Dissecting the Mechanism and Assembly of a Complex Virulence Mycobacterial Lipid

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 inve...

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Bibliographic Details
Published in:Molecular cell 2005-03, Vol.17 (5), p.631-643
Main Authors: Trivedi, Omita A., Arora, Pooja, Vats, Archana, Ansari, Mohd. Zeeshan, Tickoo, Rashmi, Sridharan, Vijayalakshmi, Mohanty, Debasisa, Gokhale, Rajesh S.
Format: Article
Language:English
Subjects:
Antigens, Bacterial - chemistry
Catalysis
Cell-Free System
Cloning, Molecular
Dose-Response Relationship, Drug
Esters - chemistry
Fatty Acids - chemistry
Kinetics
Lipids - chemistry
Models, Chemical
Models, Molecular
Mutagenesis, Site-Directed
Mycobacterium
Mycobacterium - metabolism
Mycobacterium - pathogenicity
Mycobacterium tuberculosis
Polyketide Synthases - chemistry
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Software
Time Factors
Virulence
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Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.02.009