Raman Studies of Mammalian Cytochromes P450

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DESCRIPTION (provided by applicant): The general long term goals of the research program are to gain a molecular level insight into the impressive range of functional diversity displayed by various heme proteins. These substances are of critical importance in human physiology and general biology processes. In facilitating many crucial biochemical processes, including oxygen storage and transport, electron transfer, elimination of reactive peroxides, synthesis of hormones and elimination of accumulated environmental toxins, the inherently diverse chemical reactivity of the heme sites are effectively regulated by intramolecular interactions with the associated polypeptides and controlled further by intermolecular interactions with other proteins or small regulatory molecules. In order to fully understand the pertinent relationship of structure to function, it is important to acquire structural information for not only the stable terminal states in a reaction, but also for the fleeting reaction intermediates. This research program uses powerful resonance Raman and time-resolved resonance Raman techniques applied to native and strategically manipulated heme proteins to reveal the molecular basis for modulation of heme group reactivity. The specific systems to be studied in the research being proposed here are two important sub-classes of cytochrome P450 enzymes involved in human physiology. One class, the steroidogenic P450s catalyze the chemical conversions of critical endogenous substances to form essential steroid hormones. The other subclass metabolizes exogenous substances including pharmaceuticals and environmental pollutants, preparing them for elimination. PUBLIC HEALTH RELEVANCE: Heme proteins are molecules that are of prime importance for proper functioning of many biochemical processes important to human physiology and other forms of life. The main task facing heme protein researchers is to be able to gain insight into the structure of the protein active site, where the key chemical reactions occur, such insight being expected to be very useful in designing treatments for some diseases. The resonance Raman technique being used in this work is one of the most powerful methods to acquire this critical information.