Document Detail


Conformational dynamics of the flexible catalytic loop in Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase.
MedLine Citation:
PMID:  19152632     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In mycobacteria, the biosynthesis of the precursors to the essential isoprenoids, isopentenyl diphosphate and dimethylallyl pyrophosphate is carried out by the methylerythritol phosphate pathway. This route of synthesis is absent in humans, who utilize the alternative mevalonate acid route, thus making the enzymes of the methylerythritol phosphate pathway of chemotherapeutic interest. One such identified target is the second enzyme of the pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase. Only limited information is currently available concerning the catalytic mechanism and structural dynamics of this enzyme, and only recently has a crystal structure of Mycobacterium tuberculosis species of this enzyme been resolved including all factors required for binding. Here, the dynamics of the enzyme is studied in complex with NADPH, Mn2+, in the presence and absence of the fosmidomycin inhibitor using conventional molecular dynamics and an enhanced sampling technique, reversible digitally filtered molecular dynamics. The simulations reveal significant differences in the conformational dynamics of the vital catalytic loop between the inhibitor-free and inhibitor-bound enzyme complexes and highlight the contributions of conserved residues in this region. The substantial fluctuations observed suggest that 1-deoxy-D-xylulose 5-phosphate reductoisomerase may be a promising target for computer-aided drug discovery through the relaxed complex method.
Authors:
Sarah L Williams; J Andrew McCammon
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Chemical biology & drug design     Volume:  73     ISSN:  1747-0285     ISO Abbreviation:  Chem Biol Drug Des     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-20     Completed Date:  2009-02-19     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  26-38     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aldose-Ketose Isomerases / chemistry*,  metabolism
Catalytic Domain
Cluster Analysis
Computer Simulation
Crystallography, X-Ray
Humans
Models, Molecular
Molecular Sequence Data
Multienzyme Complexes / chemistry*,  metabolism
Mycobacterium tuberculosis / enzymology*
Oxidoreductases / chemistry*,  metabolism
Pentosephosphates / metabolism
Principal Component Analysis
Protein Conformation*
Grant Support
ID/Acronym/Agency:
P41 RR006009-150315/RR/NCRR NIH HHS; P41 RR008605/RR/NCRR NIH HHS; P41 RR008605-120018/RR/NCRR NIH HHS; P41 RR008605-138229/RR/NCRR NIH HHS; P41 RR008605-147697/RR/NCRR NIH HHS; P41 RR008605-158403/RR/NCRR NIH HHS; R01 GM031749/GM/NIGMS NIH HHS; R01 GM031749-26/GM/NIGMS NIH HHS; R01 GM031749-27/GM/NIGMS NIH HHS; R01 GM031749-28/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 0/Pentosephosphates; 60802-29-1/xylulose-5-phosphate; EC 1.-/Oxidoreductases; EC 1.1.1.267/1-deoxy-D-xylulose 5-phosphate reductoisomerase; EC 5.3.1.-/Aldose-Ketose Isomerases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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