Publications

• Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation.

  Anand P., Hausladen A., Wang Y.J., Zhang G.F., Stomberski C., Brunengraber H., Hess D.T., Stamler J.S.

  Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-nitrosylation) has not been considered. Here we describe protein S-nitrosylation in yeast (heretofore unknown) that is mediated by S-nitro ... >> More

  Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-nitrosylation) has not been considered. Here we describe protein S-nitrosylation in yeast (heretofore unknown) that is mediated by S-nitroso-CoA (SNO-CoA). We identify a specific SNO-CoA reductase encoded by the alcohol dehydrogenase 6 (ADH6) gene and show that deletion of ADH6 increases cellular S-nitrosylation and alters CoA metabolism. Further, we report that Adh6, acting as a selective SNO-CoA reductase, protects acetoacetyl-CoA thiolase from inhibitory S-nitrosylation and thereby affects sterol biosynthesis. Thus, Adh6-regulated, SNO-CoA-mediated protein S-nitrosylation provides a regulatory mechanism paralleling protein acetylation. We also find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6. Our studies reveal a novel functional class of enzymes that regulate protein S-nitrosylation from yeast to mammals and suggest that SNO-CoA-mediated S-nitrosylation may subserve metabolic regulation. << Less

  Proc. Natl. Acad. Sci. U.S.A. 111:18572-18577(2014) [PubMed] [EuropePMC]

• AKR1A1 is a novel mammalian S-nitroso-glutathione reductase.

  Stomberski C.T., Anand P., Venetos N.M., Hausladen A., Zhou H.L., Premont R.T., Stamler J.S.

  Oxidative modification of Cys residues by NO results in <i>S</i>-nitrosylation, a ubiquitous post-translational modification and a primary mediator of redox-based cellular signaling. Steady-state levels of <i>S</i>-nitrosylated proteins are largely determined by denitrosylase enzymes that couple N ... >> More

  Oxidative modification of Cys residues by NO results in <i>S</i>-nitrosylation, a ubiquitous post-translational modification and a primary mediator of redox-based cellular signaling. Steady-state levels of <i>S</i>-nitrosylated proteins are largely determined by denitrosylase enzymes that couple NAD(P)H oxidation with reduction of <i>S</i>-nitrosothiols, including protein and low-molecular-weight (LMW) <i>S</i>-nitrosothiols (<i>S</i>-nitroso-GSH (GSNO) and <i>S</i>-nitroso-CoA (SNO-CoA)). SNO-CoA reductases require NADPH, whereas enzymatic reduction of GSNO can involve either NADH or NADPH. Notably, GSNO reductase (GSNOR, <i>Adh5</i>) accounts for most NADH-dependent GSNOR activity, whereas NADPH-dependent GSNOR activity is largely unaccounted for (CBR1 mediates a minor portion). Here, we <i>de novo</i> purified NADPH-coupled GSNOR activity from mammalian tissues and identified aldo-keto reductase family 1 member A1 (AKR1A1), the archetypal mammalian SNO-CoA reductase, as a primary mediator of NADPH-coupled GSNOR activity in these tissues. Kinetic analyses suggested an AKR1A1 substrate preference of SNO-CoA > GSNO. AKR1A1 deletion from murine tissues dramatically lowered NADPH-dependent GSNOR activity. Conversely, GSNOR-deficient mice had increased AKR1A1 activity, revealing potential cross-talk among GSNO-dependent denitrosylases. Molecular modeling and mutagenesis of AKR1A1 identified Arg-312 as a key residue mediating the specific interaction with GSNO; in contrast, substitution of the SNO-CoA-binding residue Lys-127 minimally affected the GSNO-reducing activity of AKR1A1. Together, these findings indicate that AKR1A1 is a multi-LMW-SNO reductase that can distinguish between and metabolize the two major LMW-SNO signaling molecules GSNO and SNO-CoA, allowing for wide-ranging control of protein <i>S</i>-nitrosylation under both physiological and pathological conditions. << Less

  J. Biol. Chem. 294:18285-18293(2019) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.