Angew. Chem. Int. Ed. Engl., published online 7 May 2013; doi:10.1002/anie.201302406

Biosynthesis of the polyketide lovastatin requires the action of two highly reducing iterative type I polyketide synthases to construct nonaketide and diketide fragments that are coupled together in late stages of the pathway. However, the mechanism by which the nonaketide intermediate dihydromonacolin L acid is released from the LovB synthase is not known as there are no annotated thioesterases in the biosynthetic gene cluster that would be expected to fill this role. Xu et al. reinvestigated the lov gene cluster and identified lovG—annotated as a member of the esterase-lipase family of serine hydrolases—as a possible candidate. A DlovG mutant of Aspergillus terreus showed substantially attenuated production of lovastatin. In vitro assays and heterologous expression of LovG, LovB and an enoylreductase LovC directly demonstrated production and release of dihydromonacolin L acid in the presence of LovG, supporting the proposed activity. To determine whether LovG might have a proofreading function, akin to that described for the thioesterase domain in aflatoxin biosynthesis, the authors examined the products formed in the absence of LovC. LovB alone primarily released two incomplete products, but the addition of LovG yielded three additional products that were consistent with incorrectly formed structures. These results identify the missing thioesterase in the pathway and, as shown in preliminary experiments, will facilitate microbial production of this important natural product.