Dynemicin is a 10-membered enediyne isolated from a soil microbe, <i>Micromonospora chersin</i>, employed for bacterial defense. The enediynes, including dynemicin, have also distinguished themselves as promising candidates for antibacterial or cancer therapeutics due to their unparalleled cytotoxicity via chromosomal double-stranded DNA cleavage. Dynemicin possesses an unusual and complex molecular architecture; the enediyne comprises the characteristic bicyclo “warhead” group and a distinctive anthraquinone peripheral moiety that acts as the anchor governing the bicyclo group’s positioning for hydrogen abstraction. The dynemicin anthraquinone group is synthesized and assembled by an extensive host of enzymes. DynU16, a putative cyclase, DynA1 and DynA2, putative oxidases were selected for pioneering structural efforts to facilitate decoding of the elaborate anthraquinone molecular assembly. Structural determination and analysis via X-ray crystallography will provide high-resolution structures exposing the biocatalytic features that enable regio-, chemo- and stereo-selectivity of the enzymes. Moreover, synergistic biochemical and structural efforts have the promising potential to reveal paradigm-shifting biological chemistry. If the proposed objectives are achieved, structural characterization of the dynemicin biosynthetic machinery will afford valuable perspectives into the intricate enediyne molecular assembly.

Structural interrogation of microbial dynemicin biosynthetic enzymes

256th National Meeting (2018)

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