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 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.
Hartung
Ingo V
IV
Department of Chemistry, Stanford University, Stanford, California 94305-5025, USA.
Rude
Mathew A
MA
Schnarr
Nathan A
NA
Hunziker
Daniel
D
Khosla
Chaitan
C
D000192:Actinomycetales / Q000201:enzymology / Q000378:metabolism; D062365:Aminobenzoates / Q000737:chemistry*; D006836:Hydro-Lyases / Q000737:chemistry*; D062385:Hydroxybenzoates; D015394:Molecular Structure; D048630:Polyketide Synthases / Q000737:chemistry*; D012294:Rifamycins / Q000096:biosynthesis*
D062365:Aminobenzoates; D062385:Hydroxybenzoates; D012294:Rifamycins; C031509:3-amino-5-hydroxybenzoic acid; D048630:Polyketide Synthases; C033974:rifamycin B; C111160:3-amino-5-hydroxybenzoic acid synthase; D006836:Hydro-Lyases