| First Author | Stomberski CT | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 48 | Pages | 18285-18293 |
| PubMed ID | 31649033 | Mgi Jnum | J:282972 |
| Mgi Id | MGI:6383570 | Doi | 10.1074/jbc.RA119.011067 |
| Citation | Stomberski CT, et al. (2019) AKR1A1 is a novel mammalian S-nitroso-glutathione reductase. J Biol Chem 294(48):18285-18293 |
| abstractText | 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. |
