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Biomimetic Analogue
Design
A third unique aspect to our program is a subset of analogues whose
structures are designed under the constraints of polyketide
biosynthesis. In addition to probing the bound conformation, the
biological activity of these compounds has implications on the
evolution of polyketide structures. These constraints include
modification to:
A. the oxidation state and
stereochemistry at odd-numbered carbons,
B. alkyl substitution and
stereochemistry at even-numbered carbons,
C. unsaturation (olefin
geometry) at even->odd positions.
D. oxygenation at even numbered carbons (added by post PKS oxidases)
If a biomimetic analogue is found to have significant activity it
may be accessible via fermentation techniques with engineered
microorganisms. In fact, recent advances in PKS technologies of the
past decade have placed polyketide natural products in a unique
position as leads in pharmaceutical discovery as well as process
research. Heterologous expression of PKS genes in alternative hosts has
provided increased production as well as the elimination of undesired
biosynthetic modifications. Moreover, precursor-directed biosynthesis
has provided access fermentation-based production of polyketide
analogues not accessible through natural product degradation and
modification
Current efforts include the development of a
fermentation based approach to 14-substituted epothilone analogues and
the characterization of PKS gene clusters of unique natural products.
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