Serena M. L. Wessely

The naturally occurring enediynesare notable for theircomplexstructures, potent DNA cleaving ability, and emerging usefulness incancer chemotherapy. They can be classified into three distinct structuralfamilies, but all are thought to originate from a common linear C-15-heptaene. Dynemicin A (DYN) is the paradigm member of anthraquinone-fusedenediynes, one of the three main classes and exceptional among themfor derivation of both its enediyne and anthraquinone portions fromthis same early biosynthetic building block. Evidence is growing abouthow two structurally dissimilar, but biosynthetically related, intermediatescombine in two heterodimerization reactions to create a nitrogen-containingC(30)-coupled product. We report here deletions of two genesthat encode biosynthetic proteins that are annotated as S-adenosylmethionine (SAM)-dependent methyltransferases. While one,DynO6, is indeed the required O-methyltransferaseimplicated long ago in the first studies of DYN biosynthesis, theother, DynA5, functions in an unanticipated manner in the post-heterodimerizationevents that complete the biosynthesis of DYN. Despite its removalfrom the genome of Micromonospora chersina, the Delta dynA5 strain retains the ability tosynthesize DYN, albeit in reduced titers, accompanied by two unusualco-metabolites. We link the appearance of these unexpected structuresto a substantial and contradictory body of other recent experimentaldata to advance a biogenetic rationale for the downstream steps thatlead to the final formation of DYN. A sequence of product-formingtransformations that is in line with new and existing experimentalresults is proposed and supported by a model reaction that also encompassesthe formation of the crucial epoxide essential for the activationof DYN for DNA cleavage.