The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin

Torsten Schwecke, Jesús F. Aparicio, Istvan Molnar, 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 journalArticle

367 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 (US)
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
StatePublished - Aug 15 1995
Externally publishedYes

Fingerprint

Polyketides
Sirolimus
Immunosuppressive Agents
Multigene Family
Immunophilins
Multienzyme Complexes
Polyketide Synthases
Genes
Streptomyces
Tacrolimus
Enzymes
Open Reading Frames
Organism Cloning
Catalytic Domain
Proteins
Cell Proliferation
T-Lymphocytes
DNA

Keywords

  • FK506
  • peptide synthetase
  • polyketide synthase
  • Streptomyces

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. / Schwecke, Torsten; Aparicio, Jesús F.; Molnar, Istvan; König, Ariane; Khaw, Lake Ee; Haydock, Stephen F.; Oliynyk, Markiyan; Caffrey, Patrick; Cortés, Jesús; Lester, John B.; Böhm, Günter A.; Staunton, James; Leadlay, Peter F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 17, 15.08.1995, p. 7839-7843.

Research output: Contribution to journalArticle

Schwecke, T, Aparicio, JF, Molnar, I, König, A, Khaw, LE, Haydock, SF, Oliynyk, M, Caffrey, P, Cortés, J, Lester, JB, Böhm, GA, Staunton, J & Leadlay, PF 1995, 'The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin', Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 17, pp. 7839-7843. https://doi.org/10.1073/pnas.92.17.7839
Schwecke, Torsten ; Aparicio, Jesús F. ; Molnar, Istvan ; König, Ariane ; Khaw, Lake Ee ; Haydock, Stephen F. ; Oliynyk, Markiyan ; Caffrey, Patrick ; Cortés, Jesús ; Lester, John B. ; Böhm, Günter A. ; Staunton, James ; Leadlay, Peter F. / The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. In: Proceedings of the National Academy of Sciences of the United States of America. 1995 ; Vol. 92, No. 17. pp. 7839-7843.
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