Date of Award

Spring 2008

Document Type

Dissertation - Restricted

Degree Name

Doctor of Philosophy (PhD)



First Advisor

Sem, Daniel

Second Advisor

Kincaid, James

Third Advisor

Rathore, Rajendra


The cytochromes P450 (CYPs) are a group of heme-containing monooxygenase enzymes that use molecular oxygen to stereoselectively hydroxylate specific substrates. A prototypical bacterial P450 is P450cam. P450cam is a 46 kDa soluble P450 that hydroxylates camphor (1). A prototypical mammalian P450 is CYP284. CYP284 is a 55 kDa membrane protein from rabbit liver that, depending upon the compound, either hydroxylates or demethylates a variety of foreign compounds, such as the drug benzphetamine (1). The mammalian CYPs, being the enzymes predominantly responsible for drug metabolism in humans, are extensively studied. They are somewhat large, membrane-bound proteins with a typical molecular weight of - 65 kDa (1). Consequently, it is difficult to obtain structural information on these proteins, either via X-ray or current multidimensional NMR techniques. Currently, there are close to 10 crystal structures, but no structures while bound to membranes; the mammalian CYPs are too large to structurally characterize with NMR. Hence, there is a need to develop new techniques that rapidly probe at least part of the structure, especially the binding site...



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