Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate

Xiao, Jingfa; Guo, Zengjun; Guo, Yuchen; Chu, Frances; Sun, Piaoyang

doi:10.1016/j.jmgm.2006.01.001

Cited by 14 publications

(8 citation statements)

References 28 publications

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“…More recently, PMI from E. coli in D 2 O has been shown to incorporate deuterium at C1 of the substrate, showing proton exchange to occur between C1H of F6P and the solvent 40. Surprisingly, a recent computational study of Type I human PMI argues in favor of a hydride shift mechanism for the hydrogen transfer between the two carbon atoms C1 and C2 of the substrate 26. This mechanistic hypothesis is in disagreement with the generally accepted proposition for PMIs detailed above.…”

Section: Introductionmentioning

confidence: 89%

“…The design of such efficient and/or species‐specific PMI inhibitors of medical relevance would be much facilitated by more information about the enzyme mechanism of action and the structure of the active site. As detailed below, despite recently reported computational26 and structural16 studies on PMIs that led to controversial mechanistic conclusions, such information is currently incomplete, and the reaction mechanism still needs to be clarified. On the basis of new inhibition and theoretical studies as well as on previously reported studies in the literature, our contribution intends to identify all the active site residues and to propose a role for each of them in the reaction mechanism catalyzed by Type I PMIs.…”

Section: Introductionmentioning

confidence: 99%

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The reaction mechanism of type I phosphomannose isomerases: New information from inhibition and polarizable molecular mechanics studies

et al. 2010

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Type I phosphomannose isomerases (PMIs) are zinc-dependent metalloenzymes involved in the reversible isomerization of D-mannose 6-phosphate (M6P) and D-fructose 6-phosphate (F6P). 5-Phospho-D-arabinonohydroxamic acid (5PAH), an inhibitor endowed with nanomolar affinity for yeast (Type I) and Pseudomonas aeruginosa (Type II) PMIs (Roux et al., Biochemistry 2004; 43:2926-2934), strongly inhibits human (Type I) PMI (for which we report an improved expression and purification procedure), as well as Escherichia coli (Type I) PMI. Its K(i) value of 41 nM for human PMI is the lowest value ever reported for an inhibitor of PMI. 5-Phospho-D-arabinonhydrazide, a neutral analogue of the reaction intermediate 1,2-cis-enediol, is about 15 times less efficient at inhibiting both enzymes, in accord with the anionic nature of the postulated high-energy reaction intermediate. Using the polarizable molecular mechanics, sum of interactions between fragments ab initio computed (SIBFA) procedure, computed structures of the complexes between Candida albicans (Type I) PMI and the cyclic substrate β-D-mannopyranose 6-phosphate (β-M6P) and between the enzyme and the high-energy intermediate analogue inhibitor 5PAH are reported. Their analysis allows us to identify clearly the nature of each individual active site amino acid and to formulate a hypothesis for the overall mechanism of the reaction catalyzed by Type I PMIs, that is, the ring-opening and isomerization steps, respectively. Following enzyme-catalyzed ring-opening of β-M6P by zinc-coordinated water and Gln111 ligands, Lys136 is identified as the probable catalytic base involved in proton transfer between the two carbon atoms C1 and C2 of the substrate D-mannose 6-phosphate.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The reaction mechanism of type I phosphomannose isomerases: New information from inhibition and polarizable molecular mechanics studies

et al. 2010

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“…Guo et al . [162] developed 3D model of human phosphate mannose isomerase based on the known crystal structure of mannose-6-phosphate isomerase (PDB code: 1PMI). The homologous protein was searched by the FASTA program and 3 reference proteins were taken i.e.…”

Section: Applications Of Homology Modelingmentioning

confidence: 99%

Homology modeling a fast tool for drug discovery: Current perspectives

Vk¹,

Ukawala²,

Ghate³

et al. 2012

Indian J Pharm Sci

219

116

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Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery.

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“…The verify score generated by Profile-3D evaluates the fitness between the 1-D sequence and 3D environment, including the side-chain area, side-chain fragment area exposed to polar atom, and local secondary structure, of c-Met tyrosine kinase. The verify score value exceeding 0 indicates that the simulated structure is reliable and accurate (Luthy et al, 1992;Xiao et al, 2006).…”

Section: Structure Validationmentioning

confidence: 99%

Discovery of novel inhibitors for c-Met by virtual screening and pharmacophore analysis

Chen

2008

Journal of the Chinese Institute of Chemical Engineers

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Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate

Cited by 14 publications

References 28 publications

The reaction mechanism of type I phosphomannose isomerases: New information from inhibition and polarizable molecular mechanics studies

The reaction mechanism of type I phosphomannose isomerases: New information from inhibition and polarizable molecular mechanics studies

Homology modeling a fast tool for drug discovery: Current perspectives

Discovery of novel inhibitors for c-Met by virtual screening and pharmacophore analysis

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