Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum

Abstract Mycobacterial pathogenesis is hallmarked by lipidic polyketides that decorate the cell envelope and mediate infection. However, factors mediating persistence remain largely unknown. Dynamic cell wall remodeling could facilitate the different pathogenic phases. Recent studies have implicated...

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Autores principales:	Amreesh Parvez, Samir Giri, Gorkha Raj Giri, Monika Kumari, Renu Bisht, Priti Saxena
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/65c763c5e12d45c4ab42447913e3d8b4
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spelling	oai:doaj.org-article:65c763c5e12d45c4ab42447913e3d8b42021-12-02T11:40:16ZNovel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum10.1038/s41598-018-24980-12045-2322https://doaj.org/article/65c763c5e12d45c4ab42447913e3d8b42018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24980-1https://doaj.org/toc/2045-2322Abstract Mycobacterial pathogenesis is hallmarked by lipidic polyketides that decorate the cell envelope and mediate infection. However, factors mediating persistence remain largely unknown. Dynamic cell wall remodeling could facilitate the different pathogenic phases. Recent studies have implicated type III polyketide synthases (PKSs) in cell wall alterations in several bacteria. Comparative genome analysis revealed several type III pks gene clusters in mycobacteria. In this study, we report the functional characterization of two novel type III PKSs, MMAR_2470 and MMAR_2474, in Mycobacterium marinum. These type III pkss belong to a unique pks genomic cluster conserved exclusively in pathogenic mycobacteria. Cell-free reconstitution assays and high-resolution mass spectrometric analyses revealed methylated polyketide products in independent reactions of both proteins. MMAR_2474 protein exceptionally biosynthesized methylated alkyl-resorcinol and methylated acyl-phloroglucinol products from the same catalytic core. Structure-based homology modeling, product docking, and mutational studies identified residues that could facilitate the distinctive catalysis of these proteins. Functional investigations in heterologous mycobacterial strain implicated MMAR_2474 protein to be vital for mycobacterial survival in stationary biofilms. Our investigations provide new insights into type III PKSs conserved in pathogenic mycobacterial species.Amreesh ParvezSamir GiriGorkha Raj GiriMonika KumariRenu BishtPriti SaxenaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amreesh Parvez Samir Giri Gorkha Raj Giri Monika Kumari Renu Bisht Priti Saxena Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
description	Abstract Mycobacterial pathogenesis is hallmarked by lipidic polyketides that decorate the cell envelope and mediate infection. However, factors mediating persistence remain largely unknown. Dynamic cell wall remodeling could facilitate the different pathogenic phases. Recent studies have implicated type III polyketide synthases (PKSs) in cell wall alterations in several bacteria. Comparative genome analysis revealed several type III pks gene clusters in mycobacteria. In this study, we report the functional characterization of two novel type III PKSs, MMAR_2470 and MMAR_2474, in Mycobacterium marinum. These type III pkss belong to a unique pks genomic cluster conserved exclusively in pathogenic mycobacteria. Cell-free reconstitution assays and high-resolution mass spectrometric analyses revealed methylated polyketide products in independent reactions of both proteins. MMAR_2474 protein exceptionally biosynthesized methylated alkyl-resorcinol and methylated acyl-phloroglucinol products from the same catalytic core. Structure-based homology modeling, product docking, and mutational studies identified residues that could facilitate the distinctive catalysis of these proteins. Functional investigations in heterologous mycobacterial strain implicated MMAR_2474 protein to be vital for mycobacterial survival in stationary biofilms. Our investigations provide new insights into type III PKSs conserved in pathogenic mycobacterial species.
format	article
author	Amreesh Parvez Samir Giri Gorkha Raj Giri Monika Kumari Renu Bisht Priti Saxena
author_facet	Amreesh Parvez Samir Giri Gorkha Raj Giri Monika Kumari Renu Bisht Priti Saxena
author_sort	Amreesh Parvez
title	Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
title_short	Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
title_full	Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
title_fullStr	Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
title_full_unstemmed	Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum
title_sort	novel type iii polyketide synthases biosynthesize methylated polyketides in mycobacterium marinum
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/65c763c5e12d45c4ab42447913e3d8b4
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Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum

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