Fungal NRPS-PKS Hybrid Enzymes Biosynthesize New γ-Lactam Compounds, Taslactams A-D, Analogous to Actinomycete Proteasome Inhibitors.

Abstract

Proteasome inhibitors with γ-lactam structure, such as lactacystin and salinosporamide A, have been isolated from actinomycetes and have attracted attention as lead compounds for anticancer drugs. Previously, we identified a unique enzyme TAS1, which is the first reported fungal NRPS-PKS hybrid enzyme, from the filamentous fungus Pyricularia oryzae for the biosynthesis of a mycotoxin tenuazonic acid, a tetramic acid compound without γ-lactam structure. Homologues of TAS1 have been identified in several fungal genomes and classified into four groups (A-D). Here, we show that the group D TAS1 homologues from two filamentous fungi can biosynthesize γ-lactam compounds, taslactams A-D, with high similarity to actinomycete proteasome inhibitors. One of the γ-lactam compounds, taslactam C, showed potent proteasome inhibitory activity. In contrast to actinomycete γ-lactam compounds which require multiple enzymes for biosynthesis, the TAS1 homologue alone was sufficient for the biosynthesis of the fungal γ-lactam compounds.