Aspergillus fumigatus, a ubiquitous saprophytic fungus, is a potentially deadly pathogen that causes invasive aspergillosis in immunocompromised individuals. Some studies have indicated a relationship between the secondary metabolites of A. fumigatus and its virulence; therefore an understanding of mycotoxin biosynthesis will shed light on aspergillosis therapy as well as basic biology regarding its pathogenicity. Here, we present a comprehensive characterization of the ftm gene cluster of A. fumigatus with the aim of elucidating the secondary metabolites that arise from the gene cluster and their biosynthesis. Although it has been suggested that the ftm cluster is involved in the biosynthesis of diketopiperazine mycotoxins, such as fumitremorgins and tryprostatins, the biosynthesis that is based on the ftm cluster is mostly obscure. The main points of our study outcomes are as follows: (i) We elucidated all the secondary metabolites that arise from the ftm cluster, including a tremorgenic mycotoxin, verruculogen. (ii) We revealed that the ftm genes direct the biosynthesis of verruculogen through eight steps. Verruculogen was isolated as a tremorgenic mycotoxin in the 1970s and contains the unique epidioxy-bridge in the structure. (iii) We discovered the novel enzyme FtmF. This enzyme catalyzes the final step in the verruculogen biosynthesis, i.e., epidioxy formation of fumitremorgin B. (iv) We collected the natural products of the verruculogen biosynthesis and characterized its breast cancer resistance protein inhibitory activity.
