Precursor-directed biosynthesis: biochemical basis of the remarkable selectivity of the erythromycin polyketide synthase toward unsaturated triketides |
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Authors: | Cane David E Kudo Fumitaka Kinoshita Kenji Khosla Chaitan |
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Institution: | Department of Chemistry, Box H, Brown University, Providence, RI 02912, USA. david_cane@brown.edu |
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Abstract: | The structural basis for the striking stereochemical discrimination among triketide analogs has been investigated by incubating a series of N-acetyl cysteamine (-SNAC) esters of unsaturated triketides with DEBS module 2+TE. The triketide analogs were first screened under a standard set of short-term incubation conditions in the presence of the extender substrate methylmalonyl-CoA and NADPH. For those triketide analogs that served as substrates for module 2+TE, the relative specificity, represented by the k(cat)/K(M) values, was quantitated. Triketide diastereomers that were converted in precursor-directed biosynthesis experiments to unsaturated 16-membered ring macrolides by DEBS(KS1(0)) were good to excellent substrates for DEBS module 2+TE, whereas analogs that were converted to the 14-membered ring analogs of 10,11-dehydro-6-deoxyerythronolide B by DEBS(KS1(0)) were not turned over at all by module 2+TE. |
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