Abnormal nitration and S-sulfhydration modification of Sp1-CSE-H2S pathway trap the progress of hyperhomocysteinemia into a vicious cycle.

This study focused on the post-translational modification of Sp1/CSE and revealed four major findings: (1) Homocysteine-accumulation augmented CSE's nitration, inhibited its bio-activity, thus caused H2S deficiency. (2) H2S deficiency inhibited the S-sulfhydration of Sp1, down-regulated CSE and decreased H2S further, which in turn weakened CSE's own S-sulfhydration. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310, among which the S-sulfhydration of Cys172 and Cys310 didn't affect its enzymatic activity, while the S-sulfhydration of Cys84, Cys109, Cys229, Cys252 and Cys307 was necessary for its bio-activity. (4) H2S deficiency trapped homocysteine-metabolism into a vicious cycle, which could be broken by either blocking nitration or restoring S-sulfhydration. This study detected a new mechanism that caused severe hyperhomocysteinemia, thereby provided new therapeutic strategies for hyperhomocysteinemia.
PMID: 33418108 [PubMed - as supplied by publisher]

Source: Free Radical Biology and Medicine - January 5, 2021 Category: Biology Authors: Luo C, Ji D, Li Y, Cao Y, Zhang S, Yan W, Xue K, Chai J, Wu Y, Liu H, Wang W Tags: Free Radic Biol Med Source Type: research