Resonance Raman Studies of Mammalian Heme Proteins

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The long term research goals of this program are to attain a molecular level understanding of the remarkable functional diversity of heme proteins, substances that are of critical importance in biological systems, in general, and in human physiology in particular. In participating in and facilitating many critical biochemical processes, including oxygen and electron transport, as well as the elimination of internally generated and environmentally accumulated toxins, the inherent reactivity of the heme sites are effectively regulated by intermolecular interactions with the associated polypeptides and further controlled by intermolecular interactions with other proteins and small regulatory molecules. In addition to the more stable initial and final states, a great deal of interest is attached to the fleeting, but functionally important, transient or intermediate states.The essential strategy of this research program is to apply powerful spectroscopic probes, especially resonance Raman and time-resolved resonance Raman techniques, to the native and strategically manipulated proteins in order to reveal the molecular basis for this modulation of heme group reactivity. In fact, it is often the case that these particular methods are uniquely effective probes of these sites. The specific systems to be addressed in the present proposal are three important classes of heme proteins involved in mammalian physiology; cytochromes P450, which catalayze the conversion of xenobiotics, preparing them for elimination; guanylate cyclase, the most important receptor molecule for the neurotransmitter, NO, which serves a crucial regulatory function in human physiology; and, finally, a group of enzymes known as peroxidases that play a critical role in human defence against invading microorganisms.