A number of enzyme catalyze the chemical reactions in biological systems. Some of these enzymes are located in the ~bottleneck~ positions of biological pathways. Thus, the study of these key enzymes and related areas is important. Methylation reactions mediated by S- adenosylmethionine (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 processess such as bacterial chemotaxis, sperm mobility, release of neurotransmission 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 catecholamine neurotransmitters). Thus, the enzymes that catalyze the methylation reactions are attractive targets for the design of chemotherapeutic agents. This is a proposal to determine the crystal structures of the enzyme in the methyl cycle. Specifically we will determine the structures of the following enzymes in this grant period: 1) Human S- sdenosylmethionine synthetase which catalyzes the formation of AdoMet from ATP and methionine. 2) Guanidinoacetate methyltransferase which catalyzes the AdoMet-dependent methylation of guanidinoacetate to form creatine. 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.
