Abstract

Bioactive peptides, which function as hormones, neurotransmitters and neuromodulators, and are thus vitally involved in virtually all cellular functions, are known to be generated from larger precursors via a variety of postranslational modifications. In particular, carboxyl terminus amidation is a key structural feature in the bioligical activity of many bioactive peptides. It is now clear that carboxyl-terminal amidation entails two sequential enzymtic steps. The first enzyme peptidylglycine a-amidating monoxygenase (PAM) catalyzes formation of the a-hydroxyglycine derivative of the glycine extended precursor. The second enzyme, peptidylamidoglycolate lyase (PGL) ---first reported by our laboratory--catalyzes dealdylation of the a- hydroxyglycine derevatives to produce the final amidated product plus glyoxylte. Our research program focuses on this carboxly-terminal amidation inhibitors, inactvator and substrate analogs and to delineate the role amidative processing in various cellular-level processes such as vascular function and tumor cell growth.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040540-07
Application #
2900696
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Kitt, Cheryl A
Project Start
1992-02-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2002-03-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Georgia Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332

  Publications

Wang, Hui; Mao, Shu; Chalovich, Joseph M et al. (2008) Tropomyosin dynamics in cardiac thin filaments: a multisite forster resonance energy transfer and anisotropy study. Biophys J 94:4358-69
Bauer, John D; Sunman, Jeffrey A; Foster, Michael S et al. (2007) Anti-inflammatory effects of 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester, potential inhibitors of neuropeptide bioactivation. J Pharmacol Exp Ther 320:1171-7
Sunman, Jeffrey A; Foster, Michael S; Folse, Stacey L et al. (2004) Reversal of the transformed phenotype and inhibition of peptidylglycine alpha-monooxygenase in Ras-transformed cells by 4-phenyl-3-butenoic acid. Mol Carcinog 41:231-46
McIninch, Jane K; McIninch, James D; May, Sheldon W (2003) Catalysis, stereochemistry, and inhibition of ureidoglycolate lyase. J Biol Chem 278:50091-100
Feng, J; May, S W (2001) High-performance liquid chromatographic enantiomeric separation of an enzyme inhibitor which possesses both a chiral center and tautomeric moieties. J Chromatogr A 905:103-9
Abou-Mohamed, G A; Huang, J; Oldham, C D et al. (2000) Vascular and endothelial actions of inhibitors of substance P amidation. J Cardiovasc Pharmacol 35:871-80
Kaesemeyer, W H; Ogonowski, A A; Jin, L et al. (2000) Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate. Br J Pharmacol 131:1019-23
Feng, J; Shi, J; Sirimanne, S R et al. (2000) Kinetic and stereochemical studies on novel inactivators of C-terminal amidation. Biochem J 350 Pt 2:521-30
Moore, A B; May, S W (1999) Kinetic and inhibition studies on substrate channelling in the bifunctional enzyme catalysing C-terminal amidation. Biochem J 341 ( Pt 1):33-40
Cutler, S J; DeWitt Blanton Jr, C; Akin, D T et al. (1998) Pharmacological evaluation of 1-(carboxymethyl)-3,5-diphenyl-2-methylbenzene, a novel arylacetic acid with potential anti-inflammatory properties. Inflamm Res 47:316-24

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