Polyketides Synthesis Essay
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).
The 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.
AbstractPolyketides are a diverse class of medically important natural products whose biosynthesis is catalysed by polyketide synthases (PKSs), in a fashion highly analogous to fatty acid biosynthesis. In modular PKSs, the polyketide chain is assembled by the successive condensation of activated carboxylic acid-derived units, where chain extension occurs with the intermediates remaining covalently bound to the enzyme, with the growing polyketide tethered to an acyl carrier domain (ACP). Carboxylated acyl-CoA precursors serve as activated donors that are selected by the acyltransferase domain (AT) providing extender units that are added to the growing chain by condensation catalysed by the ketosynthase domain (KS). The action of ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) activities can result in unreduced, partially reduced, or fully reduced centres within the polyketide chain depending on which of these enzymes are present and active. The PKS-catalysed assembly process generates stereochemical diversity, because carbon–carbon double bonds may have either cis- or trans- geometry, and because of the chirality of centres bearing hydroxyl groups (where they are retained) and branching methyl groups (the latter arising from use of propionate extender units). This review shall cover the studies that have determined the stereochemistry in many of the reactions involved in polyketide biosynthesis by modular PKSs.
Keywords: polyketides; polyketide synthase; stereochemistry; ketosynthase; acyltransferase; ketoreductase; dehydratase; enoylreductasepolyketides; polyketide synthase; stereochemistry; ketosynthase; acyltransferase; ketoreductase; dehydratase; enoylreductase
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MDPI and ACS Style
Kwan, D.H.; Schulz, F. The Stereochemistry of Complex Polyketide Biosynthesis by Modular Polyketide Synthases. Molecules2011, 16, 6092-6115.
Kwan DH, Schulz F. The Stereochemistry of Complex Polyketide Biosynthesis by Modular Polyketide Synthases. Molecules. 2011; 16(7):6092-6115.Chicago/Turabian Style
Kwan, David H.; Schulz, Frank. 2011. "The Stereochemistry of Complex Polyketide Biosynthesis by Modular Polyketide Synthases." Molecules 16, no. 7: 6092-6115.
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