This proposal seeks support for a comprehensive research program In the area of peptide glycosylation. The problems selected for investigation comprise a long range plan to uncover detailed knowledge about (l) peptide- carbohydrate interactions, and (2) the enzymic mechanism of peptide glycosylation. Asparagine glycosylation is a cotranslational protein modification catalyzed by oligosaccharyl-transferase (OST). which results in oligosaccharide attachment to the Asn gamma-carboxamide in Asn-Xaa- Ser/Thr consensus sequences. These N-linked glycoproteins mediate a variety of normal and pathological processes, including protein folding and cell- cell adhesion. Glycoproteins have been proposed to be critical for such cancer processes as tumor metastasis and viral infectivity. We propose to use organic synthesis. multi-dimensional NMR, and mechanistic enzymology to study peptide N-glycosylation. A major goal is to define the structure of Asn glycopeptides and obtain information about intramolecular peptide-sugar interactions. Our strategy relies on synthesis of structurally defined glycopeptide analogs, systematically modified in both the sugar and peptide domains. These molecules will be well suited for multi-dimensional and multinuclear NMR structural and dynamic studies. We also propose to determine, at a basic level, the peptide N-glycosylation mechanism as catalyzed by OST. Besides basic knowledge about glycopeptide structure and function, the proposed research may lead to glycosylation inhibitors with therapeutic value.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA066144-04
Application #
6172271
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$103,600
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742