[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Identifiers :
UNILU:UL-ARTICLE-2011-394
Author, co-author :
Schwecke, T.; University of Cambridge > Department of Biochemistry
Aparicio, J. F.; University of Cambridge > Department of Biochemistry
Molnár, I.; University of Cambridge > Department of Biochemistry
König, Ariane ; University of Cambridge > Department of Biochemistry > Cambridge Center for Molecular Recognition
Khaw, L. E.; University of Cambridge > Department of Biochemistry
Haydock, S. F.; University of Cambridge > Department of Biochemistry
Olinyk, M.; University of Cambridge > Department of Biochemistry
Caffrey, P.; University of Cambridge > Department of Biochemistry
Cortés, J. B.; University of Cambridge > Department of Biochemistry
Lester, J.; University of Cambridge > Department of Biochemistry
Böhm, G. A.; University of Cambridge > Department of Biochemistry
Staunton, J.; University of Cambridge > University Chemical Laboratory
Leadlay, P. F.; University of Cambridge > Department of Biochemistry
