THE DICTYOSTELIUM DISCOIDEUM DIPKS14: A MEMBRANE ANCHORED HIGHLY REDUCING ITERATIVE POLYKETIDE SYNTHASE SIMILAR TO ONES FOUND IN PATHOGENIC FUNGI AND MYCOBACTERIALAVANYA MUTHUKUMAR AND KIRAGANDUR MANJUNATHAbstract Naturally occurring iterative type I polyketide synthase enzymes are known to make therapeutic polyketide molecules that act against bacteria, cancer and cholesterol. Identifying and characterizing these enzymes will help develop novel therapeutics. The model organism Dictyostelium discoideum is a soildwelling social amoeba, one of the largest known repositories of type I polyketide synthases and is a potential host system for metabolite and biologics production. Of the 45 Dictyostelium discoideum polyketide synthases (PKS) 39 are Type-I PKSs and none has been characterised. PKSs are condensing enzymes that string together two carbon units to generate a polyketide lipid chain. Type I highly reducing polyketidesynthases are characterized by the presence of multiple catalytic domains on the same polypeptide. These domains are used to first join the subunits and then variously and iteratively reduce, dehydrate, further reduce and finally release the polyketide chain. Here we use bioinformatics and homology based structural modeling to characterize the Dictyostelium discoideum polyketide synthase 14 (DiPKS14). DiPKS14 is a polyketide synthase with evolutionary connections to PKSs from pathogenic fungi and bacteria. Multiple domains on the same polypeptide identify it as a type I PKS enzyme whereas the presence of several reducing catalytic domains define it as a highly reducing type I PKS enzyme. The presence of a C-terminal extended reductase domain confirms that it is a chain releasing enzyme. A polar- non-polar di-domain precedes the conserved catalytic triad of the reductase domain. Two transmembrane regions, one in the enoyl reductase domain and the other in the extended reductse domain predict a membrane anchored PKS. |