This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The copper enzyme, dopamine beta-monooxygenase (DbM;E.C., plays a central role in catecholamine neurotransmitter biosynthesis. Consequently, the chemical and the kinetic mechanisms of DbM have been extensively studied during the last five decades. However, the correlation of the experimental findings with the structural parameters of D-beta-M is lagging behind due to the lack of structural and molecular details of the active site of the enzyme. The overall objective of the proposed studies is to express human D-beta-M in a system suitable for site-directed mutagenesis studies and to carry out systematic biochemical, biophysical, and structural and mechanistic studies using purified recombinant wild type and mutant proteins. D-beta-M has long been recognized as an important target for the modulation of sympathetic nervous system activity for therapeutic purposes due to its central role in the biosynthesis of the neurotransmitter NE. For example, the vital role of the sympathetic nervous system and its neurotransmitter NE in the development and maintenance of hypertension and congestive heart failure have been extensively studied. Recent studies have also shown that the regulation of DbM activity in vivo may have beneficial effects on the treatment of cocaine addiction. Therefore, better understanding of the structure-activity relationship of DbM at the molecular level will be important in determining the etiology of these diseases and eventual development of effective therapeutics. In addition, DbM is prototypical of a large group of relatively more specific non-heme monooxygenases and the details of its catalytic mechanism.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
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National Center for Research Resources Initial Review Group (RIRG)
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University of Kansas Lawrence
Schools of Pharmacy
United States
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