Calicheamicin gamma1 from Micromonospora echinospora spp. calichensis is the most prominent of the 10- membered enediyne family with respect to its unprecedented molecular architecture, spectacular biological activity and clinical value. As such, calicheamicin is an excellent target for the study of natural product biosynthesis and self-resistance. The objective of the first phase of this study was to i) pursue the biosynthesis of the DNA-delivery component of calicheamicin (the aryltetrasaccharide, comprised of four uniquely functionalized sugars), ii) develop the genetic tools (transformation and gene disruption protocols) to address calicheamicin biosynthesis in Micromonospora and iii) investigate the mechanism(s) of calicheamicin self-resistance in Micromonospora. With these goals achieved and new tools/information in place, the second phase of this massive project will predominately focus upon expanding this program toward understanding and exploiting the complex biosynthesis of the enediyne core. While continuing our focus upon calicheamicin as a model for 10-membered enediyne biosynthesis, a second complimentary 10-membered enediyne model will be pursued (namely, dynemicin from Micromonospora chersina) selected for its unique architecture (an unprecedented fused enediyne-anthracycline), predominate biological activity, anticipated small gene locus size (excellent for production of dynemicin in 'genetically-friendly' heterologous hosts) and the opportunity for comparative genomics of the calicheamicin and dynemicin biosynthetic loci. The fundamental vision of this program remains constant - to present rational strategies from which to build a foundation of knowledge regarding 10-membered enediyne biosynthesis and self-resistance; the consequence of which will continue to provide pioneering discoveries in enzymatic transformation, tools for the rational biosynthetic modification of natural product drug leads, the potential for enediyne overproducing strains and possibly even an enediyne combinatorial biosynthesis program.
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