title: The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin.
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.
authors.affiliation: Department of Biochemistry, University of Cambridge, United Kingdom.
authors.forename: T
authors.initials: T
authors.lastname: Schwecke
authors.forename: J F
authors.initials: JF
authors.lastname: Aparicio
authors.forename: I
authors.initials: I
authors.lastname: Molnár
authors.forename: A
authors.initials: A
authors.lastname: König
authors.forename: L E
authors.initials: LE
authors.lastname: Khaw
authors.forename: S F
authors.initials: SF
authors.lastname: Haydock
authors.forename: M
authors.initials: M
authors.lastname: Oliynyk
authors.forename: P
authors.initials: P
authors.lastname: Caffrey
authors.forename: J
authors.initials: J
authors.lastname: Cortés
authors.forename: J B
authors.initials: JB
authors.lastname: Lester
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis / Q000235:genetics*; D003001:Cloning, Molecular; D003360:Cosmids; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli; D015723:Gene Library; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D005810:Multigene Family; D016366:Open Reading Frames; D010957:Plasmids; D011090:Polyenes / Q000378:metabolism*; D020123:Sirolimus; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
chemical_list: D004269:DNA, Bacterial; D011090:Polyenes; D000217:Acyltransferases; D020123:Sirolimus