The Substrate‐Protein and Protein‐Protein Interactions of Fatty Acid and Polyketide Mega‐Synthases

Abstract

Polyketide derived natural products are a large and diverse class of secondary metabolites used in the pharmaceutical and agricultural industry. These include antibiotics, immunosuppressant's, chemotherapeutics and insecticides. Examples of valuable polyketide compounds include tetracycline (antibiotic), lovastatin (cholesterol‐lowering) and rapamycin (immunosuppressant). The multi‐domain enzyme complex that is responsible for the biosynthesis of polyketides is known as the polyketide synthase (PKS). Similar to the PKS, the fatty acid synthase (FAS) is a multi–domain enzyme complex that utilizes acyl‐CoA's as building blocks to generate linear poly‐beta keto intermediates that can be subsequently processed via reduction, dehydration or other acyl‐chain modifying reactions. Both FAS and PKS utilize the acyl carrier protein (ACP) that functions as the transporter protein that is covalently tethered to the nascent polyketide intermediate. Polyketide and fatty acid production require three basic biosynthetic steps: (1) Polyketide elongation, (2) polyketide modification and (3) polyketide release from the ACP. How the ACP interacts with enzyme domains from all of these steps is not well understood. Unlike FAS, PKS utilize a much more diverse polyketide starter units, modification reactions that give rise to the rich chemical diversity of polyketide natural products. One of these important modifications includes the regio‐specific cyclization and aromatization of linear poly‐b‐keto intermediates. How the different PKS promote different cyclization patterns is not well understood. Lastly, how polyketide ACP‐tethered intermediates are released from the PKS machinery needs further investigation. An elucidation of the mechanism by which these bioactive polyketides are cyclized and/or released while being tethered to the ACP would be highly significant in the prediction, identification and engineered biosynthesis of new polyketides. Herein we present the structural enzymology of the effect of protein‐substrate and protein‐protein interactions on the product outcomes for these mega‐synthases.