title: Dimethyl sulfide protects against oxidative stress and extends lifespan via a methionine sulfoxide reductase A-dependent catalytic mechanism.
abstract: Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species (ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA-catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A-induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low-molecular sulfides in the cytoprotection and aging.
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Department of Pharmacy, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China.
authors: Xin-Lei
authors: XL
authors: Guan
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Peng-Fei
authors: PF
authors: Wu
authors: School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
authors: Sheng
authors: S
authors: Wang
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Juan-Juan
authors: JJ
authors: Zhang
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Zu-Cheng
authors: ZC
authors: Shen
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Han
authors: H
authors: Luo
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Hao
authors: H
authors: Chen
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Li-Hong
authors: LH
authors: Long
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.|The Collaborative Innovation Center for Brain Science, Wuhan, 430030, China.
authors: Jian-Guo
authors: JG
authors: Chen
authors: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China.|Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.|The Collaborative Innovation Center for Brain Science, Wuhan, 430030, China.
authors: Fang
authors: F
authors: Wang
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000502:physiology*; D019610:Cytoprotection / Q000187:drug effects; D004331:Drosophila melanogaster / Q000187:drug effects / Q000502:physiology*; D016166:Free Radical Scavengers / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000975:Antioxidants; D016166:Free Radical Scavengers; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013440:Sulfides; D051150:Methionine Sulfoxide Reductases; C004784:dimethyl sulfide
keywords: cell death; dimethyl sulfide; homology model; lifespan; methionine sulfoxide reductase A; oxidative stress