| Abstract | Carbamoyl-phosphate synthase (CPSase) catalyzes the ATP-dependent synthesis of carbamyl-phosphate from
glutamine or ammonia and bicarbonate [ 1972379]. This important enzyme
initiates both the urea cycle and the biosynthesis of arginine and pyrimidines. Glutamine-dependent CPSase
(CPSase II) is involved in the biosynthesis of pyrimidines and purines. In bacteria such as Escherichia coli, a
single enzyme is involved in both biosynthetic pathways while other bacteria have separate enzymes. The
bacterial enzymes are formed of two subunits. A small chain (carA) that provides glutamine amidotransferase
activity (GATase) necessary for removal of the ammonia group from glutamine, and a large chain (carB)
that provides CPSase activity. The large subunit consists of
four structural units: the carboxyphosphate synthetic component, the oligomerization domain, the carbamoyl phosphate synthetic
component and the allosteric domain [10089390]. Such a structure is also present in fungi for arginine biosynthesis (CPA1
and CPA2). Two main CPSases have been identified in mammals, CPSase I is mitochondrial, is found in
high levels in the liver and is involved in arginine biosynthesis; while CPSase II is cytosolic, is
associated with aspartate carbamoyltransferase (ATCase) and dihydroorotase (DHOase) and is involved in
pyrimidine biosynthesis. In the pyrimidine pathway in most eukaryotes, CPSase is found as a domain in a
multi-functional protein, which also has GATase, ACTase and DHOase activity. Ammonia-dependent CPSase
(CPSase I) is involved in the urea cycle in ureolytic vertebrates and is a monofunctional protein located
in the mitochondrial matrix. The CPSase domain is typically 120 kD in size and has arisen from the
duplication of an ancestral subdomain of about 500 amino acids. Each subdomain independently binds to ATP
and it is suggested that the two homologous halves act separately, one to catalyze the phosphorylation of
bicarbonate to carboxyphosphate and the other that of carbamate to carbamyl phosphate. The CPSase subdomain
is also present in a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase (ACC),
propionyl-CoA carboxylase (PCCase), pyruvate carboxylase (PC) and urea carboxylase
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