TY - JOUR
T1 - Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid
AU - Trivedi, Omita A.
AU - Arora, Pooja
AU - Vats, Archana
AU - Ansari, Mohd Zeeshan
AU - Tickoo, Rashmi
AU - Sridharan, Vijayalakshmi
AU - Mohanty, Debasisa
AU - Gokhale, Rajesh S.
N1 - Funding Information:
The authors thank Anil Bobin, Sunder Bisht, and Suresh Chand for their technical support. The authors also thank Dr. Sandip K. Basu for helpful discussions. P.A. and M.Z.A. are Senior Research Fellows of the Council of Scientific & Industrial Reaseach, India. R.S.G is a Wellcome Trust International Senior Research Fellow in India. This work was also supported by grants to the National Institute of Immunology by Department of Biotechnology, India.
PY - 2005/3/4
Y1 - 2005/3/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2005.02.009
DO - 10.1016/j.molcel.2005.02.009
M3 - Article
C2 - 15749014
AN - SCOPUS:14644408803
SN - 1097-2765
VL - 17
SP - 631
EP - 643
JO - Molecular Cell
JF - Molecular Cell
IS - 5
ER -