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Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase

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Title Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase
 
Creator Chopra, Tarun
Banerjee, Srijita
Gupta, Sarika
Yadav, Gitanjali
Anand, Swadha
Surolia, Avadhesha
Roy, Rajendra P.
Mohanty, Debasisa
Gokhale, Rajesh S.
 
Subject Polyketide synthases
Mycobacterium tuberculosis
Mycoketide Catalyzed
Biosynthesis
Intermolecular Iterative Mechanism
 
Description In recent years, remarkable versatility of polyketide synthases (PKSs) has been recognized; both in terms of their
structural and functional organization as well as their ability to produce compounds other than typical secondary
metabolites. Multifunctional Type I PKSs catalyze the biosynthesis of polyketide products by either using the same
active sites repetitively (iterative) or by using these catalytic domains only once (modular) during the entire
biosynthetic process. The largest open reading frame in Mycobacterium tuberculosis, pks12, was recently proposed to
be involved in the biosynthesis of mannosyl-b-1-phosphomycoketide (MPM). The PKS12 protein contains two complete
sets of modules and has been suggested to synthesize mycoketide by five alternating condensations of methylmalonyl
and malonyl units by using an iterative mode of catalysis. The bimodular iterative catalysis would require transfer of
intermediate chains from acyl carrier protein domain of module 2 to ketosynthase domain of module 1. Such
bimodular iterations during PKS biosynthesis have not been characterized and appear unlikely based on recent
understanding of the three-dimensional organization of these proteins. Moreover, all known examples of iterative
PKSs so far characterized involve unimodular iterations. Based on cell-free reconstitution of PKS12 enzymatic
machinery, in this study, we provide the first evidence for a novel ‘‘modularly iterative’’ mechanism of biosynthesis. By
combination of biochemical, computational, mutagenic, analytical ultracentrifugation and atomic force microscopy
studies, we propose that PKS12 protein is organized as a large supramolecular assembly mediated through specific
interactions between the C- and N-terminus linkers. PKS12 protein thus forms a modular assembly to perform
repetitive condensations analogous to iterative proteins. This novel intermolecular iterative biosynthetic mechanism
provides new perspective to our understanding of polyketide biosynthetic machinery and also suggests new ways to
engineer polyketide metabolites. The characterization of novel molecular mechanisms involved in biosynthesis of
mycobacterial virulent lipids has opened new avenues for drug discovery.
RSG is a HHMI International Research Scholar and is
also supported by Swarnajayanti Fellowship from DST, India. This
work was also supported by the Centre of Excellence grant from DBT,
India to RSG and AS.
 
Date 2013-11-07T05:15:42Z
2013-11-07T05:15:42Z
2008
27 May 2008
 
Type Article
 
Identifier PLoS Biol., 6(7): e163
http://hdl.handle.net/123456789/83
 
Language en
 
Publisher PLOS