Unraveling the biosynthesis of penicillenols by genome mining polyketide synthase and nonribosomal peptide synthetase gene clusters in Penicillium citrinum

Penicillenols belong to the family of tetramic acids with anticancer and antibacterial activities. Here, we report the discovery of the biosynthetic gene cluster (pnc) for penicillenol A₁ and E in Penicillium citrinum ATCC9849 by genome mining. We discover the pnc cluster based on the results of gene deletions in P. citrinum and gene cluster heterologous expression in Aspergillus nidulans. We also propose the assembly line of the polyketide synthase module in PncA with the reduction by PncB provides a highly reduce polyketide chain to be further linked with an l -threonine molecule and released from PncA to produce penicillenol E. Further formation of penicillenol A₁ requires the N-methylation of tetramic acid group by PncC. Our work deepens the understanding of the biosynthetic logic for N-methylated tetramic acids and contributes to the discovery of new penicillenols by genome mining.