Abstract
N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and l-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle. Recent work has shown that several different genes encode enzymes that can catalyze NAG formation. A bifunctional enzyme was identified in certain bacteria, which catalyzes both NAGS and N-acetylglutamate kinase (NAGK) activities, the first two steps of the arginine biosynthetic pathway. Interestingly, these bifunctional enzymes have higher sequence similarity to vertebrate NAGS than those of the classical (mono-functional) bacterial NAGS. Solving the structures for both classical bacterial NAGS and bifunctional vertebrate-like NAGS/K has advanced our insight into the regulation and catalytic mechanisms of NAGS, and the evolutionary relationship between the two NAGS groups.
Highlights
N-acetylglutamate (NAG) is the initial precursor of arginine in the arginine biosynthetic pathway in microorganisms and plants, while the same compound is an essential cofactor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle [1,2,3]
The recently available structure of the NAT domain alone of xfNAGS/K bound with NAG demonstrate that NAG can bind to the protein in two different conformations, implying that the glutamate binding site for vertebrate-like N-acetylglutamate synthase (NAGS) might have more plasticity than its counterpart in bacteria-like NAGS [53]
The conformation of the whole hexamer changes significantly with a ~20 Å contraction along its three-fold axis and ~10 Å expansion for its hexamer ring (Figure 5E). The magnitudes of these changes are comparable with those found in arginine-sensitive N-acetylglutamate kinase (NAGK) structures [42], implying that arginine induced global conformational changes depend on the amino acid kinases (AAK) domain only
Summary
N-acetylglutamate (NAG) is the initial precursor of arginine in the arginine biosynthetic pathway in microorganisms and plants, while the same compound is an essential cofactor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle [1,2,3]. NAGS, fungal NAGS and other vertebrate NAGS, which have tetrameric architectures, represented by the bifunctional NAGS/K from Maricaulis maris (PDB code 3S6G) These two groups of NAGS are typical NAGS enzymes in that they have both AAK and NAT domains and catalyze the formation of NAG from AcCoA and glutamate. A novel type of NAGS, the sequence of which is not related to any known NAGS, was identified in Corynebacterium glutamicum [25] The variety of these enzymes raised the question of how and why proteins with such high divergence have the ability to catalyze the formation of the same compound, NAG. A RimK-like protein [32] encoded by ArgX (a homolog of LysX), with no sequence similarity to any known NAGS, catalyzes the above reaction This mechanism was discovered in a member of the archaea, which use the same set of enzymes for L-lysine and L-arginine biosynthesis. The structural information gleaned so far offers new insights into structure-function relationships as well as the catalytic and regulatory mechanisms
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