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

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2005-08, Vol.127 (32), p.11202-11203
Main Authors: Hartung, Ingo V, Rude, Mathew A, Schnarr, Nathan A, Hunziker, Daniel, Khosla, Chaitan
Format: Article
Language:English
Subjects:
Actinomycetales - enzymology
Actinomycetales - metabolism
Aminobenzoates - chemistry
Analytical, structural and metabolic biochemistry
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Aromatic and heterocyclic compounds
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Heterocyclic compounds, pigments
Hydro-Lyases - chemistry
Hydroxybenzoates
Medical sciences
Molecular Structure
Other biological molecules
Pharmacology. Drug treatments
Polyketide Synthases - chemistry
Rifamycins - biosynthesis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja051430y