2ccd: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2ccd.gif|left|200px]] | [[Image:2ccd.gif|left|200px]] | ||
<!-- | |||
The line below this paragraph, containing "STRUCTURE_2ccd", creates the "Structure Box" on the page. | |||
You may change the PDB parameter (which sets the PDB file loaded into the applet) | |||
| | or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | ||
| | or leave the SCENE parameter empty for the default display. | ||
--> | |||
{{STRUCTURE_2ccd| PDB=2ccd | SCENE= }} | |||
}} | |||
'''CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS''' | '''CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS''' | ||
| Line 27: | Line 24: | ||
[[Category: Sacchettini, J C.]] | [[Category: Sacchettini, J C.]] | ||
[[Category: Yu, H.]] | [[Category: Yu, H.]] | ||
[[Category: | [[Category: Catalase-peroxidase]] | ||
[[Category: | [[Category: Heme]] | ||
[[Category: | [[Category: Hydrogen peroxide]] | ||
[[Category: | [[Category: Iron]] | ||
[[Category: | [[Category: Katg]] | ||
[[Category: | [[Category: Metal-binding]] | ||
[[Category: | [[Category: Organic radical]] | ||
[[Category: | [[Category: Oxidoreductase]] | ||
[[Category: | [[Category: Peroxidase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 21:46:50 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 21:46, 3 May 2008
CRYSTAL STRUCTURE OF THE CATALASE-PEROXIDASE (KATG) AND S315T MUTANT FROM MYCOBACTERIUM TUBERCULOSIS
OverviewOverview
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.
About this StructureAbout this Structure
2CCD is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
ReferenceReference
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 Page seeded by OCA on Sat May 3 21:46:50 2008