Methylation reactions mediated by S-adenosylmethlonine (AdoMet) are increasingly being recognized as significant control factors in the regulation of a variety of cellular functions. Methylation of nucleic acids is known to have regulatory effects on DNA replication and transcription, and RNA translation. Protein methylation is involved in the regulation of a variety of metabolic processes such as bacterial chemotaxis, sperm mobility, release of neurotransmitters and possibly certain enzymatic activities. AdoMet is also the methyl donor for a vast number of small molecules (e.g., the biosynthesis and/or metabolism of various catechoiamine neurotransmitters). We have studied the structures and functions of enzymes involved in the methyl cycle reactions. A relatively large conformational change has been observed in the enzyme structures upon the binding of substrate or the leaving of product from the active site. In this grant period, Dr. Takusagawa will characterize the dynamic structures as well as the catalytic mechanisms of the following enzymes by X-ray diffraction method. S-adenosylm ethionine synthetase from human, rat, Methanococcus jannaschii, and E. coli. Glycline N-methyltransferase and guanidinoacetate methyltransferase from rat liver. S-adenosylhomocysteine hydrolase from rat liver and Alcaligenes faecalis. S-adenosylmethionine decarboxylase from E. coli. N10-formyl-tetrahydrofolate synthetase from Clostridium cylindrosporum. Serine dehydratase from rat liver. For a long-term objective, we would like to design specific inhibitors of these enzymes in order to develop chemotherapeutic agents using the active site geometries and the catalytic mechanisms of the enzymes gained in this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037233-12
Application #
6385652
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lewis, Catherine D
Project Start
1988-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
12
Fiscal Year
2001
Total Cost
$199,335
Indirect Cost
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045