Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants

	Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants
	Mo, L; Zhang, W; Wang, J; Weng, XH; Chen, S; Shao, LY; Pang, MY; Chen, ZW
刊名	MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE
	2004
卷号	10 期号:4 页码:269-279
通讯作者	Zhang, W (reprint author), 330 Brookline Ave,RE113, Boston, MA 02215 USA.,wzhang@bidmc.harvard.edu ; zchen@uic.edu
英文摘要	Mycobacterium tuberculosis KatG enzyme functions both as catalase for removing hydrogen peroxide (H2O2) and as peroxidase for oxidating isoniazid (INH) to active form of anti-tuberculosis drug. Although mutations in M. tuberculosis KatG confer INH resistance in tuberculous patients, structural bases for INH-resistant mutations in the KatG gene remains poorly understood. Here, three M. tuberculosis KatG mutants bearing Arg418 --> Gln, Ser315 --> Thr, or Trp321 --> Gly replacement were assessed for changes in catalase-peroxidase activities and possible structure bases relevant to such changes. These three M. tuberculosis KatG mutants exhibited a marked impairment or loss of catalase-peroxidase activities. The possible structural bases for the mutant-induced loss of enzyme activities were then analyzed using a three-dimensional model of M. tuberculosis KatG protein constructed on the basis of the crystal structure of the catalase-peroxidase from Burkholderia pseudomallei. The model suggests that three M. tuberculosis KatG mutants bearing Arg418 --> Gln, Ser315 --> Thr, or Trp321 --> Gly replacement affect enzyme activities by different mechanisms, although each of them impacts consequently on a heme-associated structure, the putative oxidative site. Moreover, in addition to the widely accepted substrate-binding site, M. tuberculosis KatG may bear another H2O2 binding site. This H2O2 binding site appears to interact with the catalytic site by a possible electron-transfer chain, a Met255-Tyr229-Trp107 triad conserved in many catalase-peroxidases. The Ser315 --> Thr mutant may have direct effect on the catalytic site by interfering with electron transfer in addition to the previously proposed mechanism of steric constraint.
学科主题	Infectious Diseases; Microbiology; Pharmacology & Pharmacy
类目[WOS]	Infectious Diseases ; Microbiology ; Pharmacology & Pharmacy
关键词[WOS]	SITE-DIRECTED MUTAGENESIS ; CYTOCHROME-C PEROXIDASE ; COMPOUND-I ; GENE ; INHA ; PURIFICATION ; MUTATIONS ; TARGET ; ACTIVATION ; TRYPTOPHAN
收录类别	SCI
语种	英语
WOS记录号	WOS:000226169600001
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2066]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Mo, L,Zhang, W,Wang, J,et al. Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants[J]. MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE,2004,10(4):269-279.
APA	Mo, L.,Zhang, W.,Wang, J.,Weng, XH.,Chen, S.,...&Chen, ZW.(2004).Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants.MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE,10(4),269-279.
MLA	Mo, L,et al."Three-dimensional model and molecular mechanism of Mycobacterium tuberculosis catalase-peroxidase (KatG) and isoniazid-resistant KatG mutants".MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE 10.4(2004):269-279.