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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.


NAG binding site of ngNAGS (A) and hNAGS (B). The protein is shown in ribbon diagram. The bound NAG is shown as thick cyan sticks. The residues involved in binding NAG are shown as sticks. The hydrogen bonds are shown as red dashed lines. NAG binds to the protein in different conformations and using different sets of amino acid residues in ngNAGS and hNAGS.
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ijms-16-13004-f004: NAG binding site of ngNAGS (A) and hNAGS (B). The protein is shown in ribbon diagram. The bound NAG is shown as thick cyan sticks. The residues involved in binding NAG are shown as sticks. The hydrogen bonds are shown as red dashed lines. NAG binds to the protein in different conformations and using different sets of amino acid residues in ngNAGS and hNAGS.

Mentions: The NAG bound structures of both ngNAGS and human NAGS enable the glutamate binding sites to be characterized in detail. A comparison of NAG bound structures of ngNAGS and hNAGS is shown in Figure 4A,B. The acetyl and the α-amino groups of NAG bind to the protein in a very similar way for both ngNAGS and hNAGS. However, the α-carboxyl and γ-carboxyl groups of NAG are in different locations and use different sets of amino acid residues to anchor to the protein. In ngNAGS, the side-chains of Arg316, Arg425 and Ser427, in addition to the main-chain N of Leu314 and Cys356, are involved in binding the two carboxyl groups. In hNAGS, the side-chains of Lys401, Arg474, Arg476 and Asn479 contribute hydrogen-bonding interactions for positioning the carboxyl groups. Two water-mediated interactions with the side-chain of Tyr441 and the main-chain N of Ser524 are also involved in binding the α carboxyl group. The NAG binding cavity of hNAGS appears to be larger than that of ngNAGS. 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 NAGS might have more plasticity than its counterpart in bacteria-like NAGS [53].


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

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

NAG binding site of ngNAGS (A) and hNAGS (B). The protein is shown in ribbon diagram. The bound NAG is shown as thick cyan sticks. The residues involved in binding NAG are shown as sticks. The hydrogen bonds are shown as red dashed lines. NAG binds to the protein in different conformations and using different sets of amino acid residues in ngNAGS and hNAGS.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-13004-f004: NAG binding site of ngNAGS (A) and hNAGS (B). The protein is shown in ribbon diagram. The bound NAG is shown as thick cyan sticks. The residues involved in binding NAG are shown as sticks. The hydrogen bonds are shown as red dashed lines. NAG binds to the protein in different conformations and using different sets of amino acid residues in ngNAGS and hNAGS.
Mentions: The NAG bound structures of both ngNAGS and human NAGS enable the glutamate binding sites to be characterized in detail. A comparison of NAG bound structures of ngNAGS and hNAGS is shown in Figure 4A,B. The acetyl and the α-amino groups of NAG bind to the protein in a very similar way for both ngNAGS and hNAGS. However, the α-carboxyl and γ-carboxyl groups of NAG are in different locations and use different sets of amino acid residues to anchor to the protein. In ngNAGS, the side-chains of Arg316, Arg425 and Ser427, in addition to the main-chain N of Leu314 and Cys356, are involved in binding the two carboxyl groups. In hNAGS, the side-chains of Lys401, Arg474, Arg476 and Asn479 contribute hydrogen-bonding interactions for positioning the carboxyl groups. Two water-mediated interactions with the side-chain of Tyr441 and the main-chain N of Ser524 are also involved in binding the α carboxyl group. The NAG binding cavity of hNAGS appears to be larger than that of ngNAGS. 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 NAGS might have more plasticity than its counterpart in bacteria-like NAGS [53].

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.