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Polyketide Biosynthesis

Type I Polyketide Sythases

Type I modular polyketide synthases (PKS) were identified in 1990. These giant catalytic enzymes are molecular assembly lines which contain multiple active sites on a single polypetide. In the case of erythromycin biosynthesis the polyketide macrocycle is produced by three enzymes DEBS1, DEBS2, and DEBS3, which function as a complex of molecular weight ~ 2 MDa. Each protein contains numerous domains, each possessing catalytic activity to extend and alter the structure of the polyketide as it passes along the protein. The domains are grouped into extension modules. Each module specifies the chemical structure added to the growing polyketide at each stage.


First, a loading module consisting of an acyltransferase (AT) selects a propionate from propionyl CoA and transfers the propionyl group to an acyl carrier protein (ACP).

Loading1The propionyl group is then transferred to a ketosynthase domain (KS). Subsequently, the polyketide chain is extended by condensation with methylmalonate (from methylmalonyl CoA) pre-loaded on the ACP domain of an extension module.


This process continues along the PKS and other domains such as the ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) domains can reduce each carbonyl group accordingly. Because the erythromycin PKS has one loading module and six extension modules, the result is a heptaketide chain. The polyketide is then released from the enzyme by a thioesterase domain and post PKS enzymes such as glycosyl- and methyltransferases complete the biosynthesis.


Peter Leadlay 2010

Herchel Smith Professor of Biochemistry, Department of Biochemistry, University of Cambridge, Telephone: (01223) 333656, Fax: (01223) 766002