The objective of the proposed research is to elucidate the catalytic mechanism of heme oxygenase which carries out a oxidative degradation of iron protoporphyrin IX (hemin) into iron (Fe), carbon monoxide (CO), and biliverdin IXalpha. In the proposed research, the catalytic intermeditates will be prepared by using chemically synthesized alpha- hydroxyheme and verdoheme. Electronic and molecular structures of the alpha-hydroxyheme and verdoheme intermediates will be examined by optical absorption, EPR, resonance Raman, and X-ray spectroscopy. To do this, we are combining resources and skills of the research groups at Case Western Reserve Univ., Albert Einsterin College of Medicine, Rice Univ., Yamagata Univ., Riken, Argonne National Lab., and Stanford Synchrotron Radiation Lab. for an efficient utilization of the power of mergining protein engineering, porphyrin synthesis, and advanced spectroscopic techniques. In this project several specific questions concerning the structure, function and mechanisms of heme oxygenase will be addressed. How the enzyme activates molecular oxygen at each step of three mono-oxygenase cycle will be determined; how the enzyme functions when it is bound by CO, its product, will be examined; mechanisms of inhibiting the enzyme will be determined; and the catalytic mechanism will be clarified. In addition to the well- established role of heme oxygenase as a key enzyme of heme catabolism, CO and biliverdine, the products of the enzyme, are now recognized to play significant physiological functions as a free-radical scavenger and a versatile physiological messenger in neurotransmission and vasodilation, respectively. Thus, the mechanism of biliverdin and CO generation and control are of utmost biomedical importance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057272-02
Application #
6138647
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Ikeda, Richard A
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
2
Fiscal Year
2000
Total Cost
$215,738
Indirect Cost
Name
Case Western Reserve University
Department
Physiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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