Ketosynthase domain, polyketide synthase

Bingle, L. E. H., Simpson, T. J., and Lazarus, C. M. (1999). Ketosynthase domain probes identify two subclasses of fungal polyketide synthase genes. Fungal Genet. Biol. 26, 209-223. 

Figure 2 Conventional modular type I PKS paradigm, (a) Individual domains in a full type I polyketide synthase extension module. Homodimeric contacts are made in the N-terminal docking, ketosynthase, dehydratase, enoyi reductase, and C-terminal docking domains, (b) PKS system for 10-deoxymethynolide and narbonolide generation.

Figure 1 Hypothetical pentaketide biosynthetic system, which illustrates the enzymatic logic of type I modular polyketide synthases (PKSs) and the catalytic role of acyl transferase (AT) domains. Each AT domain selects substrates from the cellular pool and tethers them as thioesters to acyl carrier protein (ACP) domains. In a typical PKS module, the AT and ACP domains are present in all modules. The ketosynthase (KS) domain is present in all chain extension modules. The dehydratase (DH), enoyl reductase (ER), and ketoreductase (KR) domains are optional domains. The final thioesterase (TE) domain catalyzes the release of the product from the PKS.

Modular PKSs are large multifunctional enzymes. Active sites (domains) within these enzymes ketosynthases (KS), acyltransferases (AT), dehydratases (DH), enoyl reductases (ER), ketoreductases (KR), acyl carrier proteins (AGP) and thioesterases (TE) are organized into modules such that each module catalyzes the stereospecific addition of a new monomer onto a growing polyketide chain and also sets the reduction level of the carbon atoms of the resulting intermediate [70]. In 1994, the heterologous expression of the complete erythromycin polyketide synthase was accomplished. The recombinant... 

The Raps modules have a high degree of homology, the most striking instances of which are the extremely conserved ketosynthase domains (69). There is some sequence diversity, however, in the acyltransfeiase domains. It has been reported that this diversity reflects the specificity of the acyl transferase for an acetate or propionate extender unit (22). It has also been observed that the N-terminus of each multienzyme has a potential atnphipachic domain, which may encourage dimerization of the polyketide synthase modules into catalytically active hotnodimers (69,70). 

S.S. Chandran, H.G. Menzella, J.R. Carney, D.V. Santi, Activating hybrid modular interfaces in synthetic polyketide synthases by cassette replacement of ketosynthase domains. Chem. Biol. 13, 469 74 (2006)... 

M. Jenner et al.. Substrate specificity in ketosynthase domains from Irani-AT polyketide synthases. Angew. Chem. Int. Ed. 52, 1143-1147 (2013)... 

C. Kohlhaas et al.. Amino acid-accepting ketosynthase domain from a Irani-AT polyketide synthase exhibits high selectivity for predicted intermediate. Chem. Sci. 4, 3212-3217 (2013)... 

Substrate Specificity in Ketosynthase Domains from trans-AT Polyketide Synthases... 

Amino Acid-Accepting Ketosynthase Domain from a trans-AT Polyketide Synthase Exhibits High Selectivity for Predicted Intermediate... 

The basic principle of polyketide assembly is highly related to that of fatty acid biosynthesis [14, 16]. In both biosynthetic systems, an acyl-primed ketosynthase (KS) catalyzes chain extension by decarboxylative Claisen condensation with malonate activated by its attachment to coenzyme A or an acyl carrier protein (ACP) via a thioester bond (Scheme 2.2). hi fatty acid synthases (FASs), the resulting ketone is rednced to the corresponding alcohol by a ketore-ductase (KR), dehydrated by action of a dehydratase (DH) to give the alkene with snbseqnent donble-bond reduction by an enoyl rednctase (ER) yielding the saturated system (cf. Section 3.2). The latter can then be transferred onto the KS domain and enter the next cycle of chain extension and complete rednction. This homologation process facilitates the assembly of long-chain satnrated fatty acids, for example, palmitic acid, after seven cycles, which will ultimately be released from the catalytic system by saponification of the... 

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