The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin

Torsten Schwecke, Jesús F. Aparicio, István Molnár, Ariane König, Lake Ee Khaw, Stephen F. Haydock, Markiyan Oliynyk, Patrick Caffrey, Jesús Cortés, John B. Lester, Günter A. Böhm, James Staunton, Peter F. Leadlay

Research output: Contribution to journalArticleScientificpeer-review

385 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7839-7843
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number17
DOIs
Publication statusPublished - 15 Aug 1995
MoE publication typeA1 Journal article-refereed

Keywords

  • FK506
  • peptide synthetase
  • polyketide synthase
  • Streptomyces

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