Dimethyl sulfide protects against oxidative stress and extends lifespan via a methionine sulfoxide reductase A-dependent catalytic mechanism

Abstract

SummaryMethionine (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.

Methionine Sulfoxide Reductases of Archaea

“…Expression of fRMSR enzymes lost during evolution can lead to an increased lifespan in animals [ 77 ]. Likewise, expression of MSRA, together with DMSO, can also extend an organism’s life [ 78 , 79 ]. Thus, archaeal MSR enzymes, including those yet to be discovered, may hold a key to the fountain of youth.…”

Emerging topics in C. elegans aging research: Transcriptional regulation, stress response and epigenetics

“…Recent bioinformatics and high throughput experimental screening approaches lead to the identification of candidate CR/DR mimetics in C. elegans that now require investigation in higher organisms (Calvert et al, 2016; Lucanic et al, 2016). Additional compounds that recently were shown to increase wildtype C. elegans lifespan in candidate testing or small scale screening approaches include small molecules and metabolites such as dimethyl sulfide (Guan et al, 2017), α-ketoacids (Mishur et al, 2016), fructose (Zheng et al, 2017), the d-fructose epimer d-allulose (Shintani et al, 2017), the ω−3 polyunsaturated fatty acid alpha-linolenic acid (ALA) and ALA-derived oxylipin-metabolites (Qi et al, 2017), the proteasome activator 18α-Glycyrrhetinic Acid, a triterpenoid from licorice (Papaevgeniou et al, 2016) and FDA-approved drugs such as rifampicin for tuberculosis (Golegaonkar et al, 2015) and the angiotensin-converting enzyme inhibitor captopril (Kumar et al, 2016) and hydralazine, which are both used to treat hypertension (Dehghan et al, 2017). Many of these compounds apparently act, at least in part, by activating or stabilizing lifespan-regulatory key transcription factors (Table 1), such as daf-16 (18α-Glycyrrhetinic Acid, rifampicin, captopril), hlh-30 (selective inhibitors of nuclear export), hif-1 (α-ketoacids), nhr-49 (ALA) and skn-1 (ALA-metabolites, 18 α-Glycyrrhetinic, hydralazine).…”

S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle

“…EPR was performed as described in our previous reports with some modifications [28,29] . DMPO was used as a free radical trapper.…”

“…MsrA has historically been considered a reductase, not an ROS scavenger, for the reaction of Met with oxidizing species was widely viewed as a natural process. Recent studies from our lab have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with ROS, which may underlie the effect of MsrA on neuroinflammation and lifespan [28,29] .…”

“…Exogenous substrates like L-methionine (L-Met) could activate the Met oxidase activity [29] , but dietary supplementation with L-Met is not applicable for mitochondrial dysfunction, because Met is rapidly incorporated into protein or metabolized, and high dietary Met intake confers an increased risk of acute coronary events in patients with cardiovascular diseases [30,31] . S-methyl-L-cysteine (SMLC) is a hydrophilic cysteine-containing compound naturally found in Alium plants such as garlic and onion [32] .…”