Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid

被引：117

作者：

Trivedi, OA ^{[1
]}

Arora, P ^{[1
]}

Vats, A ^{[1
]}

Ansari, MZ ^{[1
]}

Tickoo, R ^{[1
]}

Sridharan, V ^{[1
]}

Mohanty, D ^{[1
]}

Gokhale, RS ^{[1
]}

机构：

[1] Natl Inst Immunol, New Delhi 110067, India

来源：

MOLECULAR CELL | 2005年 / 17卷 / 05期

关键词：

D O I：

10.1016/j.molcel.2005.02.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mycobacterium tuberculosis cell envelope is a treasure house of biologically active lipids of fascinating molecular architecture. Although genetic studies have alluded to an array of genes in biosynthesis of complex lipids, their mechanistic, structural, and biochemical principles have not been investigated. Here, we have dissected the molecular logic underlying the biosynthesis of a virulence lipid phthiocerol dimycocerosate (PDIM). Cell-free reconstitution studies demonstrate that polyketide synthases, which are usually involved in the biosynthesis of secondary metabolites, are responsible for generating complex lipids in mycobacteria. We show that PapA5 protein directly transfers the protein bound mycocerosic acid analogs on phthiocerol to catalyze the final esterification step. Based on precise identification of biological functions of proteins from Pps cluster, we have rationally produced a nonmethylated variant of mycocerosate esters. Apart from elucidating mechanisms that generate chemical heterogeneity with PDIMs, this study also presents an attractive approach to explore host-pathogen interactions by altering mycobacterial surface coat.

引用

页码：631 / 643

页数：13

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[1] The loading module of rifamycin synthetase is an adenylation-thiolation didomain with substrate tolerance for substituted benzoates [J].