المؤلفون: Zhang Q; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China; Key Laboratory of Brain Science, Key Laboratory of Anesthesia and Organ Protection of Ministry of Education, Zunyi Medical University, Zunyi 563000, Guizhou, China., Pan B; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Yang P; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Tian J; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Zhou S; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Xu X; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Dai Y; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Cheng X; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China., Chen Y; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, Guizhou, China., Yang J; Department of Biochemistry, School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, Guizhou, China. Electronic address: yangjw@zmu.edu.cn.

المصدر: International journal of biological macromolecules [Int J Biol Macromol] 2024 Mar; Vol. 260 (Pt 1), pp. 129540. Date of Electronic Publication: 2024 Jan 19.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/genetics , Methionine Sulfoxide Reductases*/analysis , Methionine Sulfoxide Reductases*/chemistry , Sulfoxides*/chemistry, Methionine

مستخلص: Methionine sulfoxide reductase A (MsrA) has emerged as promising biocatalysts in the enantioselective kinetic resolution of racemic (rac) sulfoxides. In this study, we engineered robust MsrA variants through directed evolution, demonstrating substantial improvements of thermostability. Mechanism analysis reveals that the enhanced thermostability results from the strengthening of intracellular interactions and increase in molecular compactness. Moreover, these variants demonstrated concurrent improvements in catalytic activities, and notably, these enhancements in stability and activity collectively contributed to a significant improvement in enzyme substrate tolerance. We achieved kinetic resolution on a series of rac-sulfoxides with high enantioselectivity under initial substrate concentrations reaching up to 93.0 g/L, representing a great improvement in the aspect of the substrate concentration for biocatalytic preparation of chiral sulfoxide. Hence, the simultaneously improved thermostability, activity and substrate tolerance of MsrA represent an excellent biocatalyst for the green synthesis of optically pure sulfoxides.
Competing Interests: Declaration of competing interest The authors confirm that they have no conflicts of interest with respect to the work described in this manuscript.
(Copyright © 2024 Elsevier B.V. All rights reserved.)

المؤلفون: Tian J; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Zhou S; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Chen Y; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Zhao Y; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Li S; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Yang P; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Xu X; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Chen Y; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Cheng X; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China., Yang J; Department of Biochemistry, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China.; Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi City, Guizhou Province, P. R. China.

المصدر: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Apr 02; Vol. 30 (19), pp. e202304081. Date of Electronic Publication: 2024 Feb 15.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 9513783 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3765 (Electronic) Linking ISSN: 09476539 NLM ISO Abbreviation: Chemistry Subsets: MEDLINE

مواضيع طبية MeSH: Sulfoxides* , Methionine Sulfoxide Reductases*, Biocatalysis ; Oxidation-Reduction ; Catalysis ; Stereoisomerism

مستخلص: Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating "non-selective oxidation and selective reduction" cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this "one-pot, one step" cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess (ee) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.
(© 2024 Wiley‐VCH GmbH.)

المؤلفون: Das J; National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India., Ghosh S; National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India.; Department of Biosciences, Durham University, Durham, UK., Tyagi K; National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India., Sahoo D; National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India., Jha G; National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi, India.

المصدر: Microbial biotechnology [Microb Biotechnol] 2024 Apr; Vol. 17 (4), pp. e14441.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101316335 Publication Model: Print Cited Medium: Internet ISSN: 1751-7915 (Electronic) Linking ISSN: 17517915 NLM ISO Abbreviation: Microb Biotechnol Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases* , Oryza*/microbiology , Rhizoctonia*, Methionine ; Hydrogen Peroxide/pharmacology ; Racemethionine/pharmacology ; Plant Diseases/microbiology

مستخلص: Rhizoctonia solani is a polyphagous necrotrophic fungal pathogen that causes sheath blight disease in rice. It deploys effector molecules as well as carbohydrate-active enzymes and enhances the production of reactive oxygen species for killing host tissues. Understanding R. solani ability to sustain growth under an oxidative-stress-enriched environment is important for developing disease control strategies. Here, we demonstrate that R. solani upregulates methionine biosynthetic genes, including Rs_MET13 during infection in rice, and double-stranded RNA-mediated silencing of these genes impairs the pathogen's ability to cause disease. Exogenous treatment with methionine restores the disease-causing ability of Rs_MET13-silenced R. solani and facilitates its growth on 10 mM H 2 O 2 -containing minimal-media. Notably, the Rs_MsrA gene that encodes methionine sulfoxide reductase A, an antioxidant enzyme involved in the repair of oxidative damage of methionine, is upregulated upon H 2 O 2 treatment and also during infection in rice. Rs_MsrA-silenced R. solani is unable to cause disease, suggesting that it is important for the repair of oxidative damage in methionine during host colonization. We propose that spray-induced gene silencing of Rs_MsrA and designing of antagonistic molecules that block MsrA activity can be exploited as a drug target for effective control of sheath blight disease in rice.
(© 2024 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd.)

SCR Organism: Rhizoctonia solani

المؤلفون: Milovanovic V; University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia. Electronic address: milovanovic.vera.mrph@gmail.com., Topic A; University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia., Milinkovic N; University of Belgrade-Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia., Lazic Z; University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia., Ivosevic A; University of Kragujevac, Faculty of Medical Sciences, Kragujevac, Serbia., Radojkovic D; Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia., Rankov AD; Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.

المصدر: Pulmonology [Pulmonology] 2024 Mar-Apr; Vol. 30 (2), pp. 122-129. Date of Electronic Publication: 2021 Oct 18.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier España Country of Publication: Spain NLM ID: 101723786 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2531-0437 (Electronic) Linking ISSN: 25310429 NLM ISO Abbreviation: Pulmonology Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/genetics , Pulmonary Disease, Chronic Obstructive*/genetics, Adult ; Humans ; Oxidative Stress ; Pancreatic Elastase/genetics ; Polymorphism, Genetic

مستخلص: 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.
Competing Interests: Declaration of interest The authors declare that there are no conflicts of interest.
(Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

المؤلفون: Sastre S; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Departamento de Biofísica, Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Programa de Doctorado en Química, Facultad de Química, Universidad de la República, Gral Flores 2124, CP 11800 Montevideo, Uruguay., Manta B; Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay.; Cátedra de Fisiopatología, Facultad de Odontología, Universidad de la República, Gral Las Heras 1925, CP 11600 Montevideo, Uruguay., Semelak JA; Departamento de Química Inorgánica, Analítica y Química Física, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and CONICET, Ciudad Universitaria, Intendente Güiraldes 2160, CP C1428EGA Buenos Aires, Argentina., Estrin D; Departamento de Química Inorgánica, Analítica y Química Física, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and CONICET, Ciudad Universitaria, Intendente Güiraldes 2160, CP C1428EGA Buenos Aires, Argentina., Trujillo M; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay., Radi R; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay., Zeida A; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.; Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Gral Flores 2125, CP 11800 Montevideo, Uruguay.

المصدر: Biochemistry [Biochemistry] 2024 Feb 20; Vol. 63 (4), pp. 533-544. Date of Electronic Publication: 2024 Jan 29.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/metabolism , Mycobacterium tuberculosis*/metabolism, Oxidation-Reduction ; Catalysis ; Oxidative Stress ; Methionine/metabolism

مستخلص: The oxidation of Met to methionine sulfoxide (MetSO) by oxidants such as hydrogen peroxide, hypochlorite, or peroxynitrite has profound effects on protein function. This modification can be reversed by methionine sulfoxide reductases (msr). In the context of pathogen infection, the reduction of oxidized proteins gains significance due to microbial oxidative damage generated by the immune system. For example, Mycobacterium tuberculosis ( Mt ) utilizes msrs ( Mt msrA and Mt msrB) as part of the repair response to the host-induced oxidative stress. The absence of these enzymes makes Mycobacteria prone to increased susceptibility to cell death, pointing them out as potential therapeutic targets. This study provides a detailed characterization of the catalytic mechanism of Mt msrA using a comprehensive approach, including experimental techniques and theoretical methodologies. Confirming a ping-pong type enzymatic mechanism, we elucidate the catalytic parameters for sulfoxide and thioredoxin substrates ( k cat / K M = 2656 ± 525 M ^-1 s ^-1 and 1.7 ± 0.8 × 10 ⁶ M ^-1 s ^-1 , respectively). Notably, the entropic nature of the activation process thermodynamics, representing ∼85% of the activation free energy at room temperature, is underscored. Furthermore, the current study questions the plausibility of a sulfurane intermediate, which may be a transition-state-like structure, suggesting the involvement of a conserved histidine residue as an acid-base catalyst in the MetSO reduction mechanism. This mechanistic insight not only advances our understanding of Mt antioxidant enzymes but also holds implications for future drug discovery and biotechnological applications.

المؤلفون: Sahoo R; Division of Biochemistry, ICAR-IVRI, Izatnagar, 243122, India., Chauhan TKS; Division of Biochemistry, ICAR-IVRI, Izatnagar, 243122, India., Lalhmangaihzuali L; Division of Biochemistry, ICAR-IVRI, Izatnagar, 243122, India., Sinha E; Division of Biological Standardization, ICAR-IVRI, Izatnagar, 243122, India., Qureshi S; Division of Biological Standardization, ICAR-IVRI, Izatnagar, 243122, India., Mahawar M; Division of Biochemistry, ICAR-IVRI, Izatnagar, 243122, India. manish.mahawar@icar.gov.in.

المصدر: Scientific reports [Sci Rep] 2023 Dec 09; Vol. 13 (1), pp. 21852. Date of Electronic Publication: 2023 Dec 09.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/genetics , Methionine Sulfoxide Reductases*/metabolism , Oxidative Stress* , Salmonella typhimurium*/genetics, Animals ; Mice ; Antioxidants/metabolism ; Oxidants ; Virulence/genetics

مستخلص: Salmonella encounters but survives host inflammatory response. To defend host-generated oxidants, Salmonella encodes primary antioxidants and protein repair enzymes. Methionine (Met) residues are highly prone to oxidation and convert into methionine sulfoxide (Met-SO) which compromises protein functions and subsequently cellular survival. However, by reducing Met-SO to Met, methionine sulfoxide reductases (Msrs) enhance cellular survival under stress conditions. Salmonella encodes five Msrs which are specific for particular Met-SO (free/protein bound), and 'R'/'S' types. Earlier studies assessed the effect of deletions of one or two msrs on the stress physiology of S. Typhimurium. We generated a pan msr gene deletion (Δ5msr) strain in S. Typhimurium. The Δ5msr mutant strain shows an initial lag in in vitro growth. However, the Δ5msr mutant strain depicts very high sensitivity (p < 0.0001) to hypochlorous acid (HOCl), chloramine T (ChT) and superoxide-generating oxidant paraquat. Further, the Δ5msr mutant strain shows high levels of malondialdehyde (MDA), protein carbonyls, and protein aggregation. On the other side, the Δ5msr mutant strain exhibits lower levels of free amines. Further, the Δ5msr mutant strain is highly susceptible to neutrophils and shows defective fitness in the spleen and liver of mice. The results of the current study suggest that the deletions of all msrs render S. Typhimurium highly prone to oxidative stress and attenuate its virulence.
(© 2023. The Author(s).)

المؤلفون: Park S; Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Trujillo-Hernandez JA; Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Levine RL; Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

المصدر: Redox report : communications in free radical research [Redox Rep] 2023 Dec; Vol. 28 (1), pp. 2168635.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Taylor & Francis Country of Publication: England NLM ID: 9511366 Publication Model: Print Cited Medium: Internet ISSN: 1743-2928 (Electronic) Linking ISSN: 13510002 NLM ISO Abbreviation: Redox Rep Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/metabolism , Proteomics*, Humans ; HEK293 Cells ; Oxidative Stress ; Methionine/metabolism ; Molecular Chaperones/metabolism ; Mitochondrial Proteins/metabolism

مستخلص: Background: Methionine sulfoxide reductases are found in all aerobic organisms. They function in antioxidant defense, cellular regulation by reversible oxidation of methionine in proteins, and in protein structure. However, very few in vivo binding partners or substrates of the reductases have been identified.
Methods: We implemented a proximity labeling method, TurboID, to covalently link mitochondrial methionine sulfoxide reductase A (MSRA) to its binding partners in HEK293 cells. Proteomic analyses were performed to identify putative binding partners.
Results: We show that human Ndufaf2, also called mimitin, is a binding partner of MSRA as well as all 3 MSRBs. We found that both methionine residues in Ndufaf2 were susceptible to oxidation by hydrogen peroxide and that the methionine sulfoxide reductases can reduce these methionine sulfoxide residues back to methionine.
Conclusion: Methionine sulfoxide reductases can reduce methionine sulfoxide back to methionine in Ndufaf2. In addition to a repair function, it also creates a mechanism that could regulate cellular processes by modulation of methionine oxidation in Ndufaf2.

المؤلفون: Thyne KM; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA., Salmon AB; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. Salmona@uthscsa.edu.; Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. Salmona@uthscsa.edu.; Geriatric Research Education and Clinical Center, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA. Salmona@uthscsa.edu.

المصدر: GeroScience [Geroscience] 2023 Oct; Vol. 45 (5), pp. 3003-3017. Date of Electronic Publication: 2023 Jun 30.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Springer International Publishing Country of Publication: Switzerland NLM ID: 101686284 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2509-2723 (Electronic) Linking ISSN: 25092723 NLM ISO Abbreviation: Geroscience Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/genetics , Methionine Sulfoxide Reductases*/metabolism , Methionine*/metabolism, Male ; Female ; Animals ; Mice ; Longevity/physiology ; Racemethionine ; Body Weight ; Mammals/metabolism

مستخلص: Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

المؤلفون: Gonzalez LN; Laboratorio de Enzimología Molecular - Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Santa Fe, Argentina; Cátedra de Bioquímica Básica de Macromoléculas. Facultad de Bioquímica y Ciencias Biológicas - Universidad Nacional del Litoral, Santa Fe, Argentina., Cabeza MS; Laboratorio de Micología y Diagnóstico Molecular. Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Cátedra de Parasitología y Micología. Facultad de Bioquímica y Ciencias Biológicas - Universidad Nacional del Litoral, Santa Fe, Argentina., Robello C; Laboratorio de Interacciones Hospedero Patógeno/UBM, Institut Pasteur de Montevideo, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Guerrero SA; Laboratorio de Enzimología Molecular - Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Santa Fe, Argentina; Cátedra de Parasitología y Micología. Facultad de Bioquímica y Ciencias Biológicas - Universidad Nacional del Litoral, Santa Fe, Argentina., Iglesias AA; Laboratorio de Enzimología Molecular - Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Santa Fe, Argentina; Cátedra de Bioquímica Básica de Macromoléculas. Facultad de Bioquímica y Ciencias Biológicas - Universidad Nacional del Litoral, Santa Fe, Argentina., Arias DG; Laboratorio de Enzimología Molecular - Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Santa Fe, Argentina; Cátedra de Bioquímica Básica de Macromoléculas. Facultad de Bioquímica y Ciencias Biológicas - Universidad Nacional del Litoral, Santa Fe, Argentina. Electronic address: darias@fbcb.unl.edu.ar.

المصدر: Biochimie [Biochimie] 2023 Oct; Vol. 213, pp. 190-204. Date of Electronic Publication: 2023 Jul 08.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 1264604 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1638-6183 (Electronic) Linking ISSN: 03009084 NLM ISO Abbreviation: Biochimie Subsets: MEDLINE

مواضيع طبية MeSH: Methionine Sulfoxide Reductases*/genetics , Methionine Sulfoxide Reductases*/chemistry , Methionine Sulfoxide Reductases*/metabolism , Trypanosoma cruzi*/genetics, Oxidation-Reduction ; Cysteine/chemistry ; Methionine/metabolism

مستخلص: Trypanosoma cruzi is the causal agent of Chagas Disease and is a unicellular parasite that infects a wide variety of mammalian hosts. The parasite exhibits auxotrophy by L-Met; consequently, it must be acquired from the extracellular environment of the host, either mammalian or invertebrate. Methionine (Met) oxidation produces a racemic mixture (R and S forms) of methionine sulfoxide (MetSO). Reduction of L-MetSO (free or protein-bound) to L-Met is catalyzed by methionine sulfoxide reductases (MSRs). Bioinformatics analyses identified the coding sequence for a free-R-MSR (fRMSR) enzyme in the genome of T. cruzi Dm28c. Structurally, this enzyme is a modular protein with a putative N-terminal GAF domain linked to a C-terminal TIP41 motif. We performed detailed biochemical and kinetic characterization of the GAF domain of fRMSR in combination with mutant versions of specific cysteine residues, namely, Cys ¹² , Cys ⁹⁸ , Cys ¹⁰⁸ , and Cys ¹³² . The isolated recombinant GAF domain and full-length fRMSR exhibited specific catalytic activity for the reduction of free L-Met(R)SO (non-protein bound), using tryparedoxins as reducing partners. We demonstrated that this process involves two Cys residues, Cys ⁹⁸ and Cys ¹³² . Cys ¹³² is the essential catalytic residue on which a sulfenic acid intermediate is formed. Cys ⁹⁸ is the resolutive Cys, which forms a disulfide bond with Cys ¹³² as a catalytic step. Overall, our results provide new insights into redox metabolism in T. cruzi, contributing to previous knowledge of L-Met metabolism in this parasite.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

المؤلفون: Lim JM; Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. Electronic address: jungmi.lim@nih.gov., Sabbasani VR; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, Rockville, Maryland, USA., Swenson RE; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, Rockville, Maryland, USA., Levine RL; Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

المصدر: The Journal of biological chemistry [J Biol Chem] 2023 Sep; Vol. 299 (9), pp. 105099. Date of Electronic Publication: 2023 Jul 26.

نوع المنشور: Journal Article; Research Support, N.I.H., Intramural

بيانات الدورية: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

مواضيع طبية MeSH: Cholesterol*/analogs & derivatives , Cholesterol*/metabolism , Hydrogen Peroxide*/metabolism , Methionine Sulfoxide Reductases*/genetics , Methionine Sulfoxide Reductases*/metabolism , Membrane Proteins*/genetics , Membrane Proteins*/metabolism, Methionine/metabolism ; Oxidation-Reduction ; Sulfoxides/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Endosomes/metabolism ; Lysosomes/metabolism

مستخلص: Methionine sulfoxide reductases (MSRs) are key enzymes in the cellular oxidative defense system. Reactive oxygen species oxidize methionine residues to methionine sulfoxide, and the methionine sulfoxide reductases catalyze their reduction back to methionine. We previously identified the cholesterol transport protein STARD3 as an in vivo binding partner of MSRA (methionine sulfoxide reductase A), an enzyme that reduces methionine-S-sulfoxide back to methionine. We hypothesized that STARD3 would also bind the cytotoxic cholesterol hydroperoxides and that its two methionine residues, Met307 and Met427, could be oxidized, thus detoxifying cholesterol hydroperoxide. We now show that in addition to binding MSRA, STARD3 binds all three MSRB (methionine sulfoxide reductase B), enzymes that reduce methionine-R-sulfoxide back to methionine. Using pure 5, 6, and 7 positional isomers of cholesterol hydroperoxide, we found that both Met307 and Met427 on STARD3 are oxidized by 6α-hydroperoxy-3β-hydroxycholest-4-ene (cholesterol-6α-hydroperoxide) and 7α-hydroperoxy-3β-hydroxycholest-5-ene (cholesterol-7α-hydroperoxide). MSRs reduce the methionine sulfoxide back to methionine, restoring the ability of STARD3 to bind cholesterol. Thus, the cyclic oxidation and reduction of methionine residues in STARD3 provides a catalytically efficient mechanism to detoxify cholesterol hydroperoxide during cholesterol transport, protecting membrane contact sites and the entire cell against the toxicity of cholesterol hydroperoxide.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Published by Elsevier Inc.)