Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases

The polyketide group of natural products includes antibiotics, immunosuppressants, anticancer drugs and other valuable bioactive compounds. The biosynthesis of these compounds is an area of considerable interest. Polyketide synthases (PKSs) resemble fatty acid synthases (FASs) and are composed of several different enzymes that assemble carbon chains. An acyltransferase (AT) loads a dicarboxylic acid extender unit onto an acyl carrier protein (ACP), where it undergoes condensation with a starter acyl unit in a reaction catalysed by a ketosynthase (KS). The product is a -ketoacyl intermediate that remains thioester-linked to the ACP. The -ketone group may then be processed by ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) domains to yield an alcohol, enoyl or methylene group before the extended chain migrates to a KS for another cycle of extension. When the final polyketide chain length is reached, termination occurs, usually accompanied by cyclisation. FASs generally use acetyl starter and malonyl extender units. As a group, PKSs use a wide range of organic acids as starter units, whereas the extenders may be malonyl, methylmalonyl, ethylmalonyl or methoxymalonyl units. The diversity of polyketide structures results in part from combinatorial assembly of different starter and extender units, together with varying degrees of processing of -ketone groups. Chiral centres are introduced by the use of branched extender units and by the reduction of -ketone groups to alcohols. The introduction of chirality increases the potential diversity further. The PKSs that assemble complex polyketides contain a module for every cycle of chain extension. Each module contains the requisite enzymatic domains, which are covalently linked in the order, KS-AT-reduction domain loop-ACP. Three main types of reduction domain loop exist. These contain KR, DH-KR or DHER-KR domains and determine the extent of -ketone group processing in each cycle. [3] a) H. F. 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