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Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases

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Abstract

Lovastatin biosynthesis in Aspergillus terreus involves two unusual type I multifunctional polyketide syntheses (PKSs). Lovastatin nonaketide synthase (LNKS), the product of the lovB gene, is an iterative PKS that interacts with LovC, a putative enoyl reductase, to catalyze the 35 separate reactions in the biosynthesis of dihydromonacolin L, a lovastatin precursor. LNKS also displays Diels-Alderase activity in vitro. Lovastatin diketide synthase (LDKS) made by lovF, in contrast, acts non-iteratively like the bacterial modular PKSs to make (2R)-2–methylbutyric acid. Then, like LNKS, LDKS interacts closely with another protein, the LovD transesterase enzyme that catalyzes attachment of the 2–methylbutyric acid to monacolin J in the final step of the lovastatin pathway. Key features of the genes for these four enzymes and others, plus the regulatory and self-resistance factors involved in lovastatin production, are also described.

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Author notes

  1. C. Richard Hutchinson, Jonathan Kennedy, Steven Kendrew & Karine Auclair

    Present address: JK, Kosan Biosciences, Hayward, CA, 94545, USA

Authors and Affiliations

  1. School of Pharmacy and Department of Bacteriology, University of Wisconsin, Madison, USA

    C. Richard Hutchinson, Jonathan Kennedy, Cheonseok Park & Steven Kendrew

  2. Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA, 94545, USA; E-mail

    C. Richard Hutchinson

  3. SK, Biotica Technology, Ltd., Cambridge, UK

    C. Richard Hutchinson, Jonathan Kennedy, Steven Kendrew & Karine Auclair

  4. KA, Department of Pharmaceutical Chemistry, University of California, San Francisco, USA

    C. Richard Hutchinson, Jonathan Kennedy, Steven Kendrew & Karine Auclair

  5. Chemistry Department, University of Alberta, Edmonton, Alberta, Canada

    Karine Auclair & John Vederas

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  1. C. Richard Hutchinson
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  2. Jonathan Kennedy
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Correspondence to C. Richard Hutchinson.

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Hutchinson, C.R., Kennedy, J., Park, C. et al. Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases. Antonie Van Leeuwenhoek 78, 287–295 (2000). https://doi.org/10.1023/A:1010294330190

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