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The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms.

Shi D, Allewell NM, Tuchman M - Int J Mol Sci (2015)

Bottom Line: Recent work has shown that several different genes encode enzymes that can catalyze NAG formation.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research and Department of Integrative Systems Biology, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA. dshi@childrensnational.org.

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.

No MeSH data available.


Related in: MedlinePlus

Enzymes that produce N-acetylglutamate. Bacteria-like N-acetylglutamate synthase (NAGS) include the classical bacterial NAGS and plant NAGS, which have hexameric architectures, represented by NAGS from Neisseria gonorrhoeae (PDB code 2R8V). Vertebrate-like NAGS include the bifunctional bacterial NAGS/K, mammalian 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. They are the focus of this review. ArgJ is the mono- or bi-functional ornithine acetyltransferase that catalyzes the production of NAG from acetylornithine and glutamate (mono-) and AcCoA and glutamate (bi-). This enzyme is likely to be a heterotetramer, represented by argJ from Mycobacterium tuberculosis (PDB code 3IT4). Other atypical NAGSs exist in certain bacteria but no structures have been determined so far. The short version of NAGS (S-NAGS), for example argA from M. tuberculosis has only NAT domain. The NAGS encoded by the argO gene of Campylobacter jejuni (O-NAGS) consists of 146 amino acids, which broadly relate to the GNAT family. H-NAGS has been identified in Moritella abyss and Moritella profunda with argH fused to the N-terminal end of the NAT related domain. C-NAGS is a novel type of NAGS, recently identified in Corynebacterium glutamicum, whose sequence does not have any relationship to other known NAGS.
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ijms-16-13004-f001: Enzymes that produce N-acetylglutamate. Bacteria-like N-acetylglutamate synthase (NAGS) include the classical bacterial NAGS and plant NAGS, which have hexameric architectures, represented by NAGS from Neisseria gonorrhoeae (PDB code 2R8V). Vertebrate-like NAGS include the bifunctional bacterial NAGS/K, mammalian 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. They are the focus of this review. ArgJ is the mono- or bi-functional ornithine acetyltransferase that catalyzes the production of NAG from acetylornithine and glutamate (mono-) and AcCoA and glutamate (bi-). This enzyme is likely to be a heterotetramer, represented by argJ from Mycobacterium tuberculosis (PDB code 3IT4). Other atypical NAGSs exist in certain bacteria but no structures have been determined so far. The short version of NAGS (S-NAGS), for example argA from M. tuberculosis has only NAT domain. The NAGS encoded by the argO gene of Campylobacter jejuni (O-NAGS) consists of 146 amino acids, which broadly relate to the GNAT family. H-NAGS has been identified in Moritella abyss and Moritella profunda with argH fused to the N-terminal end of the NAT related domain. C-NAGS is a novel type of NAGS, recently identified in Corynebacterium glutamicum, whose sequence does not have any relationship to other known NAGS.

Mentions: In addition to the above enzymes, which have AAK and NAT domains, several other proteins are able to catalyze the formation of NAG (Figure 1). The best-known is argJ encoded ornithine acetyltransferase (OAT), which catalyzes the reversible acetyl exchange between ornithine and glutamate. OATs have been characterized in vitro or in vivo as mono- or bifunctional enzymes [19,20]. The bifunctional OAT catalyzes both the acetyl transfer reaction from acetylornithine to glutamate and from acetyl-CoA to glutamate as does the typical NAGS. No detectable sequence similarity is observed between bifunctional OATs and typical NAGS. It seems that the CoA moiety of acetyl-CoA does not enter the catalytic site of OAT [19], in contrast to the typical NAGS, which recognizes CoA [21]. Mature active OAT derives from a preprotein, which undergoes autocatalytic cleavage to form a biologically active hetero tetramer [22,23].


The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms.

Shi D, Allewell NM, Tuchman M - Int J Mol Sci (2015)

Enzymes that produce N-acetylglutamate. Bacteria-like N-acetylglutamate synthase (NAGS) include the classical bacterial NAGS and plant NAGS, which have hexameric architectures, represented by NAGS from Neisseria gonorrhoeae (PDB code 2R8V). Vertebrate-like NAGS include the bifunctional bacterial NAGS/K, mammalian 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. They are the focus of this review. ArgJ is the mono- or bi-functional ornithine acetyltransferase that catalyzes the production of NAG from acetylornithine and glutamate (mono-) and AcCoA and glutamate (bi-). This enzyme is likely to be a heterotetramer, represented by argJ from Mycobacterium tuberculosis (PDB code 3IT4). Other atypical NAGSs exist in certain bacteria but no structures have been determined so far. The short version of NAGS (S-NAGS), for example argA from M. tuberculosis has only NAT domain. The NAGS encoded by the argO gene of Campylobacter jejuni (O-NAGS) consists of 146 amino acids, which broadly relate to the GNAT family. H-NAGS has been identified in Moritella abyss and Moritella profunda with argH fused to the N-terminal end of the NAT related domain. C-NAGS is a novel type of NAGS, recently identified in Corynebacterium glutamicum, whose sequence does not have any relationship to other known NAGS.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490483&req=5

ijms-16-13004-f001: Enzymes that produce N-acetylglutamate. Bacteria-like N-acetylglutamate synthase (NAGS) include the classical bacterial NAGS and plant NAGS, which have hexameric architectures, represented by NAGS from Neisseria gonorrhoeae (PDB code 2R8V). Vertebrate-like NAGS include the bifunctional bacterial NAGS/K, mammalian 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. They are the focus of this review. ArgJ is the mono- or bi-functional ornithine acetyltransferase that catalyzes the production of NAG from acetylornithine and glutamate (mono-) and AcCoA and glutamate (bi-). This enzyme is likely to be a heterotetramer, represented by argJ from Mycobacterium tuberculosis (PDB code 3IT4). Other atypical NAGSs exist in certain bacteria but no structures have been determined so far. The short version of NAGS (S-NAGS), for example argA from M. tuberculosis has only NAT domain. The NAGS encoded by the argO gene of Campylobacter jejuni (O-NAGS) consists of 146 amino acids, which broadly relate to the GNAT family. H-NAGS has been identified in Moritella abyss and Moritella profunda with argH fused to the N-terminal end of the NAT related domain. C-NAGS is a novel type of NAGS, recently identified in Corynebacterium glutamicum, whose sequence does not have any relationship to other known NAGS.
Mentions: In addition to the above enzymes, which have AAK and NAT domains, several other proteins are able to catalyze the formation of NAG (Figure 1). The best-known is argJ encoded ornithine acetyltransferase (OAT), which catalyzes the reversible acetyl exchange between ornithine and glutamate. OATs have been characterized in vitro or in vivo as mono- or bifunctional enzymes [19,20]. The bifunctional OAT catalyzes both the acetyl transfer reaction from acetylornithine to glutamate and from acetyl-CoA to glutamate as does the typical NAGS. No detectable sequence similarity is observed between bifunctional OATs and typical NAGS. It seems that the CoA moiety of acetyl-CoA does not enter the catalytic site of OAT [19], in contrast to the typical NAGS, which recognizes CoA [21]. Mature active OAT derives from a preprotein, which undergoes autocatalytic cleavage to form a biologically active hetero tetramer [22,23].

Bottom Line: Recent work has shown that several different genes encode enzymes that can catalyze NAG formation.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research and Department of Integrative Systems Biology, Children's National Medical Center, the George Washington University, Washington, DC 20010, USA. dshi@childrensnational.org.

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.

No MeSH data available.


Related in: MedlinePlus