Glutamine: a nitrogen source in urea synthesis

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Abstract
Glutamine, and, from the results of preliminary experiments, isoglutamine were far more effective N sources of urea than NH3 when incubated with rat-liver slices. The effect of glutamine was not due to its hydrolysis to ammonium glutamate. Evidence for this view was obtained by experiments in which glutaminase action was inhibited in one case and activated in another. The inhibition of the enzyme had no effect on urea synthesis from glutamine, and activation of glutaminase almost completely suppressed urea formation. The synthesis of urea which is observed when ammonium chloride is added to liver slices is believed to be due to the intermediary formation of glutamine from NH3 and tissue glutamic acid. Evidence for a notable glutamine synthesis from NH3 during urea formation was obtained by paper chromatography. In the absence of bicarbonate not only was urea synthesis suppressed but both the nitrogenous groups of glutamine remained intact. In the presence of bicarbonate the amide and amino nitrogen of glutamine were utilized for urea synthesis to approximately the same extent, and the whole of the urea N could be accounted for by the disappearance of the 2 nitrogenous groups during the synthesis. Therefore, the following overall reaction is suggested: glutamine amide nitrogen + glutamine amino nitrogen [forward arrow]urea nitrogen. It is suggested that the first step in the synthesis of urea from glutamine consists of a reaction between bicarbonate and the 2 nitrogenous groups of glutamine or isoglutamine, which results in the formation of ureido compounds of 2 types, and which through oxtdative or hydrolytic fission would yield carbamyl compounds. The carbamyl groups of the above compounds may take part in the synthesis of citrulline from ornithine. Alternatively, if the oxidative and the hydrolytic split of the ureldes occurred concurrently, a direct formation of urea could be visualized.