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

Abstract

Sp1-CSE-H₂S pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. H₂S deficiency in hyperhomocysteinemia has been reported, while the underlying mechanism and whether it in turn affects the progress of hyperhomocysteinemia are unclear. 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.

Keywords: Cystathionine-γ-lyase; Hydrogen sulfide; Hyperhomocysteinemia; Nitration; S-sulfhydration; Specificity protein 1.