Arginases I and II: do their functions overlap?

Abstract

Arginase, often perceived solely as the last of the now six enzymes of the urea cycle, exists in two forms and has a broad tissue distribution. A cytosolic form, AI, is highly expressed in the liver and is thought to be primarily involved in ureagenesis. A mitochondrial form, AII, has been thought to be more widely expressed and to be involved in the biosynthesis of polyamines, the amino acids ornithine, proline, and glutamate and in the inflammatory process, among others. This paper will address recent experiments that cast some doubt on the validity of these distinctions. Studies have now suggested that macrophages may express AI or AII in different experimental conditions, both in vivo and in vitro. In contrast, most studies, at least in cell culture, suggest that AII may be most highly expressed in cancers of a number of different types. Inhibition of arginase activity in vivo and in vitro has implicated this activity in maintaining ornithine levels for polyamine synthesis. In situ and "quantitative" PCR studies in mouse have demonstrated that AI and not AII is the predominant isoform expressed during development and in the majority of organs. Mouse knockout models for both AI and AII have been produced and are available to address their functions. Surprisingly, the AII knockout animal has no apparent phenotype except for some diminished fertility in homozygous males, consistent with the belief that AII, highly expressed in prostate, is important for sperm function in semen. The AI knockout animal has a more dramatic phenotype and dies at 10-12 days of life of hyperammonemia. The reason for the prolonged survival, as compared to other urea cycle knockout animals, may be due to the later occurrence of hypo-ornithinemia, a contention not yet proven. Transgenic manipulation of the AI knockout animal and breeding the AI and AII knockouts into single animals may address the ability of AII to rescue animals from some of the metabolic consequences of AI deficiency, as appears to happen in man. Newborn screening has given particular hope to patients affected by arginase (AI) deficiency. Increased arginine appears to be detectable by newborn screening with tandem mass spectrometry and the past years continue to demonstrate the therapeutic effectiveness of dietary management of the disorder, with patients treated from birth remaining normal and those treated late, ceasing to deteriorate and even improving in cognitive and physical functioning. Finally, prenatal diagnosis appears to be possible as was predicted, but never proven, some years ago.