The inhibition of mammalian d-amino acid oxidase by metabolites and drugs. Inferences concerning physiological function

Abstract

The inhibition of d-amino acid oxidase (EC 1.4.3.3) by a large number of metabolites and drugs is reported. When the substrate is an adduct (thiazolidine-2-carboxylate) formed from cysteamine and glyoxylate, at least five different mechanisms of inhibition are possible, and examples of each are given. Effective inhibitors include (a) some adenosine containing nucleotides, in particular ADP, AMP, ADP ribose, NADH, NADPH and dephospho-CoA; (b) diuretics, especially furosemide, ethacrynic acid, and mersalyl; (c) anti-inflammatory agents, such as salicylate, indomethacin, phenylbutazone, acetylsalicylate, mefenamic, and flufenamic acids; (d) hypoglycemic, hypocalcemic, and hypolipidemic compounds, including 5-methylpyrazole-3-carboxylate, pyrrole-2-carboxylate, 5-methylthiophene-2-carboxylate, thiophene-2-carboxylate, benzoate, and nicotinate; (e) aldehydes, for example, formaldehyde, acetaldehyde, and succinate semialdehyde; (f) thiols, especially β-aminothiols such as cysteine and penicillamine; (g) tropolone, and (h) hydrogen peroxide. The rate of the reaction is also very sensitive to oxygen presure; at pH 7.4 and 25°C the K m for O 2 is 1.1 m M. These data, in conjunction with literature information concerning the biological affects of such compounds, are used to suggest possible physiological processes in which the d-amino acid oxidase reaction may be involved. Although such correlations based on circumstantial evidence are not conclusive, they suggest that d-amino acid oxidase may play a major role in the control of metabolism in animals. Some processes in which it may participate include maintenance of ion and water balance in the kidney, inflammatory response, transmission of nerve impulses, sensing of O 2 concentration, control of cell growth, and as part of an intracellular messenger system for some hormones, especially insulin.