ENZYMES IN ANIMAL METABOLISM OF OXALATE DERIVATIVES

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Several lines of research in this laboratory have recently converged to suggest that various derivatives of oxalic acid, especially oxalyl thiolesters (RSCOCOO-), may play an important role in controlling metabolism in animals, and may function as mediators for some hormones, especially insulin and growth factors. If this is the case, then it seems imperative to fully characterize, both the overall metabolic pathways involved in the biosynthesis and catabolism of such compounds, and the specific enzymes that catalyze the individual steps in the pathways. That is the general goal of the proposed research. Some specific approaches and enzymes that will be investigated in the proposed research include: (1) a membrane bound amidase that cleaves S- acyl coenzyme A derivatives to S-acylcysteamines will be isolated and characterized, (2) the reactivity of various S-acylcysteamines toward hydrolysis, catalyzed by cholinesterases will be investigated, (3) explore whether the oxalate derivative (thiazoline-2-carboxylate), that is the product of the suspected physiological reaction catalyzed by D-amino acid oxidase, is enzymically converted into oxalyl thiolesters, (4) isolate and characterize an enzyme that causes the disappearance (hydrolysis?) of N-oxalylcysteine from kidney homogenates, and (5) explore whether oxalyl thiolesters may be intermediates in the metabolism of aromatic amino acids and ascorbic acid (vitamin C) to oxalate. The research potentially could lead to the elucidation of a whole new system of metabolic control in animals. Not only may it be particularly relevant to the insulin related disease, diabetes, but also to diseases such as cancer, since various growth factors and protein products of oncogenes seem closely related to insulin. In characterizing new metabolic pathways to oxalate in animals, it may aid in our understanding of the reasons for the development of kidney stones due to calcium oxalate. Finally, if oxalyl derivatives are found to be intermediates in ascorbate catabolism, it will clarify considerably the role of this vitamin in the prevention of diseases such as scurvy.