Work

Stereochemical Assignment of Intermediates in the Rifamycin Biosynthetic Pathway by Precursor-Directed Biosynthesis

Year: 2005

Type: article

Abstract: Natural and semisynthetic rifamycins are clinically important inhibitors of bacterial DNA-dependent RNA polymerase. Although the polyketide-nonribosomal peptide origin of the naphthalene core of rifamycin B is well established, the absolute and relative configuration of both stereocenters introduced by the first polyketide synthase module is obscured by aromatization of the naphthalene ring. To decode the stereochemistry of the rifamycin polyketide precursor, we synthesized all four diastereomers of the biosynthetic substrate for module 2 of the rifamycin synthetase in the form of their N-acetylcysteamine (SNAC) thioester. Only one diastereomer was turned over in vivo into rifamycin B, thus establishing the absolute and relative configuration of the native biosynthetic intermediates.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja051430y

Authors: Ingo V. Hartung, Mathew A. Rude, Nathan A. Schnarr, Daniel Hunziker, Chaitan Khosla

Institution: Stanford University

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases

Awards: G1379865062, Recognition Specificity in Modular Polyketide Synthases, G3768768601, RIFAMYCIN BIOSYNTHETIC ANALOGS, Metabolic Engineering of Polketide Production in E.coli