Transcriptional regulation of genes for ornithine cycle enzymes.

The omithine cycle [1], also called the urea cycle, is an enzyme system that converts ammonia into urea (for recent reviews, see [2-4]) (Figure 1). Ammonia, which is produced mainly by amino acid metabolism, is toxic to higher animals, and must be excreted or detoxified. Fish and amphibian larvae such as tadpoles excrete ammonia from the gills directly into the surrounding water. Mammalian fetuses transfer ammonia to their mothers. Amphibian metamorphosis and mammalian birth, which lead to independent life on land, are accompanied by induction of the ornithine cycle in the liver. This enables the animals to convert ammonia into urea, which is less toxic and can be stored prior to excretion. Urea synthesized in the liver is transported to the kidney, and then excreted. On the other hand, in birds and terrestrial reptiles, ammonia is converted into uric acid, which is practically water-insoluble and can be stored in a solid form in a shelled egg. The ornithine cycle consists of five enzymes (Figure 1); the first enzyme, carbamoyl-phosphate synthase I (CPS; EC 6.3.4.16), and the second enzyme, ornithine transcarbamylase (OTC; EC 2.1.3.3), are located in the mitochondrial matrix, and the remaining three enzymes, argininosuccinate synthase (AS; EC 6.3.4.5), argininosuccinate lyase (AL; EC 4.3.2.1) and arginase (EC 3.5.3.1), are present in the cytosol. CPS and OTC have provided useful systems for the study of intracellular traffic and the processing of nuclear-gene-encoded mitochondrial proteins [5-8]. Inborn errors in any of the five enzymes can result in insufficient ammonia detoxification, leading to hyperammonaemia (reviewed in [4]). Besides these five enzymes, Nacetylglutamate synthase (EC 2.3.1.1), which catalyses the formation of N-acetylglutamate, an obligatory allosteric activator of CPS, participates in the regulation of urea biosynthesis. This enzyme has been purified and characterized from the rat [9,10] and human [11] liver. A deficiency of this enzyme also results in hyperammonaemia [12]. The ornithine cycle enzymes, except for arginase, that are present in non-hepatic tissues (see below) are mainly involved in arginine biosynthesis (as recent reviews, see introductions of [13,14]). In fact, the ornithine cycle is thought to have evolved from the arginine-synthetic pathway (reviewed in [15]). This notion is substantiated by sequence identities between the ornithine cycle enzymes of mammals and the corresponding arginine-biosynthetic enzymes of micro-organisms such as Escherichia coli and yeast (reviewed in [16]).