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2cca

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[[Image:2cca.gif|left|200px]]
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{{STRUCTURE_2cca| PDB=2cca | SCENE= }}
{{STRUCTURE_2cca| PDB=2cca | SCENE= }}
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'''CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS'''
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===CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS===
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==Overview==
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Inhibition of the enzyme Mycobacterium tuberculosis InhA (enoyl-acyl carrier protein reductase) due to formation of an isonicotinoyl-NAD adduct (IN-NAD) from isoniazid (INH) and nicotinamide adenine dinucleotide cofactor is considered central to the mode of action of INH, a first-line treatment for tuberculosis infection. INH action against mycobacteria requires catalase-peroxidase (KatG) function, and IN-NAD adduct formation is catalyzed in vitro by M. tuberculosis KatG under a variety of conditions, yet a physiologically relevant approach to the process has not emerged that allows scrutiny of the mechanism and the origins of INH resistance in the most prevalent drug-resistant strain bearing KatG[S315T]. In this report, we describe how hydrogen peroxide, delivered at very low concentrations to ferric KatG, leads to efficient inhibition of InhA due to formation of the IN-NAD adduct. The rate of adduct formation mediated by wild-type KatG was about 20-fold greater than by the isoniazid-resistant KatG[S315T] mutant under optimal conditions (H2O2 supplied along with NAD+ and INH). Slow adduct formation also occurs starting with NADH and INH, in the presence of KatG even in the absence of added peroxide, due to endogenous peroxide. The poor efficiency of the KatG[S315T] mutant can be enhanced merely by increasing the concentration of INH, consistent with this enzyme's reduced affinity for INH binding to the resting enzyme and the catalytically competent enzyme intermediate (Compound I). Origins of drug resistance in the KatG[S315T] mutant enzyme are analyzed at the structural level through examination of the three-dimensional X-ray crystal structure of the mutant enzyme.
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(as it appears on PubMed at http://www.pubmed.gov), where 16566587 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16566587}}
==About this Structure==
==About this Structure==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Peroxidase]]
[[Category: Peroxidase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 21:46:30 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 14:26:23 2008''

Revision as of 11:26, 29 July 2008

Image:2cca.png

Template:STRUCTURE 2cca

CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS

Template:ABSTRACT PUBMED 16566587

About this Structure

2CCA is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.

Reference

Hydrogen peroxide-mediated isoniazid activation catalyzed by Mycobacterium tuberculosis catalase-peroxidase (KatG) and its S315T mutant., Zhao X, Yu H, Yu S, Wang F, Sacchettini JC, Magliozzo RS, Biochemistry. 2006 Apr 4;45(13):4131-40. PMID:16566587

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