Solving the Puzzle of One-Carbon Loss in Ripostatin Biosynthesis.

Authors :: Fu C
Auerbach D
Li Y
Scheid U
Luxenburger E
Garcia R
Irschik H
Müller R
Source :: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Feb 13; Vol. 56 (8), pp. 2192-2197. Date of Electronic Publication: 2017 Jan 18.
Publication Year :: 2017
Abstract: Ripostatin is a promising antibiotic that inhibits RNA polymerase by binding to a novel binding site. In this study, the characterization of the biosynthetic gene cluster of ripostatin, which is a peculiar polyketide synthase (PKS) hybrid cluster encoding cis- and trans-acyltransferase PKS genes, is reported. Moreover, an unprecedented mechanism for phenyl acetic acid formation and loading as a starter unit was discovered. This phenyl-C2 unit is derived from phenylpyruvate (phenyl-C3) and the mechanism described herein explains the mysterious loss of one carbon atom in ripostatin biosynthesis from the phenyl-C3 precursor. Through in vitro reconstitution of the whole loading process, a pyruvate dehydrogenase like protein complex was revealed that performs thiamine pyrophosphate dependent decarboxylation of phenylpyruvate to form a phenylacetyl-S-acyl carrier protein species, which is supplied to the subsequent biosynthetic assembly line for chain extension to finally yield ripostatin.<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)