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

被引：69

作者：

Ferreras, Julian A. ^{[1
]}

Stirrett, Karen L. ^{[1
]}

Lu, Xuequan ^{[2
,3
]}

Ryu, Jae-Sang ^{[2
,3
]}

Soll, Clifford E. ^{[4
]}

Tan, Derek S. ^{[2
,3
]}

Quadri, Luis E. N. ^{[1
,5
,6
]}

机构：

[1] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Tri Inst Res Program, New York, NY 10065 USA

[4] CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA

[5] Cornell Univ, Weill Grad Sch Med Sci, Mol Biol Program, New York, NY 10021 USA

[6] Cornell Univ, Weill Grad Sch Med Sci, Tri Inst Training Program Chem Biol, New York, NY 10021 USA

来源：

CHEMISTRY & BIOLOGY | 2008年 / 15卷 / 01期

关键词：

D O I：

10.1016/j.chembiol.2007.11.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-hydroxyphenyi-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-hydroxyphenyi-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.

引用

页码：51 / 61

页数：11

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