Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the resulting acyl chain is two carbon atoms longer than before. KSs exist as individual enzymes, as they do in type II fatty acid synthesis and type II polyketide synthesis, or as domains in large multidomain enzymes, such as type I fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs are divided into five families: KS1, KS2, KS3, KS4, and KS5.
Multidomain enzyme systems
Fatty acid synthase Fatty acid synthase (FAS) is the enzyme system involved in de novo fatty acid synthesis. FAS is an iterative multienzyme consisting of several component enzymes, one of which is ketoacyl synthase. There are two types of FASs: type I and type II. Type I FASs are highly integrated multidomain enzymes. They contain discrete functional domains responsible for specific catalytic activities of the reaction sequence, either on a single polypeptide chain or on two different multifunctional proteins. Type II FASs are dissociated systems, meaning the component enzymes are independent proteins encoded by a series of separate genes.
Polyketide synthase Polyketide synthases (PKS) are structurally and functionally related to FAS's, both which are enzymes that catalyze the condensation of activated primary metabolites such as acetyl-CoA and malonyl-CoA. The main reaction they catalyze is:
CO2-CH2-CO-S-CoA + CH3-CO-S-PKS → CH3-CO-CH2-CO-S-PKS + CoA-H + CO2 Like FASs, PKSs will use a β-ketoacylsynthase (KS), an optional (malonyl) acyl transferase (MAT/AT), and a phosphopantethienylated acyl carrier protein (ACP) or coenzymeA (CoA). They also both used a ketoreductase, dehydratase, and enoyl reductase to create a fully saturated acyl backbone. Unlike FASs, however, PKSs typically use a larger number of biosynthetic building blocks and form a more varied number of tail lengths. The reductive steps that FASs use are also optional for the PKSs. By potentially omitting them, there is potential for a more complex pattern of functionalization. There are three main types of polyketides: Type I, type II and type III. Type I is very similar to the FAS type I, in that it contains linearly aligned and covalently fused catalytic domains within large multifunctional enzymes. Type II tends to be a more dissociable complex with monofunctional enzyme domains. Another way that PKSs differ is that they have one other type, Type III. Type III PKSs are multifunctional when choosing a starting unit, assembling the chain, and promoting the folding.
Ketoacyl synthase family 1 Nearly all KS1 members are produced by bacteria, with a few formed by eukaryota and only one by an archaeon. There are 12 subfamilies. The dominant enzyme in the KS1 family is 3-ketoacyl-ACP synthase III (KAS III), also known as 3-oxoacyl-ACP synthase III and β-ketoacyl-ACP synthase III, and is defined as EC 2.3.1.180.
β-Ketoacyl-ACP synthase III
The characteristic reaction of β-ketoacyl-ACP synthase III is malonyl-ACP + acetyl-CoA => acetoacyl-ACP + CO2 + CoA. Cysteine, histidine, and asparagine form the catalytic triad in KAS III, which uses the ping-pong kinetic mechanism. In Escherichia coli, one organism KAS III is typically found in, KASIII is weakly inhibited by thiolactomycin. In the same organism, KAS III will have an optimum pH of 7 and an optimum temperature of 30-37 °C. Each organism's inhibitors, optimum pH, and optimum temperatures will vary slightly. However, these numbers are fairly indicative of the enzyme's ideal environment in general.
Ketoacyl synthase family 2 All KS2 enzymes are produced by eukaryota, with nearly all from plants. The most common enzymes in this family are 3-ketoacyl-CoA synthases, fatty acid elongases and very long-chain fatty acid condensing enzymes. The most common general characterization for these enzymes is E.C. 2.3.1.-; however, some are defined as 2.3.1.119. Most enzymes in the KS2 family catalyze reactions to produce very long-chain fatty acids. KS2 can be divided into 10 subfamilies.
3-Ketoacyl-CoA synthase I 3-Ketoacyl-CoA synthase I in Arabidopsis thaliana is involved in very long chain fatty acid synthesis, which plays a role in wax biosynthesis. The enzyme catalyzes the following reaction: very-long-chain acyl-CoA + malonyl-CoA ⇒ very-long-chain 3-oxoacyl-CoA + CoA + CO2 It is an elongase that appears to be involved in the production of very-long-chain fatty acids that are 26 carbons and longer. Mefluidide and perfluidone are selective inhibitors of this enzyme.
Ketoacyl synthase family 3 The KS3 family is the largest family in the KS system, with 14 subfamilies. KS3 enzymes are primarily produced in bacteria, with a small number of eukaryotes and archaea. KSs in this family contain KS domains present in both Type I FASs and the modular Type I of PKSs. While there are many slightly different enzymes in this family, the two most common 3-ketoacyl-ACP synthase I and synthase II.
3-Ketoacyl-ACP synthase I 3-Ketoacyl-ACP synthase I (E.C. 2.3.1.41) is involved in the process of chain-elongation in type II FAS. A consequence of not having this enzyme will be a deficit in unsaturated fatty acids. It uses fatty acyl thioesters of ACP and CoA as substrates and has a specificity close to that of beta-ketoacyl-ACP synthase II.
Typically, this enzyme is used in condensation reactions, as well as decarboxylation and acyl group transfer. The reaction proceeds as such:
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