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Abnormal nitration and S-sulfhydration modification of Sp1-CSE-H2S pathway trap the progress of hyperhomocysteinemia into a vicious cycle.
- Source :
-
Free Radical Biology & Medicine . Feb2021, Vol. 164, p20-33. 14p. - Publication Year :
- 2021
-
Abstract
- Sp1-CSE-H 2 S pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. H 2 S 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 H 2 S deficiency. (2) H 2 S deficiency inhibited the S-sulfhydration of Sp1, down-regulated CSE and decreased H 2 S 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) H 2 S 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. Image 1 • Hcy augmented the nitration of CSE, blunted its bio-activity and caused H 2 S deficiency. • Deficiency of Sp1's S-sulfhydration down-regulated CSE, lowered H 2 S level further, which weakened CSE's S-sulfhydration. • CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310 under physiological conditions. • H 2 S deficiency trapped HHcy into a vicious cycle, blocking nitration or restoring S-sulfhydration could break this cycle. [ABSTRACT FROM AUTHOR]
- Subjects :
- *NITRATION
*HYPERHOMOCYSTEINEMIA
*POST-translational modification
*TRAPPING
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Volume :
- 164
- Database :
- Academic Search Index
- Journal :
- Free Radical Biology & Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 148776364
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2020.12.440