Modulation of Polyketide Synthase Activity by Accessory Proteins During Lovastatin Biosynthesis

Abstract

Polyketides, the ubiquitous products of secondary metabolism in microorganisms, are made by a process resembling fatty acid biosynthesis that allows the suppression of reduction or dehydration reactions at specific biosynthetic steps, giving rise to a wide range of often medically useful products. The lovastatin biosynthesis cluster contains two type I polyketide synthase genes. Synthesis of the main nonaketide-derived skeleton was found to require the previously known iterative lovastatin nonaketide synthase (LNKS), plus at least one additional protein (LovC) that interacts with LNKS and is necessary for the correct processing of the growing polyketide chain and production of dihydromonacolin L. The noniterative lovastatin diketide synthase (LDKS) enzyme specifies formation of 2-methylbutyrate and interacts closely with an additional transesterase (LovD) responsible for assembling lovastatin from this polyketide and monacolin J.

Production of lovastatin by Aspergillus terreus: effects of the C:N ratio and the principal nutrients on growth and metabolite production

“…tatin is synthesized via the polyketide pathway [18,19]. After addition of lactose at 144 h of culture, a lovastatin specific generation rate of 0.242 mg (g biomass) −1 h −1 was obtained for the three C:N values tested.…”

Type III polyketide synthases in natural product biosynthesis

“…In a noniterative modular PKS, each module is used only once, and the polyketide intermediate is transferred to a downstream module for chain elongation. The well-known anti-cholesterol natural product lovastatin is synthesized by two noniterative type I PKSs in Aspergillus terreus (2), whereas the antibiotic erythromycin is synthesized by a bacterial iterative type I PKS consisting of a loading module and six extension modules (3). Different from both of these is type II PKS, a large multienzyme complex of small, discrete enzymes with particular functions.…”

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

“…Selective processing during two successive iterations of polyketide chain extension is a known feature in highly reducing fully iterative polyketide synthases 29, 30, 31. In the LovB PKS, for example, which synthesizes the nonaketide core of the cholesterol‐lowering compound lovastatin using a single PKS module, an integral methyltransferase domain selectively methylates the β‐ketothioester formed after three rounds of chain extension 29.…”

“…In the LovB PKS, for example, which synthesizes the nonaketide core of the cholesterol‐lowering compound lovastatin using a single PKS module, an integral methyltransferase domain selectively methylates the β‐ketothioester formed after three rounds of chain extension 29. In vitro analysis of model thioester substrates for LovB has demonstrated that the methyltransferase is exquisitely specific for the tetraketide substrate, and that for this substrate, methylation effectively outcompetes prior ketoreduction 32.…”