Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/993
Full metadata record
DC FieldValueLanguage
dc.contributor.authorChopra, Tarun-
dc.contributor.authorBanerjee, Srijita-
dc.contributor.authorGupta, Sarika-
dc.contributor.authorYadav, Gitanjali-
dc.contributor.authorAnand, Swadha-
dc.contributor.authorSurolia, Avadhesha-
dc.contributor.authorRoy, Rajendra P-
dc.contributor.authorMohanty, Debasisa-
dc.contributor.authorGokhale, Rajesh S-
dc.date.accessioned2017-10-24T07:44:27Z-
dc.date.available2017-10-24T07:44:27Z-
dc.date.issued2008-07-
dc.identifier.urihttp://hdl.handle.net/123456789/993-
dc.description.abstractIn 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-beta-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.en_US
dc.publisherPLOSen_US
dc.titleNovel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthaseen_US
dc.journalPLoS Biologyen_US
dc.volumeno6en_US
dc.issueno7en_US
dc.pagese163en_US
Appears in Collections:Molecular Sciences, Publications

Files in This Item:
File Description SizeFormat 
journal.pbio.0060163.PDFOpen access article727.82 kBAdobe PDFView/Open    Request a copy


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.