P136: Identification of the Viridicatumtoxin and Griseofulvin Gene Clusters from Penicillium aethiopicum

Penicillium aethiopicum produces two structurally interesting and biologically active polyketides: the tetracycline-like viridicatumtoxin 1 and the classic antifungal agent griseofulvin 2. Here, we report the concurrent discovery of the two corresponding biosynthetic gene clusters (vrt and gsf) by 454 shotgun sequencing. Gene deletions confirmed that two nonreducing PKSs (NRPKSs), vrtA and gsfA, are required for the biosynthesis of 1 and 2, respectively. Both PKSs share similar domain architectures and lack a C-terminal thioesterase domain. We also identified gsfI as the chlorinase involved in the biosynthesis of 2, because deletion of gsfI resulted in the accumulation of decholorogriseofulvin 3. Comparative analysis with the P. chrysogenum genome revealed that both clusters are embedded within conserved syntenic regions of P. aethiopicum chromosomes. Understanding the enzymatic mechanism by which the anhydrotetracycline-like core of 1 is formed may provide new chemical insights and open up the possibilities to generate novel tetracycline analogs using combinatorial biosynthetic strategies by integrating bacterial and fungal genes that can act on the tetracycline scaffolds. The unusual folding and cyclization of the isoprenoid moiety to form the spirobicylic ring also deserves further investigation. There is also renewed interest in 2 owing to its newly discovered anticancer and antiviral properties. Further functional characterization of the gene cluster may have important implications in producing useful structural analogs either by enzymatic or chemical modifications. In conclusion, discovery of the vrt and gsf clusters have provided the basis for genetic and biochemical studies of the pathways.