engleski

Predicting the nature and timing of epimerisation on a modular polyketide synthase

Modular polyketide synthases (PKSs) are multifunctional enzyme complexes that catalyse the synthesis of a structurally diverse group of secondary metabolites – the polyketides. Many polyketides are produced by Streptomyces and related filamentous bacteria ; some are of commercial significance including the antibiotics erythromycin A and rifamycin, the immunosuppressive macrolide rapamycin and the antitumour compound mithramycin. Since many of these compounds are high value biopharmaceuticals there has been intense interest over recent years in studying the chemistry and molecular biology of biosynthesis on these megasynthases. The modular PKS leading to the formation of the erythromycin polyketide backbone (6-deoxyerythronolide B synthase or DEBS) in Saccharopolyspora erythraea is one of the best studied, especially regarding stereochemistry. Polyketide biosynthesis proceeds via a Claisen condensation between simple carboxylic acids with inversion of configuration to give a (2R) methyl centre. However, the methyl stereochemistry present in the erythromycin polyketide backbone, namely (2R), (4R), (6S), (8R), (10R) and (12S), implies that two epimerisation steps occur. We used a bioinformatics approach to identify a putative epimerase function in the relevant ketoreduction (KR) domains. We postulate that C2 epimerization and C3 ketoreduction are coordinated processes and that the KR domains within modular polyketide synthases should be referred to as isomeroreductases to reflect their bifunctional nature.

Saccharopolyspora erythraea; polyketide synthase; methyl stereochemistry; putative epimerase

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