Condensation reaction, polyketide

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

Tropf, S. et al., Reaction mechanisms of homodimeric plant polyketide synthases (stilbenes and chalcone synthase) a single active site for the condensing reaction is sufficient for synthesis of stilbenes, chalcones, and 6 -deoxychalcones. J. Biol. Chem., 270, 7922, 1995. 

Schroder, J., Plant polyketide synthases a chalcone synthase-type enzyme which performs a condensation reaction with methylmalonyl-CoA in the biosynthesis of C-methylated chalcones. 

Polyketides constitute a large class of natural products grouped together on purely biosynthetic grounds. Their diverse structures can be explained as being derived from poly-P-keto chains, formed by coupling of acetic acid (C2) units via condensation reactions,... 

Despite their enormous structural diversity, polyketide metabolites are related by their common derivation from highly functionalised carbon chains whose assemblies are controlled by multifunctional enzyme complexes, the polyketide synthases (PKSs) which, like the closely related fatty acid synthases, catalyse repetitious sequences of decarboxylative condensation reactions between simple acyl thioesters and malonate, as shown in Fig. 3 [7]. Each condensation is followed by a cycle of modifying reactions ketoreduction, dehydration and enoyl reduction. In contrast to fatty acid biosynthesis where the full cycle of essentially reductive modifications normally follow each condensation reduction, the PKSs can use this sequence in a highly selective and controlled manner to assemble polyketide intermediates with an enormous number of permutations of functionality along the chain. As shown in Fig. 3, the reduction sequence can be largely or entirely omitted to produce the classical polyketide intermediate which bears a carbonyl on every alternate carbon and which normally cyclises to aromatic polyketide metabolites. On the other hand, the reductive sequence can be used fully or partially after each condensation to produce highly functionalised intermediates such as the Reduced polyketide in Fig. 3. Basic questions to be answered are (i) what is the actual polyketide intermediate... 

Figure 1. General condensation reaction in polyketide biosynthesis. The starter units are attached to thiol groups of the ketosynthase (KS), and extender units to thiol groups of either acyl carrier protein or acetyl coenzyme A (X).

Type II PKS complexes are comprised at a minimum of four types of subunits encoded by discrete open reading frames acyl carrier protein, ketosynthase a, ketosynthase p (also referred to as chain length factor ), and a malonyl CoA acyltransferase responsible for loading acyl-CoA extender units on to the acyl carrier protein subunit (34 Fig. 4). Additional subunits containing ketoreductase, cyclase, or aromatase activity may also occur in more complex type II synthases. Typically, the four core subunits (acyl carrier protein, ketosynthase a, ketosynthase p, and malonyl-CoA acyltransferase) participate in the iterative series of condensation reactions until a specified polyketide chain length is achieved, then folding and cyclization reactions yielding the final... 

The type III plant and bacterial synthases feature the least complex architecture among the three PKS types, occurring as comparatively small homodimers possessing subunits between 40-45 kDa in size. As in the case for type II enzymes, type III PKSs catalyze iterative decarboxylative condensation reactions typically using malonyl-CoA extender units, however in contrast to type II synthases, the subsequent cyclization and aromatization of the nascent polyketide chains occurs within the same enzyme active site (25). Also unique to this family of PKSs, free CoA thioesters are used directly as substrates (both starter an extender units) without the involvement of acyl carrier proteins. 

Polyketides are a diverse class of compounds that are often created by a series of modular enzymes which condense and then modify chains of acetate or propionate units primarily through reduction, dehydration, cyclization, and aromatization reactions. Polyketides, with their enormous structural variety, show a broad range of biological activities (see Chapters 1.10 and 1.11). 

Fig. 5.3 Key reactions in polyketide biosynthesis. (A) The decarb-oxylative condensation reaction that builds the polyketide chain. (B) Modifications that can occur between condensation steps.

The polyketide synthesis chemically and biochemically resembles that of fatty acids. The reaction of fatty acid synthesis is inhibited by the fungal product ceru-lenin [9]. It inhibits all known types of fatty acid synthases, both multifunctional enzyme complex and unassociated enzyme from different sources like that of some bacteria, yeast, plants, and mammalians [10]. Cerulenin also blocks synthesis of polyketides in a wide variety of organisms, including actinomycetes, fungi, and plants [11, 12]. The inhibition of fatty acid synthesis by cerulenin is based on binding to the cysteine residue in the condensation reaction domain [13]. Synthesis of both polyketide and fatty acids is initiated by a Claisen condensation reaction between a starter carboxylic acid and a dicarboxylic acid such as malonic or methylmalonic acid. An example of this type of synthesis is shown in Fig. 1. An acetate and malonate as enzyme-linked thioesters are used as starter and extender, respectively. The starter unit is linked through a thioester linkage to the cysteine residue in the active site of the enzymatic unit, p-ketoacyl ACP synthase (KS), which catalyzes the condensation reaction. On the other hand, the extender... 

The less clearly understood aromatic PKSs utilize a single KS(CLF)/ACP pair capable of multiple elongation reactions to construct the complete polyketide backbone. The number of elongation events is controlled by the CLF associated with the KS domain. Transthioesterification and decarboxylative condensation reactions proceed in an analogous fashion to modular systems. The ultimate topology of advanced aromatic polyketides is controlled by precise combination of tailoring enzymes responsible for redox chemistry and cyclization pattern. 

The term polyketide may be used to describe a vast array of natural products whose structures differ extensively but which are related to each other by an overall similarity in biosynthetic origin. They are all formed from Q units by condensation reactions and share a number of other features. These... 

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