Prof. Hung-Wen Liu
Department of Chemistry and College of Pharmacy
University of Texas, Austin
Atypical Reactions in the Biosynthesis of Herbicidins
Abstract: Herbicidins are adenosine-derived nucleoside antibiotics with an unusual tricyclic core structure. Deletion of the genes responsible for formation of the tricyclic skeleton in Streptomyces sp. L-9-10 reveals the in vivo importance of Her4, Her5 and Her6 during the early stages of herbicidin biosynthesis. In vitro characterization of Her4 and Her5 demonstrates their involvement in an initial, two stage CāC coupling reaction that results in net C5′-glycosylation of ADP/ATP by UDP/TDP-glucuronic acid. Biochemical analyses and intermediate trapping experiments imply a non-canonical mechanism of C-glycosylation reminiscent of NAD-dependent S-adenosylhomocysteine hydrolase. Structural characterization of the isolated metabolites suggested possible reactions catalyzed by Her6 and Her7, and subsequent biochemical experiments confirmed the functions of Her6 and Her7 as the C3ā epimerase and C8ā reductase, respectively. An overall herbicidin biosynthetic pathway is thus established based on these observations.
Department of Chemistry and College of Pharmacy
University of Texas, Austin