Structural classification and properties of ketoacyl synthases and biotin-dependent carboxylases

Abstract

<p>Acyl-CoA carboxylases (ACCs) and ketoacyl synthases (KSs) are two important enzymes in the fatty acid synthesis and polyketide synthesis systems. ACCs carboxylate acetyl-coenzyme A (acetyl-CoA) to produce malonyl-CoA. After conversion of malonyl-CoA to malonyl-acyl carrier protein (ACP) by acyltransferase catalysis, KSs catalyze the addition of malonyl-CoA to an acyl chain to make the chain two carbon atoms longer. This critical step makes the fatty acid chain grow to a variety of carbon atom lengths.</p> <p>There are tens of thousands of amino acid sequences (primary structures) and hundreds of three-dimensional (tertiary) structures of these enzymes available on public databases such as GenBank (Benson et al., 2005) and the Protein Data Bank (PDB) (Rose et al., 2011). Nevertheless, classification of ACCs and KSs, along with the other enzymes of the fatty acid and polyketide synthesis systems, by their primary and tertiary structures had not been fully done. Such classification should cast new light in these enzyme groups in terms of their catalytic mechanisms, active sites, and substrate specificities.</p> <p>Thus, we constructed a new database to classify thioester-active enzymes (ThYme) by their primary and tertiary structures (Cantu et al., 2011). ThYme, as its name suggests, includes the enzymes working on thioester-containing substrates. It covers eight enzyme groups: the acyl-CoA synthases, ACCs, acyltransferases, KSs, hydroxyacyl dehydratases, enoyl reductases, and thioesterases, and one noncatalytic protein group, the acyl carrier proteins, in the fatty acid and polyketide synthesis systems.</p> <p>This thesis presents the results of structurally classifying the ACCs and KSs. This includes the classification protocols to separate enzymes into families and subfamilies, the contents within each family and subfamily, and further observations and conclusions.</p>