Abstract
We have been studying the biosynthesis of the diterpene antibiotic pleuromutilin, which is produced by the fungus Clitopilus passeckerianus. The diterpene synthase (DS) that produces the alcohol core, pleuromutol, has been cloned and characterized. The DS catalyzes a two-step rearrangement of the linear precursor GGPP, with the first step being a protonation-initiated cyclization and the second step being promoted by ionization of the allylic diphosphate. Although the sequence of the pleuromutol DS is related to sequences of other bifunctional fungal DS enzymes, the tricyclic core that is formed is unique. A BLAST search with the pleuromutol DS revealed an uncharacterized protein from the dry-rot fungus Serpula lacrymans as having the highest identity (39%; 59% similarity). The S. lacrymans DS gene has been cloned and the product of the cyclase has been identified as ent-kauranol. While ent-kauranol is also a tricyclic diterpene, the overall structure is quite distinct from the pleuromutol skeleton. Attempts are being made to discern the sequence differences that lead to these divergent structures.
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