PEDIATRICS Vol. 68 No. 2 August 1981, pp. 273-283
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Biochemical Aspects of Urea Cycle Disorders

P. J. Snodgrass MD1

1 Veteran's Administration Medical Center, Indianapolis

In this paper I will review the biochemistry of the urea cycle of mammalian liver and point out the important clinical implications of this biochemistry. Second, I will consider some problems that arise in the use of human liver enzyme assays for evaluating deficiencies of urea cycle enzymes. Finally, I will comment on our own research concerning enzyme induction of the urea cycle of mammalian liver.

In Fig 1 the urea cycle is reviewed. Within the mitochondrion of the liver cell, ammonium cation combines with bicarbonate anion and 2 moles of adenosine 5'-triphosphate (ATP) in the presence of an activator, N-acetylglutamate, to form carbamylphosphate. Enzyme 1, which carries out this reaction is carbamylphosphate synthetase I (CPS1). There is also another enzyme, CPS2, in the cytoplasm of liver cells about which more will be said later. Once carbamylphosphate is formed, the carbamyl group is transferred to the dgr-amino group of ornithine to form citrulline. The enzyme in this reaction, enzyme 2, is ornithine transcarbamylase (OTC). Citrulline escapes, by a process other than active transport, into the cytoplasm where it is conjugated with aspartate to form argininosuccinate; this is accomplished by enzyme 3, argininosuccinate synthetase (AS). Argininosuccinate, a double amino acid, is then cleaved to yield fumarate, and the nitrogen of aspartate moves to arginine. The enzyme in this reaction, enzyme 4, is argininosuccinate lyase (AL); its trivial name is argininosuccinase. Finally, arginine undergoes cleavage of its ureido group by enzyme 5, arginase, to form urea and regenerate ornithine. Ornithine is then taken up into the mitochondria by an active transport process to combine again with carbamylphosphate.