, and exchange with bone. The transient receptor potential melastatin type 6 (TRPM6) is an epithelial Mg(2+) channel, which is abundantly expressed in the luminal membrane of the renal and intestinal cells. It functions as the gatekeeper of transepithelial Mg(2+) transport. Remarkably, TRPM6 combines a Mg(2+)-permeable channel with an alpha-kinase domain. Here, by the Ras recruitment system, we identified methionine sulfoxide reductase B1 (MsrB1) as an interacting protein of the TRPM6 alpha-kinase domain. Importantly, MsrB1 and TRPM6 are both present in the renal Mg(2+)-transporting distal convoluted tubules. MsrB1 has no effect on TRPM6 channel activity in the normoxic conditions. However, hydrogen peroxide (H(2)O(2)) decreased TRPM6 channel activity. Co-expression of MsrB1 with TRPM6 attenuated the inhibitory effect of H(2)O(2) (TRPM6, 67 +/- 5% of control; TRPM6 + MsrB1, 81 +/- 5% of control). Cell surface biotinylation assays showed that H(2)O(2) treatment does not affect the expression of TRPM6 at the plasma membrane. Next, mutation of Met(1755) to Ala in TRPM6 reduced the inhibitory effect of H(2)O(2) on TRPM6 channel activity (TRPM6 M1755A: 84 +/- 10% of control), thereby mimicking the action of MsrB1. Thus, these data suggest that MsrB1 recovers TRPM6 channel activity by reducing the oxidation of Met(1755) and could, thereby, function as a modulator of TRPM6 during oxidative stress.
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Affiliation(s)
- Gang Cao
- Department of Physiology, Radboud University Nijmegen Medical Centre, HB Nijmegen, The Netherlands
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42
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Ogawa F, Shimizu K, Hara T, Muroi E, Komura K, Takenaka M, Hasegawa M, Fujimoto M, Takehara K, Sato S. Autoantibody against one of the antioxidant repair enzymes, methionine sulfoxide reductase A, in systemic sclerosis: association with pulmonary fibrosis and vascular damage. Arch Dermatol Res 2009; 302:27-35. [PMID: 19844733 DOI: 10.1007/s00403-009-0996-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 08/14/2009] [Accepted: 10/05/2009] [Indexed: 11/28/2022]
Abstract
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis and vascular changes in the skin and internal organs with autoimmune background. It has been suggested that oxidative stress plays an important role in the development of SSc. To determine the prevalence and clinical correlation of autoantibody to methionine sulfoxide reductase A (MSRA), one of the antioxidant repair enzymes, in SSc, serum anti-MSRA autoantibody levels were examined in patients with SSc by enzyme-linked immunosorbent assay using recombinant MSRA. The presence of anti-MSRA antibody was evaluated by immunoblotting. To determine the functional relevance of anti-MSRA antibody in vivo, we assessed whether anti-MSRA antibody was able to inhibit MSRA enzymatic activity. Serum anti-MSRA antibody levels in SSc patients were significantly higher compared to controls and this autoantibody was detected in 33% of SSc patients. Serum anti-MSRA levels were significantly elevated in SSc patients with pulmonary fibrosis, cardiac involvement, or decreased total antioxidant power compared with those without them. Anti-MSRA antibodies also correlated positively with renal vascular damage determined as pulsatility index by color-flow Doppler ultrasonography of the renal interlobar arteries and negatively with pulmonary function tests. Furthermore, anti-MSRA antibody levels correlated positively with serum levels of 8-isoprostane and heat shock protein 70 that are markers of oxidative and cellular stresses. Remarkably, MSRA activity was inhibited by IgG isolated from SSc sera containing IgG anti-MSRA antibody. These results suggest that elevated anti-MSRA autoantibody is associated with the disease severity of SSc and may enhance the oxidative stress by inhibiting MSRA enzymatic activity.
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Affiliation(s)
- Fumihide Ogawa
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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43
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Walss-Bass C, Soto-Bernardini MC, Johnson-Pais T, Leach RJ, Ontiveros A, Nicolini H, Mendoza R, Jerez A, Dassori A, Chavarria-Siles I, Escamilla MA, Raventos H. Methionine sulfoxide reductase: a novel schizophrenia candidate gene. Am J Med Genet B Neuropsychiatr Genet 2009; 150B:219-25. [PMID: 18506707 PMCID: PMC3781017 DOI: 10.1002/ajmg.b.30791] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential three-marker at risk haplotype within MSRA in the same CVCR sample, with a global P-value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel 4-base pair deletion 1,792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.
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Affiliation(s)
- Consuelo Walss-Bass
- Department of Psychiatry, The University of Texas Health Science Center at San Antonio, USA.
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Karunakaran-Datt A, Kennepohl P. Redox Photochemistry of Methionine by Sulfur K-edge X-ray Absorption Spectroscopy: Potential Implications for Cataract Formation. J Am Chem Soc 2009; 131:3577-82. [DOI: 10.1021/ja806946r] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
| | - Pierre Kennepohl
- The University of British Columbia, Department of Chemistry, Vancouver, BC V6T 1Z1
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Cabreiro F, Picot CR, Perichon M, Friguet B, Petropoulos I. Overexpression of methionine sulfoxide reductases A and B2 protects MOLT-4 cells against zinc-induced oxidative stress. Antioxid Redox Signal 2009; 11:215-25. [PMID: 18715149 DOI: 10.1089/ars.2008.2102] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Among the amino acids, methionine is the most susceptible to oxidation, and methionine sulfoxide can be catalytically reduced within proteins by methionine sulfoxide reductase A (MsrA) and B (MsrB). As one of the very few repair systems for oxidized proteins, MsrA and MsrB enzymes play a major role in protein homeostasis during aging and have also been involved in cellular defenses against oxidative stress, by scavenging reactive oxygen species. To elucidate the role of zinc on the Msr system, the effects of zinc treatment on control and stably overexpressing MsrA and MsrB2 MOLT-4 leukemia cells have been analyzed. Here we show that zinc treatment has a pro-antioxidant effect in MOLT-4 cells by inducing the transcription of metallothioneins and positively modulating the activity of the Msr enzymes. In contrast, due to its pro-oxidant effect, zinc also led to increased cell death, reactive oxygen species production, and protein damage. Our results indicate that overexpression of the Msr enzymes, due to their antioxidant properties, counteracts the pro-oxidant effects of zinc treatment, which lead to a cellular protection against protein oxidative damage and cell death, by reducing the production of reactive oxygen species.
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Affiliation(s)
- Filipe Cabreiro
- Laboratoire de Biologie et Biochimie Cellulaire du vieillissement, Université Paris-Diderot-Paris, Paris, France
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Pascual I, Larrayoz IM, Rodriguez IR. Retinoic acid regulates the human methionine sulfoxide reductase A (MSRA) gene via two distinct promoters. Genomics 2009; 93:62-71. [PMID: 18845237 PMCID: PMC2645438 DOI: 10.1016/j.ygeno.2008.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Revised: 09/12/2008] [Accepted: 09/16/2008] [Indexed: 01/30/2023]
Abstract
MSRAs (methionine sulfoxide reductases A) are enzymes that reverse the effects of oxidative damage by reducing methionine sulfoxide back to methionine and recovering protein function. In this study we demonstrate that the transcriptional regulation of the human MSRA gene is complex and driven by two distinct promoters. Both promoters demonstrate high expression in human brain and kidney tissues. The upstream (promoter 1) regulates the msrA1 transcript that codes for the mitochondrial form of MSRA and is highly active in a broad range of cell lines. The downstream promoter (promoter 2) regulates the msrA2/3 transcripts that code for the cytosolic/nuclear forms of MSRA and is generally less active. Promoter 2 contains a 65 bp putative enhancer region that is very active in the retinal pigment epithelium-derived D407 cell line. Both promoters are partially regulated by all-trans retinoic acid via RARA and other RARs.
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Affiliation(s)
- Iranzu Pascual
- Laboratory of Retinal cell and Molecular Biology, Mechanisms of Retinal Diseases Section,National Eye Institute, NIH, Bethesda, MD, USA
| | - Ignacio M. Larrayoz
- Laboratory of Retinal cell and Molecular Biology, Mechanisms of Retinal Diseases Section,National Eye Institute, NIH, Bethesda, MD, USA
| | - Ignacio R. Rodriguez
- Laboratory of Retinal cell and Molecular Biology, Mechanisms of Retinal Diseases Section,National Eye Institute, NIH, Bethesda, MD, USA
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Kassmann M, Hansel A, Leipold E, Birkenbeil J, Lu SQ, Hoshi T, Heinemann SH. Oxidation of multiple methionine residues impairs rapid sodium channel inactivation. Pflugers Arch 2008; 456:1085-95. [PMID: 18369661 PMCID: PMC2913308 DOI: 10.1007/s00424-008-0477-6] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2007] [Accepted: 02/16/2008] [Indexed: 12/21/2022]
Abstract
Reactive oxygen species (ROS) readily oxidize the sulfur-containing amino acids cysteine and methionine (Met). The impact of Met oxidation on the fast inactivation of the skeletal muscle sodium channel Na(V)1.4 expressed in mammalian cells was studied by applying the Met-preferring oxidant chloramine-T or by irradiating the ROS-producing dye Lucifer Yellow in the patch pipettes. Both interventions dramatically slowed down inactivation of the sodium channels. Replacement of Met in the Ile-Phe-Met inactivation motif with Leu (M1305L) strongly attenuated the oxidizing effect on inactivation but did not eliminate it completely. Mutagenesis of Met1470 in the putative receptor of the inactivation lid also markedly diminished the oxidation sensitivity of the channel, while that of other conserved Met residues in intracellular linkers connecting the membrane-spanning segments (442, 1139, 1154, 1316, 1469) were of minor importance. The results of mutagenesis, assays of other Na(V) channel isoforms (Na(V)1.2, Na(V)1.5, Na(V)1.7), and the kinetics of the oxidation-induced removal of inactivation collectively indicate that multiple Met residues need to be oxidized to completely impair inactivation. This arrangement using multiple Met residues confers a finely graded oxidative modulation of Na(V) channels and allows organisms to adapt to a variety of oxidative stress conditions, such as ischemic reperfusion.
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Affiliation(s)
- Mario Kassmann
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
| | - Alfred Hansel
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
| | - Enrico Leipold
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
| | - Jan Birkenbeil
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
| | - Song-Qing Lu
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
| | - Toshinori Hoshi
- Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Stefan H. Heinemann
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, D-07745 Jena, Germany
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Binger KJ, Griffin MDW, Howlett GJ. Methionine oxidation inhibits assembly and promotes disassembly of apolipoprotein C-II amyloid fibrils. Biochemistry 2008; 47:10208-17. [PMID: 18729385 DOI: 10.1021/bi8009339] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Methionine residues are linked to the pathogenicity of several amyloid diseases; however, the mechanism of this relationship is largely unknown. These diseases are characterized, in vivo, by the accumulation of insoluble proteinaceous plaques, of which the major constituents are amyloid fibrils. In vitro, methionine oxidation has been shown to modulate fibril assembly in several well-characterized amyloid systems. Human apolipoprotein (apo) C-II contains two methionine residues (Met-9 and Met-60) and readily self-assembles in vitro to form homogeneous amyloid fibrils, thus providing a convenient system to examine the effect of methionine oxidation on amyloid fibril formation and stability. Upon oxidation of the methionine residues of apoC-II with hydrogen peroxide, fibril formation was inhibited. Oxidized apoC-II molecules did not inhibit native apoC-II assembly, indicating that the oxidized molecules had a reduced ability to interact with the growing fibrils. Single Met-Val substitutions were performed and showed that oxidation of Met-60 had a more significant inhibitory effect than oxidation of Met-9. In addition, Met-Gln substitutions designed to mimic the effect of oxidation on side chain hydrophilicity showed that a change in hydrophobicity at position 60 within the core region of the fibril had a potent inhibitory effect. The oxidation of preformed apoC-II fibrils caused their dissociation; however, mutants in which the Met-60 was substituted with a valine were protected from this peroxide-induced dissociation. This work highlights an important role for methionine in the formation of amyloid fibril structure and gives new insight into how oxidation affects the stability of mature fibrils.
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Affiliation(s)
- Katrina J Binger
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
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Cabreiro F, Picot CR, Perichon M, Castel J, Friguet B, Petropoulos I. Overexpression of mitochondrial methionine sulfoxide reductase B2 protects leukemia cells from oxidative stress-induced cell death and protein damage. J Biol Chem 2008; 283:16673-81. [PMID: 18424444 DOI: 10.1074/jbc.m708580200] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
According to the mitochondrial theory of aging, mitochondrial dysfunction increases intracellular reactive oxidative species production, leading to the oxidation of macromolecules and ultimately to cell death. In this study, we investigated the role of the mitochondrial methionine sulfoxide reductase B2 in the protection against oxidative stress. We report, for the first time, that overexpression of methionine sulfoxide reductase B2 in mitochondria of acute T-lymphoblastic leukemia MOLT-4 cell line, in which methionine sulfoxide reductase A is missing, markedly protects against hydrogen peroxide-induced oxidative stress by scavenging reactive oxygen species. The addition of hydrogen peroxide provoked a time-gradual increase of intracellular reactive oxygen species, leading to a loss in mitochondrial membrane potential and to protein carbonyl accumulation, whereas in methionine sulfoxide reductase B2-overexpressing cells, intracellular reactive oxygen species and protein oxidation remained low with the mitochondrial membrane potential highly maintained. Moreover, in these cells, delayed apoptosis was shown by a decrease in the cleavage of the apoptotic marker poly(ADP-ribose) polymerase-1 and by the lower percentage of Annexin-V-positive cells in the late and early apoptotic stages. We also provide evidence for the protective mechanism of methionine sulfoxide reductase B2 against protein oxidative damages. Our results emphasize that upon oxidative stress, the overexpression of methionine sulfoxide reductase B2 leads to the preservation of mitochondrial integrity by decreasing the intracellular reactive oxygen species build-up through its scavenging role, hence contributing to cell survival and protein maintenance.
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Affiliation(s)
- Filipe Cabreiro
- Laboratoire de Biologie et Biochimie Cellulaire du Vieillissement, EA 3106, Université Paris Diderot-Paris 7, 2 Place Jussieu, 75251 Paris Cedex 05, France
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50
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Methionine sulfoxide reductase A and a dietary supplement S-methyl-L-cysteine prevent Parkinson's-like symptoms. J Neurosci 2007; 27:12808-16. [PMID: 18032652 DOI: 10.1523/jneurosci.0322-07.2007] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Parkinson's disease (PD), a common neurodegenerative disease, is caused by loss of dopaminergic neurons in the substantia nigra. Although the underlying cause of the neuronal loss is unknown, oxidative stress is thought to play a major role in the pathogenesis of PD. The amino acid methionine is readily oxidized to methionine sulfoxide, and its reduction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs). The reversible oxidation-reduction cycle of methionine involving MSRs has been postulated to act as a catalytic antioxidant system protecting cells from oxidative damage. Here, we show that one member of the MSR family, MSRA, inhibits development of the locomotor and circadian rhythm defects caused by ectopic expression of human alpha-synuclein in the Drosophila nervous system. Furthermore, we demonstrate that one way to enhance the MSRA antioxidant system is dietary supplementation with S-methyl-L-cysteine (SMLC), found abundantly in garlic, cabbage, and turnips. SMLC, a substrate in the catalytic antioxidant system mediated by MSRA, prevents the alpha-synuclein-induced abnormalities. Therefore, interventions focusing on the enzymatic reduction of oxidized methionine catalyzed by MSRA represent a new prevention and therapeutic approach for PD and potentially for other neurodegenerative diseases involving oxidative stress.
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