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PolyketidePolyketides are secondary metabolites from bacteria, fungi, plants, and animals. They are formally derived from the polymerization of acetyl and propionyl subunits. They also serve as building blocks for a broad range of natural products or are derivatized. Polyketides are structurally a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Polyketide antibiotics, antifungals, cytostatics, immunosuppressants, anticholesterolemics, antiparasitics, coccidiostatics, animal growth promotants and natural insecticides are in commercial use. Examples Biosynthesis The biosynthesis of polyketides shares striking similarities with the fatty acid biosynthesis. Polyketides are synthesized by one or more specialized polyketide-synthase (PKS) enzyme. The PKS genes for a certain polyketide are usually organized in one operon in bacteria and in gene clusters in eukaryotes. The type I polyketide-synthases are large, highly modular proteins, while type II polyketide-synthases are aggregates of monofunctional proteins. Each type I polyketide-synthase module consists of several domains with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus): - Starting or loading module: AT-ACP-
- Elongation or extending modules: -KS-AT-DH-ER-KR-ACP-
- Termination or releasing module: -TE
Domains: - AT: Acyl-transferase
- ACP: Acyl-carrier-protein with an SH group on the cofactor, a serine-attached 4'PP (4'-phospho-pantethein)
- KS: Keto-synthase with an SH group on a cysteine side-chain
- KR: Keto-reductase
- DH: Dehydratatase
- ER: Enoyl-reductase
- TE: Thio-esterase
The polyketide chain and the starter groups are bound with their carboxy group to the SH groups of the ACP and the KS domain through a thioester linkage: R-C(=O)OH + HS-protein <=> R-C(=O)S-protein + H2O. The growing chain is handed over from one SH group to the next by trans-acylations and is releases at the end by hydrolysis or by cyclization (alcoholysis or aminolysis). Starting stage: - The starter group, usually acetyl-CoA or malonyl-CoA, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.
Elongation stages: - The polyketide chain is handed over from the ACP domain of the previous module to the KS domain of the current module, catalyzed by the KS domain.
- The elongation group, usually malonyl-CoA or methyl-malonyl-CoA, is loaded onto the current ACP domain catalyzed by the current AT domain.
- The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain under CO2 evolution, leaving a free KS domain and an ACP-bound elongated polyketide chain. The reaction takes place at the KSn-bound end of the chain, so that the chain moves out one position and the elangation group becomes the new bound group.
- Optionally, the new fragment of the polyketide chain can be altered stepwise by additional domains. The KR (keto-reductase) domain reduces the β-keto group to a β-hydroxy group, the DH (dehytratatase) domain splits off H2O, resulting in the α-β-unsaturated alkene, and the ER (enoyl-reductase) domain reduces the α-β-double-bond to a single-bond.
- This cycle is repeated for each elongation module.
Termination stage: - The TE (thio-esterase) domain hydrolyzes the completed polyketide chain from the ACP-domain of the previous module.
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