The Biosynthetic Gene Cluster for the Polyketide Immunosuppressant Rapamycin

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1995 Aug 15

PMID 7644502

Citations 112

Authors

T Schwecke

J F Aparicio

I Molnar

A Konig

L E Khaw

S F Haydock

M Oliynyk

P Caffrey

J Cortes

J B Lester

Affiliations

Soon will be listed here.

Abstract

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis.

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