Nitric oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation.
Using conditions that produced chronic inflammation in rat liver, we were able to find a correlation between induction of nitric oxide production and inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12). This enzyme is a tetramer composed of identical M(r) 37,000 subunits. The tetramer contains 16 thiol groups, four of which are essential for enzymatic activity. Our information indicates that four thiol groups are S-nitrosylated by exposure to authentic nitric oxide (NO) gas. Furthermore, NO decreased GAPDH activity while increasing its auto-ADP-ribosylation. Reduced nicotinamide adenine dinucleotide and dithiothreitol are required for the S-nitrosylation of GAPDH caused by the NO-generating compound sodium nitroprusside. Our results suggests that a new and important action of nitric oxide on cells is the S-nitrosylation and inactivation of GAPDH. S-Nitrosylation of GAPDH may be a key covalent modification of multiple regulatory consequences in chronic liver inflammation.
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016908:Gram-Positive Bacterial Infections / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D046911:Macromolecular Substances; D008297:Male; D009243:NAD / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D009603:Nitroso Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D011425:Propionibacterium acnes; D051381:Rats; D017207:Rats, Sprague-Dawley
D046911:Macromolecular Substances; D009603:Nitroso Compounds; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D009569:Nitric Oxide; D004228:Dithionitrobenzoic Acid; D019001:Nitric Oxide Synthase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000594:Amino Acid Oxidoreductases; D004229:Dithiothreitol