Mycobacterial phenolic glycolipid virulence factor biosynthesis: Mechanism and small-molecule inhibition of polyketide chain initiation Journal Article

   

Authors:	Ferreras, J. A.; Stirrett, K. L.; Lu, X.; Ryu, J. S.; Soll, C. E.; Tan, D. S.; Quadri, LuisE N.
Article 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. © 2008 Elsevier Ltd. All rights reserved.
Keywords:	unclassified drug; genetics; metabolism; enzymology; enzyme inhibitor; biosynthesis; chembio; microbio; chemistry; drug antagonism; mycobacterium tuberculosis; adenosine; enzyme inhibitors; phenols; macrolide; models, chemical; phenol derivative; glycolipid; glycolipids; macrolides; chemical model; long chain fatty acid coenzyme a ligase; coenzyme a ligases; virulence factors; mycobacterium leprae; 4 hydroxybenzoic acid; 4 hydroxybenzoic acid ester; 4-hydroxybenzoic acid; virulence factor; parabens
Journal Title:	Chemistry and Biology
Volume:	15
Issue:	1
ISSN:	1074-5521
Publisher:	Elsevier Inc.
Date Published:	2008-01-01
Start Page:	51
End Page:	61
Language:	English
DOI:	10.1016/j.chembiol.2007.11.010
PUBMED:	18158259
PROVIDER:	scopus
PMCID:	PMC2276623
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-38349074340&partnerID=40&md5=e2649ae9ec0991c768ab0a4ee7c2283b
Notes:	--- - "Cited By (since 1996): 20" - "Export Date: 17 November 2011" - "CODEN: CBOLE" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/14392