Ketosynthase

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.

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 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:

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.

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.

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