Polyketides are a pharmalogically important class of natural products biosynthetically produced by polyketide synthases (PKSs). Type I, or modular PKSs function via sequential catalytic sites organized into modules responsible for a single ketide unit elongation of the growing polyketide chain. Incorporation of specific molecular properties is controlled at the module level. Introduction of structural and functional diversity in polyketides may be realized given an effective modular rearrangement strategy. This requires specific knowledge of assembly processes that control recognition between proteins. As modular interfaces consist of acyl carrier protein (ACP) and ketosynthase (KS) domains, alteration of specificity at these sites should prove critical to harnessing true combinatorial potential of modular PKSs. As no direct structural information s available for these systems, comparison to well-characterized, analogous domains from other sources provides insight into possible recognition interfaces. Appropriate amino acid substitutions should result kinetically competent heterologous ACP/KS pairs. The impact of the proposed mutations on communication between modified ACP and other relevant domains will also be addressed. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM072293-02
Application #
6937106
Study Section
Special Emphasis Panel (ZRG1-F04A (20))
Program Officer
Okita, Richard T
Project Start
2004-08-16
Project End
2007-08-15
Budget Start
2005-08-16
Budget End
2006-08-15
Support Year
2
Fiscal Year
2005
Total Cost
$43,976
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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Hicks, Leslie M; Mazur, Matthew T; Miller, Leah M et al. (2006) Investigating nonribosomal peptide and polyketide biosynthesis by direct detection of intermediates on >70 kDa polypeptides by using Fourier-transform mass spectrometry. Chembiochem 7:904-7
Schnarr, Nathan A; Chen, Alice Y; Cane, David E et al. (2005) Analysis of covalently bound polyketide intermediates on 6-deoxyerythronolide B synthase by tandem proteolysis-mass spectrometry. Biochemistry 44:11836-42