4.8 Article

Supersulfide catalysis for nitric oxide and aldehyde metabolism

Journal

SCIENCE ADVANCES
Volume 9, Issue 33, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.adg8631

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Research has found that abundant formation of endogenous supersulfides catalyzes S-nitrosoglutathione (GSNO) metabolism by utilizing alcohol dehydrogenase 5 (ADH5), which serves as GSNO reductase (GSNOR) and formaldehyde dehydrogenase (FDH). The C174S mutation in ADH5 significantly reduces supersulfidation and GSNOR activity but spares FDH activity. ADH5 supersulfides play a substantial role in GSNO metabolism by mediating electron transfer from aldehydes.
Abundant formation of endogenous supersulfides, which include reactive persulfide species and sulfur catenated residues in thiols and proteins (supersulfidation), has been observed. We found here that supersulfides catalyze S-nitrosoglutathione (GSNO) metabolism via glutathione-dependent electron transfer from aldehydes by exploiting alcohol dehydrogenase 5 (ADH5). ADH5 is a highly conserved bifunctional enzyme serving as GSNO reductase (GSNOR) that down-regulates NO signaling and formaldehyde dehydrogenase (FDH) that detoxifies formaldehyde in the form of glutathione hemithioacetal. C174S mutation significantly reduced the supersulfidation of ADH5 and almost abolished GSNOR activity but spared FDH activity. Notably, Adh5(C174S/C174S) mice manifested improved cardiac functions possibly because of GSNOR elimination and consequent increased NO bioavailability. Therefore, we successfully separated dual functions (GSNOR and FDH) of ADH5 (mediated by the supersulfide catalysis) through the biochemical analysis for supersulfides in vitro and characterizing in vivo phenotypes of the GSNOR-deficient organisms that we established herein. Supersulfides in ADH5 thus constitute a substantial catalytic center for GSNO metabolism mediating electron transfer from aldehydes.

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