THE BIOSYNTHETIC GENE-CLUSTER FOR THE POLYKETIDE IMMUNOSUPPRESSANT RAPAMYCIN

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