Formation of Urea in the Mammalian Body without Participation of Arginase

Abstract

THE synthesis of urea as the main end-product in protein metabolism in the mammalian body has been the subject of investigation since the early days of biochemical studies. The discovery by Kossel and Dakin of arginase, the enzyme splitting arginine into urea and ornithine, appeared to provide a solution for the problem, the more so since the enzyme was found to be abundant in mammalian tissue. The insufficient endogenous and exogenous supply of arginine, however, presented a difficulty since the quantities of arginine available for urea production were found to represent only a small fraction of what was necessary to account for the comparatively large excretion of urea in the urine. So early workers supported the view that urea could not possibly be produced by hydrolysis of arginine only, but that the bulk of urea was oxidatively synthesized from ammonia or ammonia sources such as amino acids. The role of arginase was thus considered of minor importance until Krebs and Henseleit¹ published their attractive theory in 1932, according to which the ammonia was used in the synthesis of arginine from ornithine and citrulline, followed by hydrolysis of arginine to urea and ornithine through the action of arginase. In this way a continuous resynthesis of arginine was to take place in the mammalian liver for which ornithine and citrulline acted as catalysts and urea was eventually obtained by the action of arginase on arginine.