Enzyme Molecular Mechanism as a Starting Point to Design New Inhibitors: A Theoretical Study of O-GlcNAcase
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Otros documentos de la autoría: Lameira, Jerônimo; Nahum Alves, Cláudio; Tuñón, Iñaki; Martí Forés, Sergio; Moliner, Vicent
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http://dx.doi.org/10.1021/jp202079e |
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Título
Enzyme Molecular Mechanism as a Starting Point to Design New Inhibitors: A Theoretical Study of O-GlcNAcaseFecha de publicación
2011-05Editor
ACSISSN
1520-6106Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://pubs.acs.org/doi/full/10.1021/jp202079eVersión
info:eu-repo/semantics/publishedVersionResumen
O-Glycoprotein 2-acetamino-2-deoxy-β-d-glucopyranosidase (O-GlcNAcase) hydrolyzes O-linked 2-acetamido-2-deoxy-β-d-glucopyranoside (O-GlcNAc) residues from post-translationally modified serine/threonine residues of ... [+]
O-Glycoprotein 2-acetamino-2-deoxy-β-d-glucopyranosidase (O-GlcNAcase) hydrolyzes O-linked 2-acetamido-2-deoxy-β-d-glucopyranoside (O-GlcNAc) residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. The chemical process involves substrate-assisted catalysis, where two aspartate residues have been identified as the two key catalytic residues of O-GlcNAcase. In this report, the first step of the catalytic mechanism used by O-GlcNAcase involving substrate-assisted catalysis has been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) Molecular Dynamics (MD) calculations. The free energy profile shows that the formation of the oxazoline intermediate in the O-GlcNAcase catalytic reaction takes place by means of a stepwise mechanism. The first step would be a cyclization of the acetomide group, which seems to be dependent on the proton transfer from a conserved aspartate, Asp298 in Clostridium perfringens O-GlcNAcase. From this new intermediate, a proton is transferred from the azoline ring to another conserved aspartate (Asp297) thus forming the oxazoline ion and departure of the aglycone. In addition, averaged values of protein–substrate interaction energy along the reaction path shows that, in fact, the transition states present the highest binding affinities. A deeper analysis of the binding contribution of the individual residues shows that Asp297, Asp298, and Asp401 are basically responsible of the stabilization of these complexes. These results would explain why O-(2-acetamido-2deoxy-d-glucopyranosylidene)amino-N-phenycarbamate (PUGNAc), 1,2-dideoxy-2′-methyl-α-d-glucopyranoso-[2,1-d]-Δ2′-thiazoline (NAG-thiazoline), and GlcNAcstatin derivatives are potent inhibitors of this enzyme, resembling the two transition states of the O-GlcNAcase catalytic reaction path. These results may be useful to rational design compounds with more interesting inhibitory activity. [-]
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Journal of Physical Chemistry B, 2011, 115 (20)Derechos de acceso
Copyright © 2011 American Chemical Society
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