Bacterial aromatic polyketide synthases (PKS) are multi-functional enzyme complexes responsible for the biosynthesis of numerous biologically and medicinally important molecules. The biosynthesis of the product closely parallels fatty acid biosynthesis, as repeated condensations of malonyl-CoA monomers onto a growing polyketide chain proceeds prior to cyclization to form the product. These PKS use an enzyme from fatty acid biosynthesis, malonyl-CoA acyl carrier protein transacylase (MAT) to initially recruit and incorporate malonyl-CoA groups. The MAT enzyme is specific for malonyl-CoA, however structural data has allowed us to identify residues, which we believe exert an influence on substrate specificity. A mutational analysis is described which we propose will affect a relaxation of this specificity with a minimal affect on the catalytic capabilities of the enzyme. This work will help define the factors involved in substrate recruitment of the MAT enzymes, as well as providing insight into the general determinants of substrate specificity. This information is desirable for the rational design of efficiently biosynthesized unique polyketide metabolites.
