INVESTIGADORES
FERRERAS Julian Alberto
artículos
Título:
Mycobacterial phenolic glycolipid virulence factor biosynthesis: mechanism and small-molecule inhibition of polyketide chain initiation.
Autor/es:
FERRERAS JA, STIRRETT KL, LU X, RYU JS, SOLL CE, TAN DS, QUADRI LE
Revista:
Chemistry & biology
Referencias:
Año: 2008 vol. 15 p. 51 - 61
ISSN:
1074-5521
Resumen:
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