The conversion of L-histidine to glutamic acid by liver enzymes

Edlbacher and Neber (1) showed in 1934 that the liver enzyme named histidase degrades histidine to NH3, formic acid, and an unknown product which on further treatment with strong alkali yields glutamic acid. This led to the suggestion that glutamic acid is a metabolic product of histidine, a suggestion that was supported by the finding that glycogen was formed from histidine about as well as from glutamic acid (2). These findings did not prove that glutamic acid was one of the products of histidine metabolism, and the idea became questionable when the evidence from subsequent investigations with non-isotopic histidine (3), imidazole-N16-histidine (4), and carboxyl-C14-histidine (5) were negative or inconclusive. In studies on the fate of carboxyl-C14-L-histidine in the liver of rabbits after injection and after incubation with guinea pig liver slices, we have found direct evidence that glutamic acid is a major product of histdine metabolism. Another highly radioactive compound was isolated by ion exchange chromatography, whose properties with respect to chromatography and lability to alkali and acid appear to correspond to those reported for isoglutamine. Takeuchi (6) isolated and identified isoglutamine as a product of the action of urocanicase on urocanic acid, which was obtained by the action of another liver enzyme on histidine. The formation of isoglutamine as an intermediate is consistent with our finding that the label in the radioactive glutamic acid formed from carboxyl-C14-histidine is not in the α-carboxyl group, and the inference is very strong that the label is in the γ-carboxyl group.