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The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin.
Open accessAbstract
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.
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Citations
Cited by
Genetic Contributions to Understanding Polyketide Synthases
Hopwood, D. A. (1997) · Chemical Reviews · doi:10.1021/cr960034i · Cited by 710
The Ecological Role of Volatile and Soluble Secondary Metabolites Produced by Soil Bacteria
Tyc, Song, C., Dickschat, J. S., Vos, M., & Garbeva, P. (2017) · Trends in Microbiology · doi:10.1016/j.tim.2016.12.002 · Cited by 490
Nonproteinogenic Amino Acid Building Blocks for Nonribosomal Peptide and Hybrid Polyketide Scaffolds
Walsh, C. T., O'Brien, R. V., & Khosla, C. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201208344 · Cited by 406
Biosynthesis of polyketide synthase extender units
Chan, Y. A., Podevels, A. M., Kevany, B. M., & Thomas, M. G. (2009) · Nat. Prod. Rep. · doi:10.1039/b801658p · Cited by 337
Wu, K., Chung, L., Revill, W. P., Katz, L., & Reeves, C. D. (2000) · Gene · doi:10.1016/s0378-1119(00)00171-2 · Cited by 259
Metadata
- Authors
- Schwecke, T., Aparicio, J. F., Molnár, I., König, A., Khaw, L. E., Haydock, S. F., Oliynyk, M., Caffrey, P., Cortés, J., & Lester, J. B.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1995-08-15
- Volume
- 92
- Issue
- 17
- Pages
- 7839-7843
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1995136001
- Cited by
- 445
- References
- 0
- FWCI
- 20.44
- Type
- journal article
- Language
- en
- Open access
- green
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- Schwecke, T., Aparicio, J. F., Molnár, I., König, A., Khaw, L. E., Haydock, S. F., Oliynyk, M., Caffrey, P., Cortés, J., & Lester, J. B. (1995). The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.92.17.7839
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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