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• W4380769042 abstract "While the causative factors of smoking and hypertension leading to cardiovascular disease (CVD) are well understood, those involved with diet-induced CVD are not. One metabolite regulated by diet that is involved with cardio-protection and vasodilation is the gasotransmitter hydrogen sulfide (H 2 S). However, the molecular inhibition of H 2 S-generating enzymes via CVD-inducing diets is not fully understood, nor is it known if this is the causative event leading to CVD. Enzymatic H 2 S production in mammalian tissues and cells is primarily via the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL). A high fat Western diet contributes to CVD through gut microbiome metabolic pathways and subsequent host enzymes converting choline and carnitine into the metabolites trimethylamine (TMA) and trimethylamine-N-oxide (TMAO). We hypothesized that TMA and TMAO lower H 2 S production by directly interacting with CGL to reduce enzymatic activity and that these gut-related metabolites’ inhibition account for some of the CVD risks. Results: Using a lead acetate assay, we discovered that these metabolites reduce enzymatic H 2 S production in a CGL-dependent manner from tissues ex vivo as well as from purified human CGL in vitro to a similar extent as propargylglycine (PAG), a known CGL suicide inhibitor that also happens to be a bacterial metabolite. We found that in vivo , hepatic and renal H 2 S production increased in antibiotic treated mice surface plasma resonance (SPR) and micro-scale thermophoresis (MST) assays revealed direct and specific physical interactions between TMA and TMAO with CGL. Additionally, pre-incubation with PAG blocked the binding of TMAO with CGL, indicating that the mechanism and location of inhibition are shared. Conclusion: Diet-induced gut metabolites TMA and TMAO bind CGL enzyme and suppress enzymatic production of cardioprotective H 2 S." @default.
• W4380769042 created "2023-06-16" @default.
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• W4380769042 date "2022-11-08" @default.
• W4380769042 modified "2023-10-16" @default.
• W4380769042 title "Abstract 9410: Cardiovascular Disease Associated Metabolites TMA and TMAO Bind to Cystathionine Gamma-Lyase and Repress Its Enzymatic Production of Hydrogen Sulfide" @default.
• W4380769042 doi "https://doi.org/10.1161/circ.146.suppl_1.9410" @default.
• W4380769042 hasPublicationYear "2022" @default.
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