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Abnormal nitration and S-sulfhydration of Sp1-CSE-H2S pathway contribute to the progress of HHcy

By Chenghua Luo, Dengyu Ji, Yan Li, Yan Cao, Shangyue Zhang, Wenjing Yan, Ke Xue, Jiayin Chai, Ye Wu, Huirong Liu, Wen Wang

Posted 19 Nov 2019
bioRxiv DOI: 10.1101/843854

Sp1-CSE-H2S pathway plays an important role in homocysteine-metabolism, whose disorder can cause hyperhomocysteinemia. H2S deficiency in hyperhomocysteinemia has been reported but it's unclear whether this deficiency affects hyperhomocysteinemia. Furthermore, it's unknown whether the post-translational modification of Sp1-CSE can affect hyperhomocysteinemia. We detected the post-translational modification of Sp1-CSE-H2S pathway and revealed four major findings: (1) the accumulation of homocysteine augmented the nitration of CSE, blunted its bio-activity and caused H2S deficiency. (2) H2S deficiency lowered the S-sulfhydration of Sp1, inhibited its transcriptional activity, resulted in lower expression of CSE. CSE deficiency decreased H2S level further, which in turn lowered the S-sulfhydration level of CSE. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310 under physiological conditions, mutation of Cys84, Cys109, Cys229, Cys252 and Cys307 decreased its S-sulfhydration level and bio-activity. (4) H2S deficiency could trap hyperhomocysteinemia into a progressive vicious circle, while blocking nitration or restoring S-sulfhydration could break this circle. This study reveals a novel mechanism involved in the disorder of Hcy-metabolism, which may provide a candidate therapeutic strategy for hyperhomocysteinemia.

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