title: Mycobacterial phenolic glycolipid virulence factor biosynthesis: mechanism and small-molecule inhibition of polyketide chain initiation.
abstract: Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by Mycobacterium tuberculosis, M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-S-enzyme covalent intermediate in the p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Ferreras
authors.forename: Karen L
authors.initials: KL
authors.lastname: Stirrett
authors.forename: Xuequan
authors.initials: X
authors.lastname: Lu
authors.forename: Jae-Sang
authors.initials: JS
authors.lastname: Ryu
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Soll
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
authors.forename: Luis E N
authors.initials: LE
authors.lastname: Quadri
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006017:Glycolipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D010226:Parabens / Q000737:chemistry / Q000378:metabolism; D010636:Phenols / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006017:Glycolipids; D018942:Macrolides; D010226:Parabens; D010636:Phenols; D037521:Virulence Factors; D003066:Coenzyme A Ligases; C038193:4-hydroxybenzoic acid; D000241:Adenosine