N-acetyl-gamma-glutamyl-phosphate reductase, type 1 (AGPR_type-1)
Type: Family

N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined .

The pathway from glutamate to arginine is:

NAGS; N-acetylglutamate synthase (

) (glutamate to N-acetylglutamate)

NAGK; N-acetylglutamate kinase (

) (N-acetylglutamate to N-acetylglutamate-5P)

N-acetyl-gamma-glutamyl-phosphate reductase (

) (N-acetylglutamate-5P to N-acetylglumate semialdehyde)

Acetylornithine aminotransferase (

) (N-acetylglumate semialdehyde to N-acetylornithine)

Acetylornithine deacetylase (

) (N-acetylornithine to ornithine)

Arginase (

) (ornithine to arginine)

N-acetyl-gamma-glutamyl-phosphate reductase (

) (AGPR, NAGSA dehydrogenase) is the enzyme that catalyses the third step in the biosynthesis of arginine from glutamate, the NADP-dependent reduction of N-acetyl-5-glutamyl phosphate into N-acetylglutamate 5-semialdehyde. In bacteria it is a monofunctional protein of 35 to 38kDa (gene argC), while in fungi it is part of a bifunctional mitochondrial enzyme (gene ARG5,6, arg11 or arg-6) which contains a N-terminal acetylglutamate kinase (

) domain and a C-terminal AGPR domain. In the Escherichia coli enzyme, a cysteine has been shown to be implicated in the catalytic activity, and the region around this residue is well conserved.

This entry represents the more common of two related families of N-acetyl-gamma-glutamyl-phosphate reductase, an enzyme catalyzing the third step or Arg biosynthesis from Glu. The two families differ by phylogeny, similarity clustering, and the gap architecture in a multiple sequence alignment. Bacterial members of this family tend to be found within Arg biosynthesis operons.

This family also includes LysY (LysW-L-2-aminoadipate/LysW-L-glutamate phosphate reductase), which is involved in both the arginine and lysine biosynthetic pathways. Several bacteria and archaea utilize the amino group-carrier protein, LysW, for lysine biosynthesis from alpha-aminoadipate (AAA). In some cases, such as Sulfolobus, LysW is also used to protect the amino group of glutamate in arginine biosynthesis. After LysW modification, AAA and glutamate are converted to lysine and ornithine, respectively, by a single set of enzymes with dual functions . LysY is the third enzyme in lysine biosynthesis from AAA . LysY shows high sequence identity and functional similarities with ArgC, and they are considered to have evolved from a common ancestor .