S111: Natural Products and Biofuels in the Cyanobacterial Biosynthetic Continuum

During the past decade we have expanded our analysis of microbial natural product systems by investigating a range of marine and terrestrial cyanobacterial pathways. This includes detailed studies of the curacin and cryptophycin biosynthetic pathways, and others.  The curacin gene cluster has provided a rich array of unique biossynthetic enzymes, including a novel initiation module, unusual embedded catalytic domains, a uniquely diverse b-branching cassette, and a novel termination domain.  Our studies of the CurA PKS module bearing a tándem triple ACP provided the motivation to visualize and dissect the structure and function of complete PKS proteins using negative staining and cryoEM technology.  The cryptophycin system has continued to provide fascinating insights toward the study of a range of new analogues within this class of cyclic depsiptides. We have synthesized, purified and analyzed a series of synthetic linear chain elongation intermediates bearing unique A subunits to develop a novel chemoenzymatic synthesis of the cryptophycin/arenastatin class of anti-tumor agents.  These studies reveal the remarkable flexibility of the cryptophycin thioesterase domain and the CrpE P450 epoxidase in catalyzing cyclization and epoxidation against a range of unnatural substrates.

This work was supported by NIH grants GM076477, CA108874, and GM078553 and the H. W. Vahlteich Professorship.