Cytochrome P450 enzyme细胞色素P450酶.pptVIP

Cytochrome P450 F.G. Guengerich S.D. Black T. Wolff, G. Strobl and H. Greim Sean Ekins F.J. Gonzalez Lecture Introduction to Cytochrome P450. Cytochrome P450 reactions Cytochrome P450 Structure P450 Substrates and Inhibitors prediction and design Introduction R.T. Williams - in vivo, 1947. Brodie – in vitro, from late 40s till the 60s. Cytochrome P450 enzymes (hemoproteins) play an important role in the intra-cellular metabolism. Exist in prokaryotic and eukaryotic (plants insects fish and mammal, as well as microorganisms) Different P450 enzymes can be found in almost any tissue: liver, kidney, lungs and even brain. Plays important role in drugs metabolism and xenobiotics. P450 Reactions Cytochrome P450 enzymes catalyze thousands of different reaction. Oxidative reactions. SH + O2 + NADPH + H+ SOH + H2O + NADPH+ The protein structure is believed to determines the catalytic specificity through complementarity to the transition state. General Features of Cytochrome P450 Catalysis Substrate binding (presumably near the site of the heme ligand) 1-electorn reduction of the iron by flavprotein NADPH cytochrome P450 reductase Reaction of ferrous iron with O2 to yield an unstable FeO2 complex Addition of the second electron from NADPH or cytochrome b5 Heterolytic scission of the FeO-O(H) bond to generate a formal (FeO)3+ Oxidation of the substrate. Formal abstraction of hydrogen atom or electron Radical recombination Release of the product. Oxidative Reactions Carbon Hydroxylation Heteroatom Hydroxylation Heteroatom Release Rearangement Related to Heteroatom Oxidations Oxidation of π-System Hypervalent Oxygen substrate Reductive Reactions Humans CYP450 -18 families, 43 subfamilies CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene) CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes) CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes) CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudoge