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WIREs Comput Mol Sci
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Glutamine synthetase structure‐catalysis relationship—Recent advances and applications

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Glutamine synthetase is a key enzyme that exists in every living organism. It is responsible for incorporating ammonium into glutamate, generating glutamine. Research on this enzyme has grown substantially over the last decades. The recent advances in the determination of its structure, through the crystallization of novel classes of glutamine synthetase with increased resolution, greatly contributed to a shift in the glutamine synthetase research from fundamental to more applied. Here, we explore the active sites of glutamine synthetases, review the structural and catalytic roles of their active sites' ions Mg2+s, combine the information gathered from recent computational studies dedicated to unravel their catalytic mechanisms with the hypothesis raised at the beginning of the XXI century based on experimental studies, glance at the development of competitive glutamine synthetase inhibitors, and highlight the high value of these enzymes to industry, namely in the fields of agriculture and medicine. This article is categorized under: Molecular and Statistical Mechanics > Molecular Mechanics Structure and Mechanism > Reaction Mechanisms and Catalysis
General proposed biosynthetic reaction catalyzed by glutamine synthetase (GS): (1) ATP transfers a phosphate group to glutamine; (2) ammonium is combined with glutamyl phosphate to yield glutamine
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Schematic representation of the most promising ATP‐competitive inhibitor of each class of compounds designed to inhibit M. tuberculosis GSI
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Representation of the protein–protein interface in hmGSII decamer; left) a single monomers is highlighted in pink, surrounded by the remaining nine monomers in a gray surface, with the residues that are within 5 Å of adjacent monomers colored in cyan (interacting with the right monomer of the same ring), lilac (interacting with the left monomer of the same ring) and green (interacting with the adjacent monomer located on the other ring); centre and right) location of the important residues in each of the protein–protein interfaces of hmGSII, colored in red (hot spots) and orange (warm spots)
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Representation of the protein–protein interface in mtGSI dodecamer; left) a single monomers is highlighted in pink, surrounded by the remaining 11 monomers in a gray surface, with the residues that are within 5 Å of adjacent monomers colored in cyan (interacting with the right monomer of the same ring), lilac (interacting with the left monomer of the same ring) and green (interacting with the adjacent monomer located on the other ring); right) location of the important residues in each of the protein–protein interfaces of mtGSI, colored in red (hot spots) and orange (warm spots) and with indication of the novel druggable pocket by the black dashed line
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Representation of the transition state for the glutamine formation reaction, highlighting the atoms involved (yellow) in bond breaking (red arrow) that release the phosphate group, and bond formation (green arrow) that unite ammonia to the Cγ of glutamyl phosphate to originate glutamine. The proton transfer from ammonia/glutamine is not represented here
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Representation of the transition state for the phosphate transfer reaction that occurs in the reactants activation phase, highlighting the atoms involved (yellow) in bond breaking (red arrow) and bond formation (green arrow) during this reaction
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Reaction mechanism of hsGSII computed with the SCC‐DFTB/MM molecular dynamics. The reaction occurs in two steps: The first is a phosphate transfer from ATP to glutamate, yielding γ‐glutamyl phosphate. The second describes a nucleophilic attack of ammonia to the γ‐glutamyl phosphate with concomitant phosphate release and proton transfer to E196
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Multimeric structures of the three different glutamine synthetase (GS) classes: Top view of homo‐oligomer (left column), side view of the homo‐oligomer (central column) and a single monomer highlighted in the quaternary structure (right column), with indication of the “head” and “tail” sides of the monomer
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Reaction mechanism as described by atomistic models computed at the ONIOM (M06‐D3/6‐311++G(2d,2p):ff99SB//B3LYP/6‐31G(d):ff99SB level of theory for hsGSII (E305 in blue) and mtGSI (D63 in pink). The reaction mechanisms are similar, only varying in the basic residue that deprotonates ammonium. First, the reactants are activated in two separate spontaneous reactions; second, glutamine is formed by condensation of ammonia and glutamate
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Schematic representation of glutamine synthetase (GS) active site location and organization. The GS active site (yellow stars on the top view of GS enzyme and bifunnel shape on the bottom side view of GS enzyme) is located in between two adjacent monomers (surfaces colored in three different shades of pink) of the GSII pentameric ring structure. Its bifunnel structure comprises the aminoacid binding site and the nucleotide binding site, with three Mg2+ ions (orange spheres numbered 1–3) binding in the middle of the two pockets. The two conserved negative regions of the aminoacid binding site known to interact with ammonium (Z1) and backbone amide group (Z3) are represented in transparent red spheres named Z1 and Z3. The conserved positive region containing aminoacids that are known to interact with the carboxylic groups of glutamate are indicated by the transparent blue sphere Z2
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Structure and Mechanism > Reaction Mechanisms and Catalysis
Molecular and Statistical Mechanics > Molecular Mechanics

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