The Metabolism of Glutaric

Glutaric acid has been shown to be metabolized in part to acetoacetate and acetate in the rat, most probably by way of butyrate or acetonedicarboxylate (1). In addition, it was pointed out that part of the glutaric acid might also be converted to a-ketoglutarate by a more or less direct pathway. Study of the metabolism of lysine-6-Cl4 (2) has since provided substantial evidence in favor of this conversion by showing that glutaric acid-l ,5-Cl4 gives rise to radioactive or-ketoglutaric acid by a pathway other than by way of acetate. A possible mechanism for this conversion of glutarate to cu-ketoglutarate, excluding acetate, lies in the sequence of reactions, glutarate -+ glutaconate -+ a-hydroxyglutarate --+ oc-ketoglutarate. Very little is known about the metabolic behavior of glutaconic acid except for an early report by Dakin (3) stating that a small amount of /3-hydroxyglutarate is formed when glutaconic acid is acted upon in vitro by dog muscle. On the other hand, the metabolism in vitro of L-cr-hydroxyglutaric acid has been more thoroughly investigated (4). WeilMalherbe had found that this compound is reversibly oxidized to oc-ketoglutarate by many animal tissues (4, 5), presumably by the action of a dehydrogenase. In addition, ol-hydroxyglutarate has recently been described as a product of the anaerobic breakdown of citric acid by liver mince (6). It is the purpose of this paper to clarify the aspects of glutaric acid metabolism concerned with its conversion to ac-ketoglutarate in the rat. Evidence is presented for the view that the carbon chain of glutaric acid1, 5-Cl4 remains in large measure intact in this conversion, passing through n-a-hydroxyglutarate and possibly glutaconate. The pathway appears to be independent of the conversion of glutarate to acetate.