InChI=1S/C21H35N8O17P3S/c1-21(2,16(32)19(33)24-4-3-12(30)23-5-6-50-28-34)8-43-49(40,41)46-48(38,39)42-7-11-15(45-47(35,36)37)14(31)20(44-11)29-10-27-13-17(22)25-9-26-18(13)29/h9-11,14-16,20,31-32H,3-8H2,1-2H3,(H,23,30)(H,24,33)(H,38,39)(H,40,41)(H2,22,25,26)(H2,35,36,37)/p-4/t11-,14-,15-,16+,20-/m1/s1 |
CNWRHTNOZSOAKE-IBOSZNHHSA-J |
CC(C)(COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)N1C=NC2=C1N=CN=C2N)[C@@H](O)C(=O)NCCC(=O)NCCSN=O |
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S-nitroso-CoA
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UniProt
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S-nitroso-coenzyme A tetraanion
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ChEBI
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Stomberski CT, Anand P, Venetos NM, Hausladen A, Zhou HL, Premont RT, Stamler JS (2019) AKR1A1 is a novel mammalian S-nitroso-glutathione reductase. The Journal of biological chemistry 294, 18285-18293 (Source: SUBMITTER) [PubMed:31649033] [show Abstract] Oxidative modification of Cys residues by NO results in S-nitrosylation, a ubiquitous post-translational modification and a primary mediator of redox-based cellular signaling. Steady-state levels of S-nitrosylated proteins are largely determined by denitrosylase enzymes that couple NAD(P)H oxidation with reduction of S-nitrosothiols, including protein and low-molecular-weight (LMW) S-nitrosothiols (S-nitroso-GSH (GSNO) and S-nitroso-CoA (SNO-CoA)). SNO-CoA reductases require NADPH, whereas enzymatic reduction of GSNO can involve either NADH or NADPH. Notably, GSNO reductase (GSNOR, Adh5) accounts for most NADH-dependent GSNOR activity, whereas NADPH-dependent GSNOR activity is largely unaccounted for (CBR1 mediates a minor portion). Here, we de novo 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 S-nitrosylation under both physiological and pathological conditions. |
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