? Small molecule peptide, polyketide and hybrid polyketide/polypeptide natural products are characterized by their potent biological activities and modular biosyntheses. These compounds typically are generated by modular polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS) and hybrid NRPS/PKS enzymes. To date, there has been limited study of the NRPS/PKS interface of hybrid NRPS/PKS enzymes. This proposal seeks to examine the NRPS/PKS interface of epothilone synthase by exploring the promiscuity of the ketosynthase (KS) domain of epoC towards solid phase bound peptide substrates. EpoC, which sits at the hybrid NRPS/PKS interface of epothilone synthase, was chosen for this study because of the pharmaceutical significance of the epothilones and the extensive body of work regarding their biosynthesis. By applying this technology to libraries of peptide substrates a detailed understanding of the substrate specificity of epoC will be developed, opening the door to reengineering epothilone biosynthesis to generation of novel epothilone derivatives. Also, by fusing epoC to additional PKS modules, combinatorial libraries of hybrid polypeptide/polyketide molecules can be accessed for drug discovery by semibiosynthesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM072299-03
Application #
7179269
Study Section
Special Emphasis Panel (ZRG1-F04B (20))
Program Officer
Fabian, Miles
Project Start
2005-01-03
Project End
2007-05-31
Budget Start
2007-01-03
Budget End
2007-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$20,799
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Aron, Zachary D; Fortin, Pascal D; Calderone, Christopher T et al. (2007) FenF: servicing the Mycosubtilin synthetase assembly line in trans. Chembiochem 8:613-6
Aron, Zachary D; Dorrestein, Pieter C; Blackhall, Jonathan R et al. (2005) Characterization of a new tailoring domain in polyketide biogenesis: the amine transferase domain of MycA in the mycosubtilin gene cluster. J Am Chem Soc 127:14986-7