Natural products biosynthesized by filamentous fungi exhibit complex structures and exciting biological activities.  For example, fumagillin and cytochalasin E produced from Aspergillus species are potent inhibitors of methionine aminopeptidase and angiogenesis, respectively.   Both compounds have been considered for anticancer therapies.  The biosynthesis mechanisms of fumagillin and cytochalasin E have remained relatively unexplored from genetic and biochemical perspectives.  In this presentation, we will focus on the elucidation of the biosynthesis of these two compounds to illustrate the potential for finding new enzymes from fungal biosynthetic pathways.  First, we will talk about the identification of a new membrane bound type I terpene cyclase that converts farnesyl pyrophosphate into trans-b-bergamotene in the fumagillin pathway.  This is the first example of an integral membrane enzyme catalyzing terpene cyclization through ionization of the allylic diphosphate ester to generate an allylic cation.  Then we will talk about a fascinating flavin-dependent monooxygenase that oxidizes a ketone intermediate in the cytochalasin E pathway into a carbonate-containing product.  This is the first example of enzymatic carbonate formation in nature.  Several possible mechanisms for the ketone to carbonate transformation will be considered.   Additional recent examples from our lab will be presented if time is permitted.

Exciting new enzymes from fungal biosynthetic pathways

248th National Meeting (2014)

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