Thursday, August 15, 2013: 4:00 PM
Nautilus 5 (Sheraton San Diego)
A-74528 is a C30 polyketide natural product
that functions as an inhibitor of 2′,5′-oligoadenylate
phosphodiesterase (2′-PDE), a key regulatory enzyme of
the interferon pathway. Modulation of 2′-PDE represents a
unique therapeutic approach for regulating viral infections.
The gene cluster responsible for biosynthesis of A-74528
yields minute amounts of this natural product together
with considerably larger quantities of a structurally
dissimilar C30 cytotoxic agent, fredericamycin. Through
construction and analysis of a series of knockout mutants,
we identified the genes necessary for A-74528 biosynthesis.
Remarkably, the formation of six stereocenters and the
regiospecific formation of six rings in A-74528 appear to be
catalyzed by only two tailoring enzymes, a cyclase and an
oxygenase, in addition to the core polyketide synthase.
The inferred pathway was genetically refactored in a
heterologous host, Streptomyces coelicolor CH999, to
produce 3 mg/L A-74528 in the absence of fredericamycin.
that functions as an inhibitor of 2′,5′-oligoadenylate
phosphodiesterase (2′-PDE), a key regulatory enzyme of
the interferon pathway. Modulation of 2′-PDE represents a
unique therapeutic approach for regulating viral infections.
The gene cluster responsible for biosynthesis of A-74528
yields minute amounts of this natural product together
with considerably larger quantities of a structurally
dissimilar C30 cytotoxic agent, fredericamycin. Through
construction and analysis of a series of knockout mutants,
we identified the genes necessary for A-74528 biosynthesis.
Remarkably, the formation of six stereocenters and the
regiospecific formation of six rings in A-74528 appear to be
catalyzed by only two tailoring enzymes, a cyclase and an
oxygenase, in addition to the core polyketide synthase.
The inferred pathway was genetically refactored in a
heterologous host, Streptomyces coelicolor CH999, to
produce 3 mg/L A-74528 in the absence of fredericamycin.