Functional Characterization of a Novel ArgA from
            <i>Mycobacterium tuberculosis</i>

Errey, James C.; Blanchard, John S.

doi:10.1128/jb.187.9.3039-3044.2005

Cited by 45 publications

(48 citation statements)

References 34 publications

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“…However, it is believed that most present day NAGS genes were derived from the fusion of two ancestral genes encoding NAGK and N-acetyltransferase (NAT). The discovery of a bifunctional enzyme capable of catalyzing the first two reactions of arginine biosynthesis (9) and the existence of a "short" version of NAGS in some bacteria (10) lend support to this hypothesis.…”

mentioning

confidence: 73%

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

Shi

Sagar

Jin

et al. 2008

Journal of Biological Chemistry

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mentioning

confidence: 73%

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

Shi

Sagar

Jin

et al. 2008

Journal of Biological Chemistry

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“…Since NAGK is homologous to the N-terminal domain of NAGS, Ramon-Maiques et al (59) were able to localize the molecular signature for arginine inhibition in that domain. However, Mycobacterium S-NAGS, where this domain is absent, is also inhibited by arginine (24). Both the arginine and glutamate binding sites thus remain to be identified in S-NAGS.…”

Section: Feedback Inhibition Of Ornithine Synthesismentioning

confidence: 99%

Surprising Arginine Biosynthesis: a Reappraisal of the Enzymology and Evolution of the Pathway in Microorganisms

Labedan

Glansdorff

2007

Microbiol Mol Biol Rev

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SUMMARY Major aspects of the pathway of de novo arginine biosynthesis via acetylated intermediates in microorganisms must be revised in light of recent enzymatic and genomic investigations. The enzyme N-acetylglutamate synthase (NAGS), which used to be considered responsible for the first committed step of the pathway, is present in a limited number of bacterial phyla only and is absent from Archaea. In many Bacteria, shorter proteins related to the Gcn5-related N-acetyltransferase family appear to acetylate l-glutamate; some are clearly similar to the C-terminal, acetyl-coenzyme A (CoA) binding domain of classical NAGS, while others are more distantly related. Short NAGSs can be single gene products, as in Mycobacterium spp. and Thermus spp., or fused to the enzyme catalyzing the last step of the pathway (argininosuccinase), as in members of the Alteromonas-Vibrio group. How these proteins bind glutamate remains to be determined. In some Bacteria, a bifunctional ornithine acetyltransferase (i.e., using both acetylornithine and acetyl-CoA as donors of the acetyl group) accounts for glutamate acetylation. In many Archaea, the enzyme responsible for glutamate acetylation remains elusive, but possible connections with a novel lysine biosynthetic pathway arose recently from genomic investigations. In some Proteobacteria (notably Xanthomonadaceae) and Bacteroidetes, the carbamoylation step of the pathway appears to involve N-acetylornithine or N-succinylornithine rather than ornithine. The product N-acetylcitrulline is deacetylated by an enzyme that is also involved in the provision of ornithine from acetylornithine; this is an important metabolic function, as ornithine itself can become essential as a source of other metabolites. This review insists on the biochemical and evolutionary implications of these findings.

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“…Its first role is to form an R-state hexamer that promotes the catalytic reaction via inter-subunit AAK-NAT domain interactions that maintain the L-glutamate binding loops in the correct conformation. A short version of NAGS from Mycobacterium tuberculosis has an extremely low affinity for L-glutamate, probably because it lacks the AAK domain (28). The second role is to reduce catalytic activity in the presence of L-arginine.…”

Section: L-arginine Binding Changes the Interactions Between Aak And mentioning

confidence: 99%

Mechanism of Allosteric Inhibition of N-Acetyl-L-glutamate Synthase by L-Arginine

Jin

Caldovic

et al. 2009

Journal of Biological Chemistry

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N-Acetylglutamate synthase (NAGS) catalyzes the first committed step in L-arginine biosynthesis in plants and micro-organisms and is subject to feedback inhibition by L-arginine. This study compares the crystal structures of NAGS from Neisseria gonorrhoeae (ngNAGS) in the inactive T-state with L-arginine bound and in the active R-state complexed with CoA and L-glutamate. Under all of the conditions examined, the enzyme consists of two stacked trimers. Each monomer has two domains: an amino acid kinase (AAK) domain with an AAK-like fold but lacking kinase activity and an N-acetyltransferase (NAT) domain homologous to other GCN5-related transferases. Binding of L-arginine to the AAK domain induces a global conformational change that increases the diameter of the hexamer by ϳ10 Å and decreases its height by ϳ20 Å . AAK dimers move 5 Å outward along their 2-fold axes, and their tilt relative to the plane of the hexamer decreases by ϳ4°. The NAT domains rotate ϳ109°relative to AAK domains enabling new interdomain interactions. Interactions between AAK and NAT domains on different subunits also change. Local motions of several loops at the L-arginine-binding site enable the protein to close around the bound ligand, whereas several loops at the NAT active site become disordered, markedly reducing enzymatic specific activity.L-Arginine biosynthesis in most micro-organisms and plants involves the initial acetylation of L-glutamate by N-acetylglutamate synthase (NAGS, EC 2.3.1.1) 2 to produce N-acetylglutamate (NAG). NAG is then converted by NAG kinase (NAGK, EC 2.7.2.8) to NAG-phosphate and subsequently to N-acetylornithine (1, 2). Two alternative reactions are used to remove the acetyl group from acetylornithine. The linear pathway uses N-acetylornithine deacetylase (EC 3.5.1.16) to catalyze the metal-dependent hydrolysis of the acetyl group to form L-ornithine and acetate, whereas the acetyl recycling pathway transfers the acetyl group from N-acetylornithine to L-glutamate, producing L-ornithine and NAG. This reaction is catalyzed by ornithine acetyltransferase (EC 2.3.1.35).In the linear pathway, NAGS is the only target of feedback inhibition by L-arginine. In contrast, in the acetyl cycling pathway L-arginine may inhibit NAGS and NAGK or ornithine acetyltransferase (3). Structure determinations of L-arginineinsensitive (4) and L-arginine-sensitive NAGKs (5) provided insights into the structural basis of L-arginine inhibition of NAGK. L-Arginine-insensitive Escherichia coli (ec) NAGK is a homodimer (4), whereas L-arginine-sensitive NAGKs from Thermotoga maritima (tm) and Pseudomonas aeruginosa (pa) are hexamers formed by pair-wise interlacing of the N-terminal helices of three ecNAGK-like dimers, to create a second type of dimer interface. L-Arginine binding to a site close to the C terminus induces global conformational changes that expands the ring by ϳ8 Å and decreases the tilt of the ecNAGK-like dimers relative to the plane of the ring by ϳ6°. The inhibition mechanism was proposed to involve the enlargement of an ...

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Functional Characterization of a Novel ArgA from Mycobacterium tuberculosis

Cited by 45 publications

References 34 publications

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

Surprising Arginine Biosynthesis: a Reappraisal of the Enzymology and Evolution of the Pathway in Microorganisms

Mechanism of Allosteric Inhibition of N-Acetyl-L-glutamate Synthase by L-Arginine

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