Why Is The Liver Microsomal Cytochrome P450 Such A Versatile And Unique Enzyme?
Dr. Anthony Lu, PhD
Adjunct Professor In Residence
Susan Lehman Cullman Laboratory for Cancer Research
Rutgers State University of New Jersey
Piscataway, New Jersey
Unlike traditional, well-behaved enzymes, liver microsomal cytochrome P450 has very broad substrate specificity, low turnover rate, poor coupling in catalytic cycle and other unusual properties. What structural features of cytochrome P450 contribute to the uniqueness and versatility of this group of enzyme? A spacious and flexible active site of liver microsomal P450 can accommodate large number of drug substrates. The considerable mobility of substrates at the P450 active site makes it possible for the enzyme to generate multiple metabolites from a single substrate. The active oxygen species generated during catalysis at the heme iron are powerful oxidants, capable of catalyzing carbon and heteroatom oxidation and other reactions. Lack of complementary binding of substrates to the P450 active site contributes to the low turnover rate and poor electron transport efficiency. The interaction of camphor and CYP101 (P450cam) will be used to illustrate the importance of complementary substrate-enzyme interaction in catalysis and to contrast the properties of P450cam and the liver microsomal cytochrome P450.
Anthony Lu received his Ph.D. degree in Biochemistry from the University of North Carolina and did his postdoctoral work with Professor Minor J. Coon at the University of Michigan. The focus of his postdoctoral research was on the solubilization, resolution and reconstitution of the cytochrome P450 system. He spent the next 30 years working in the area of drug metabolism, first at Hoffmann-La Roche, then at Merck Research Laboratories. In addition to pursuing his research interests on the structure, function and regulation of cytochrome P450, he was heavily involved in preclinical and clinical ADME studies, particularly the application of basic cytochrome P450 knowledge in support of drug discovery and development. After his retirement from Merck in 1997, he joined the Department of Chemical Biology, College of Pharmacy, Rutgers University as an adjunct Professor. He is currently involved in teaching, consulting, and research related to individual variability in drug response and drug safety. He is an author or co-author of 245 research papers, and received the B. B. Brodie Award in 1996. The 1998 December issue of Drug Metabolism and Disposition was dedicated to honor his contributions to drug metabolism research.
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