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Lovastatin, Compactin, and Related Anticholesterolemic Agents

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Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites

Part of the book series: Fungal Biology ((FUNGBIO))

Abstract

Lovastatin and compactin are two fungal polyketide secondary metabolites isolated from Aspergillus terreus and Penicillium citrinum respectively. They are potent inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase, a key enzyme involved in the regulation of cholesterol biosynthesis, and have spawned a revolution in cholesterol-lowering medications. The biosynthetic pathways of lovastatin and compactin have been studied in great detail, and there are a number of remarkable features. The main 18-carbon skeleton is prepared by an iterative highly reducing polyketide synthase (PKS) that requires an endogenous enoyl reductase (ER) for activity. The PKS and ER work in concert with a high level of selectivity to ensure correct product formation. The bicyclic skeleton is furnished by an enzyme-catalyzed Diels-Alder reaction to provide an unfavored stereoisomer. Further processing by an oxidase and transesterification with a second PKS product furnishes these substrates. Knowledge of the enzymes involved in this biosynthetic pathway has allowed for metabolic engineering processes that improve culture production and allow for the in vivo production of unnatural metabolites with greater pharmaceutical value.

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Authors and Affiliations

  1. Department of Chemistry, University of Alberta, Edmonton, AB, Canada

    David Dietrich & John C. Vederas

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  1. David Dietrich
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  2. John C. Vederas
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Correspondence to John C. Vederas .

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Editors and Affiliations

  1. Department of Molecular Biology, University of León, León, Spain

    Juan-Francisco Martín

  2. Parque Científico de León, Instituto de Biotecnología de León (INBIOTEC), León, Spain

    Carlos García-Estrada

  3. Institute of Chemical Engineering, Vienna University of Technology, Vienna, Austria

    Susanne Zeilinger

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Dietrich, D., Vederas, J.C. (2014). Lovastatin, Compactin, and Related Anticholesterolemic Agents. In: Martín, JF., García-Estrada, C., Zeilinger, S. (eds) Biosynthesis and Molecular Genetics of Fungal Secondary Metabolites. Fungal Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1191-2_12

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