Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum

Olivia Vergnolle, Sivagami Sundaram Chavadi, Uthamaphani R. Edupuganti, Poornima Mohandas, Catherine Chan, Julie Zeng, Mykhailo Kopylov, Nicholas G. Angelo, J. David Warren, Clifford E. Soll, Luis E.N. Quadri

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Phenolic glycolipids (PGLs) are polyketide synthase-derived glycolipids unique to pathogenic mycobacteria. PGLs are found in several clinically relevant species, including various Mycobacterium tuberculosis strains, Mycobacterium leprae, and several nontuberculous mycobacterial pathogens, such as M. marinum. Multiple lines of investigation implicate PGLs in virulence, thus underscoring the relevance of a deep understanding of PGL biosynthesis. We report mutational and biochemical studies that interrogate the mechanism by which PGL biosynthetic intermediates (p-hydroxyphenylalkanoates) synthesized by the iterative polyketide synthase Pks15/1 are transferred to the noniterative polyketide synthase PpsA for acyl chain extension in M. marinum. Our findings support a model in which the transfer of the intermediates is dependent on a p-hydroxyphenylalkanoyl-AMP ligase (FadD29) acting as an intermediary between the iterative and the noniterative synthase systems. Our results also establish the p-hydroxyphenylalkanoate extension ability of PpsA, the first-acting enzyme of a multisubunit noniterative polyketide synthase system. Notably, this noniterative system is also loaded with fatty acids by a specific fatty acyl-AMP ligase (FadD26) for biosynthesis of phthiocerol dimycocerosates (PDIMs), which are nonglycosylated lipids structurally related to PGLs. To our knowledge, the partially overlapping PGL and PDIM biosynthetic pathways provide the first example of two distinct, pathwaydedicated acyl-AMP ligases loading the same type I polyketide synthase system with two alternate starter units to produce two structurally different families of metabolites. The studies reported here advance our understanding of the biosynthesis of an important group of mycobacterial glycolipids.

Original languageEnglish (US)
Pages (from-to)1040-1050
Number of pages11
JournalJournal of Bacteriology
Volume197
Issue number6
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum'. Together they form a unique fingerprint.

  • Cite this

    Vergnolle, O., Chavadi, S. S., Edupuganti, U. R., Mohandas, P., Chan, C., Zeng, J., Kopylov, M., Angelo, N. G., Warren, J. D., Soll, C. E., & Quadri, L. E. N. (2015). Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum. Journal of Bacteriology, 197(6), 1040-1050. https://doi.org/10.1128/JB.02546-14