The Fumagillin Biosynthetic Gene Cluster in <i>Aspergillus fumigatus</i> Encodes a Cryptic Terpene Cyclase Involved in the Formation of β-<i>trans</i>-Bergamotene

Fumagillin <b>1</b> is a meroterpenoid from <i>Aspergillus fumigatus</i> that is known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The genetic and molecular basis for biosynthesis of <b>1</b> had been an enigma despite the availability of the <i>A. fumigatus</i> genome sequence. Here, we report the identification and verification of the <i>fma</i> gene cluster, followed by characterization of the polyketide synthase and acyltransferase involved in biosynthesis of the dioic acid portion of <b>1</b>. More significantly, we uncovered the elusive β-<i>trans</i>-bergamotene synthase in <i>A. fumigatus</i> as a membrane-bound terpene cyclase.