U.S.-Japan Cooperative Science: Structural Analysis of Histamine N-methyltransferase and Development of Specific Inhibitors for Clinical Use

Emory University, Atlanta GA

Investigators

Abstract

0003815 Cheng This award supports a three-year collaborative research project between Professor Xiaodong Cheng of Emory University in Georgia and Professor Masahiro Nishibori of Okayama University in Japan. The researchers will be undertaking a study of the structural analysis of histamine N-methyltransferase and the development of specific inhibitors for clinical use. Histamine mediates a variety of physiologic and pathologic responses in different tissues and cells. In addition to being an important chemical mediator of inflammation, histamine is also involved in neurotransmission. In the central nervous system, histamine signaling is terminated by methylation via N.-methyltransferase (HNMT) which converts histamine to methylhistamine. The goal of the proposal is to design specific and potent inhibitors of HNMT to elevate the histamine level in the central nervous system. The researchers will determine the ternary structures of human HNMT in complex with histamine (substrate) and known inhibitors. These structures will illustrate (l) the interaction between the enzyme and histamine and the reason for it's restricted specificity and (2) the interactions between the enzyme and inhibitors, and the origins of potency and selectivity. The combined knowledge could lead to development of more potent and selective inhibitors. The project brings together the efforts of two laboratories that have complementary expertise and research capabilities. Since Alzheimer's disease is associated with a decrease of the histamine level in the brain, the results of the research could have a potential therapeutic value for treatment of Alzheimer's disease. This research advances international human resources through the participation of postdocs. Through the exchange of ideas and technology, this project will broaden our base of basic knowledge and promote international understanding and cooperation. The researchers plan to publish results of the research in scientific journals and report on the findings at scientific meetings.