This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polyketides are a structurally diverse class of natural products that have pharmacologically important activities, such as anti-cancer, antibiotic, anti-virus, and immunosuppressive properties. (20% of the top selling drugs in the world are polyketides.) The biosynthesis of polyketides is catalyzed by polykeitde synthases(PKSs), which assemble the carbon backbones of polyketides through repeated condensations between acyl-CoA thioesters, so the diversity in polyketide structures is in part derived from the incorporation of different starter or extender units, selection of the starter and extender units is carried out by acyltransferase(AT) in PKS. Determination of the crystal structures of AT will greatly facilitate the production of novel polyketides by protein engineering or substrate-engineering. Thus far, only the malonyl-specific AT (MAT) in actinorhodin polyketide synthase has been crystallized, while none of the structures of AT domains with different substrate specificities in modular PKSs have been solved and little is known about the structural basis for their substrate specificities. Beam time at SSRL will be utilized to solve crystal structures of MAT mutants, substrate-MAT cocrystals and AT domains in modular PKS, aiming at structural-based novel polyketide design. Our second major discovery utilizing beam time at SSRL is the crystal structure of a functionally unknown enzyme ZhuC in R1128 polyketide synthase. The sequence of ZhuC is homologous to MAT; it was proposed to be the acyltransferase in R1128 polyketide synthase, but its actual function is still not clear. Third, we are currently persuing structure determination of an intact multidalton DEBS protein. Fourth, we will determine the crystal structure of HLA-DQ2 complexed with the immunogenic alpha2-peptide, that is responsible for celiac disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-27
Application #
7370466
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2006-03-01
Project End
2007-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
27
Fiscal Year
2006
Total Cost
$1,929
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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