6-deoxyerythronolide B synthase 1 is specifically acylated by a diketide intermediate at the beta-ketoacyl-acyl carrier protein synthase domain of module 2

Biochemistry
N TsukamotoDavid E Cane

Abstract

We have used 6-deoxyerythronolide B synthase (DEBS) as a model system to investigate molecular recognition by a modular polyketide synthase (PKS). DEBS consists of three proteins (DEBS1, -2, and -3) that biosynthesize the polyketide skeleton of the antibiotic erythromycin from propionyl-CoA and methylmalonyl-CoA. Active sites within these multifunctional proteins are organized into biosynthetic "modules", each of which catalyzes a discrete round of polyketide chain elongation and adjusts the appropriate level of beta-ketoacylthioester reduction. Using DEBS1, we demonstrate that there is a substantial degree of molecular recognition in the processing of the natural diketide chain elongation intermediate. Exogenously added (2S,3R)-2-methyl-3-hydroxypentanoic acid N-acetylcysteamine thioester is exclusively recognized by its cognate beta-ketoacyl-acyl carrier protein synthase domain in module 2 (KS2). Labeled diketide specifically acylated DEBS1 in crude protein extracts and limited proteolysis localized the binding to module 2. The precise site of acylation in DEBS1 was established by the finding that a Cys2200 Ala mutant of DEBS1, lacking the KS2 active-site cysteine, did not undergo acylation by the diketide. Pretreatment of th...Continue Reading

Citations

Sep 30, 1998·Current Opinion in Biotechnology·C W Carreras, D V Santi
Feb 19, 2000·Current Opinion in Chemical Biology·R S Gokhale, C Khosla
Jan 30, 2013·Journal of the American Chemical Society·Zhizeng GaoJohn C Vederas
Jun 29, 2000·Annual Review of Biochemistry·C KhoslaD E Cane
Nov 6, 2003·Journal of the American Chemical Society·Suzanne J AdmiraalChristopher T Walsh
Feb 20, 2002·Chemical Reviews·Chaitan Khosla

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