Insufficient S-Sulfhydration of Methylenetetrahydrofolate Reductase Contributes to the Progress of Hyperhomocysteinemia.

Hyperhomocysteinemia (HHcy) has been considered as a risk factor for cardiovascular disease, Alzheimer's disease, nonalcoholic fatty liver, and many other pathological conditions. Vitamin B6, Vitamin B12, and folate have been used to treat HHcy in clinics. However, at present, clinical therapies of HHcy display unsatisfactory effects. Here, we would like to explore a new mechanism involved in homocysteine (Hcy) metabolic disorders and a novel target for HHcy treatment. The key enzymes involved in Hcy metabolism deserve more insightful investigation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular Hcy metabolism. Until now, the effect of post-translational modification on the bioactivity of still remains unclear. This study aimed at exploring the relationship between S-sulfhydration and its bioactivity, and at identifying the contribution of an elevated Hcy level on bioactivity. By both and studies, we observed the following results: (i) The bioactivity of was positively associated with its S-sulfhydration level; (ii) was modified at Cys32, Cys130, Cys131, Cys193, and Cys306 by S-sulfhydration under physiological conditions; (iii) Hydrogen sulfide (HS) deficiency caused the decrease of S-sulfhydration level and bioactivity in HHcy, which resulted in further aggravation of HHcy; and (iv) HS donors reversed the decreased bioactivity of in HHcy, thus reducing the excessive Hcy level. Our study suggested that HS could improve bioactivity by S-sulfhydration, which might provide a candidate therapeutic strategy for HHcy. . 36, 1-14.