Many important pharmaceuticals, including the antibiotic erythromycin and the immunosuppressant rapamycin, belong to a diverse class of molecules called polyketides. These complex molecules are synthesized by modular polyketide synthases (PKSs) - enormous enzymes that are directly analogous to assembly lines. Our group seeks to understand this chemical machinery and engineer it to produce new molecules and new medicines.
Each enzyme within these megasynthases operates on a polyketide only once during its synthesis. Transformations catalyzed by PKS enzymes include carbon-carbon bond formation, cyclizations, and stereospecific reductions and eliminations. Our research attempts to determine the mechanisms and specificities of each enzyme type in order to genetically engineer PKSs to make both derivatives of known polyketides and libraries of completely novel polyketides.
The domain boundaries of enzymes within PKSs have recently been identified, enabling structural studies of isolated domains. The atomic resolution structures of PKS enzymes help build a description of the overall PKS assembly line architecture. They also help elucidate what interactions between PKS enzymes and their substrates are required for correct polyketide processing. The structures of several key PKS enzymes remain to be determined.
PKSs are the enzymatic champions of organic synthesis, performing complex, stereocontrolled reactions on diverse carbon chains. Our lab is learning how to harness the catalytic potential of isolated PKS enzymes and utilize them to perform desirable chemical transformations. As PKS biocatalysts are catalytically active under ambient conditions in an aqueous environment, they can be considered a new paradigm in "green chemistry."