The 2002 Bernard B. Brodie Award lecture: deciphering substrate recognition by drug-metabolizing cytochromes P450.

It is an honor to be the recipient of the 2002 Bernard B. Brodie Award in Drug Metabolism from the American Society for Pharmacology and Experimental Therapeutics. In receiving this award, I join a distinguished group of honorees ([Coon, 1981][1]; [Jerina, 1983][2]; [Mannering, 1986][3]; [Nebert,

[1]  C David Stout,et al.  Structure of a substrate complex of mammalian cytochrome P450 2C5 at 2.3 A resolution: evidence for multiple substrate binding modes. , 2003, Biochemistry.

[2]  T. Poulos,et al.  The structure of the cytochrome p450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid , 1997, Nature Structural Biology.

[3]  J Deisenhofer,et al.  Structure and function of cytochromes P450: a comparative analysis of three crystal structures. , 1995, Structure.

[4]  D. Jerina.  The 1982 Bernard B. brodie Award Lecture. Metabolism of Aromatic hydrocarbons by the cytochrome P-450 system and epoxide hydrolase. , 1983, Drug metabolism and disposition: the biological fate of chemicals.

[5]  T. Poulos,et al.  The FMN to Heme Electron Transfer in Cytochrome P450BM-3 , 1999, The Journal of Biological Chemistry.

[6]  M. J. Coon,et al.  Membrane topology of cytochrome P450 2B4 in Langmuir-Blodgett monolayers. , 1998, Archives of Biochemistry and Biophysics.

[7]  H. H. Dieter,et al.  Functional and structural polymorphism of rabbit microsomal cytochrome P-450 form 3b. , 1982, The Journal of biological chemistry.

[8]  T. Poulos,et al.  Structure of cytochrome P450eryF involved in erythromycin biosynthesis , 1995, Nature Structural Biology.

[9]  D E McRee,et al.  Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. , 2000, Molecular cell.

[10]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[11]  T. Richardson,et al.  A universal approach to the expression of human and rabbit cytochrome P450s of the 2C subfamily in Escherichia coli. , 1995, Archives of biochemistry and biophysics.

[12]  D L Harris,et al.  High-valent intermediates of heme proteins and model compounds. , 2001, Current opinion in chemical biology.

[13]  P. R. Montellano.  The 1994 Bernard B. Brodie Award Lecture. Structure, mechanism, and inhibition of cytochrome P450. , 1995 .

[14]  M. Machius,et al.  Pivotal role of water in the mechanism of P450BM-3. , 2001, Biochemistry.

[15]  S. Sligar,et al.  Single-molecule height measurements on microsomal cytochrome P450 in nanometer-scale phospholipid bilayer disks , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Raucy,et al.  Variations among untreated rabbits in benzo(a)pyrene metabolism and its modulation by 7,8-benzoflavone. , 1985, Molecular pharmacology.

[17]  J. Halpert,et al.  A Rational Approach to Re-engineer Cytochrome P450 2B1 Regioselectivity Based on the Crystal Structure of Cytochrome P450 2C5* , 2003, The Journal of Biological Chemistry.

[18]  E. Johnson,et al.  Allosteric regulation of the 16 alpha-hydroxylation of progesterone as catalyzed by rabbit microsomal cytochrome P-450 3b. , 1983, The Journal of biological chemistry.

[19]  B. Masters,et al.  Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  P. R. Montellano,et al.  Oxidizing species in the mechanism of cytochrome P450 , 2002 .

[21]  M. J. Coon,et al.  Multiple activated oxygen species in P450 catalysis: contributions To specificity in drug metabolism. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[22]  T. Poulos,et al.  Structure of a cytochrome P450-redox partner electron-transfer complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Frey,et al.  Determination of the membrane topology of the phenobarbital-inducible rat liver cytochrome P-450 isoenzyme PB-4 using site-specific antibodies , 1987, The Journal of cell biology.

[24]  D. Ziegler.  The 1990 Bernard B. Brodie Award Lecture. Unique properties of the enzymes of detoxication. , 1991, Drug metabolism and disposition: the biological fate of chemicals.

[25]  U. Muller-eberhard,et al.  Identification of rabbit microsomal cytochrome P-450 isozyme, form 1, as a hepatic progesterone 21-hydroxylase. , 1982, Biochemical and biophysical research communications.

[26]  B. Kemper,et al.  A single amino acid substitution confers progesterone 6 beta-hydroxylase activity to rabbit cytochrome P450 2C3. , 1993, The Journal of biological chemistry.

[27]  Eric F. Johnson,et al.  Sulfaphenazole derivatives as tools for comparing cytochrome P450 2C5 and human cytochromes P450 2Cs: identification of a new high affinity substrate common to those enzymes. , 2003, Biochemistry.

[28]  D. Nebert.  The 1986 Bernard B. Brodie award lecture. The genetic regulation of drug-metabolizing enzymes. , 1988, Drug metabolism and disposition: the biological fate of chemicals.

[29]  Colin N. Dewey,et al.  Initial sequencing and comparative analysis of the mouse genome. , 2002 .

[30]  S. Kawato,et al.  Dynamic structures of adrenocortical cytochrome P-450 in proteoliposomes and microsomes: protein rotation study. , 1992, Biochemistry.

[31]  I. Vakser,et al.  Identification of the Binding Site on Cytochrome P450 2B4 for Cytochrome b 5 and Cytochrome P450 Reductase* , 1998, The Journal of Biological Chemistry.

[32]  O. Gotoh,et al.  Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. , 1992, The Journal of biological chemistry.

[33]  S. Thorgeirsson,et al.  Metabolic processing of 2-acetylaminofluorene by microsomes and six highly purified cytochrome P-450 forms from rabbit liver. , 1984, Carcinogenesis.

[34]  E. Johnson,et al.  Isolation and characterization of a constitutive form of rabbit liver microsomal cytochrome P-450. , 1980, The Journal of biological chemistry.

[35]  Andrew D. Ellington,et al.  genetic analysis: Selection and amplification of rare functional nucleic acids , 1991 .

[36]  W. Kalow.  Pharmacogenetics: Past and future , 1990 .

[37]  G J Kleywegt,et al.  Detection, delineation, measurement and display of cavities in macromolecular structures. , 1994, Acta crystallographica. Section D, Biological crystallography.

[38]  D. Jerina,et al.  Arene oxides and the NIH shift: The metabolism, toxicity and carcinogenicity of aromatic compounds , 1972, Experientia.

[39]  T. Poulos,et al.  Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J Berendzen,et al.  The catalytic pathway of cytochrome p450cam at atomic resolution. , 2000, Science.

[41]  Eric F. Johnson,et al.  Engineering Microsomal Cytochrome P450 2C5 to Be a Soluble, Monomeric Enzyme , 2000, The Journal of Biological Chemistry.

[42]  Benjamin A. Neely,et al.  The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1 , 2003, The Journal of Biological Chemistry.

[43]  E A Merritt,et al.  Raster3D: photorealistic molecular graphics. , 1997, Methods in enzymology.

[44]  T. Poulos,et al.  High-resolution crystal structure of cytochrome P450cam. , 1987, Journal of molecular biology.

[45]  S. Sligar,et al.  A role for Asp-251 in cytochrome P-450cam oxygen activation. , 1994, The Journal of biological chemistry.

[46]  H. Yamazaki,et al.  Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. , 1997, Archives of biochemistry and biophysics.

[47]  G. Vergères,et al.  Identification of the membrane anchor of microsomal rat liver cytochrome P-450. , 1989, Biochemistry.

[48]  C David Stout,et al.  Structure of mammalian cytochrome P450 2C5 complexed with diclofenac at 2.1 A resolution: evidence for an induced fit model of substrate binding. , 2003, Biochemistry.

[49]  Ortiz de Montellano,et al.  Cytochrome P-450: Structure, Mechanism, and Biochemistry , 1986 .

[50]  R. Tukey,et al.  Genetic contributions to the variation among rabbits of liver microsomal deoxycorticosterone synthesis. , 1989, Archives of biochemistry and biophysics.

[51]  F. Guengerich.  The 1992 Bernard B. Brodie Award Lecture. Bioactivation and detoxication of toxic and carcinogenic chemicals. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[52]  S. Sligar,et al.  Hydroxylation of camphor by reduced oxy-cytochrome P450cam: mechanistic implications of EPR and ENDOR studies of catalytic intermediates in native and mutant enzymes. , 2001, Journal of the American Chemical Society.

[53]  M. J. Coon.  The 1980 Bernard B. Brodie award lecture. Drug metabolism by cytochrome P-450: progress and perspectives. , 1981, Drug metabolism and disposition: the biological fate of chemicals.

[54]  V. Njar,et al.  Mechanistic studies on aromatase and related CC bond cleaving P-450 enzymes , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[55]  A. Ito,et al.  Biosynthesis and intracellular sorting of mitochondrial forms of cytochrome P450. , 1991, Methods in Enzymology.

[56]  F. Guengerich.  Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. , 2003, Archives of biochemistry and biophysics.

[57]  J Deisenhofer,et al.  Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450's. , 1993, Science.

[58]  Eric F. Johnson,et al.  Structures of Eukaryotic Cytochrome P450 Enzymes , 1995 .

[59]  A. Y. Lu.  The 1996 Bernard B. Brodie lecture: A journey in cytochrome P450 and drug metabolism research. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[60]  J. Gillette.  The Pennsylvania State University College of Medicine 1991 Bernard B. Brodie Lecture. Insights into deuterium isotope effects on the metabolism of steroid hormones and foreign compounds by cytochrome P-450 enzymes. , 1991, Life sciences.

[61]  S D Black,et al.  Membrane topology of liver microsomal cytochrome P450 2B4 determined via monoclonal antibodies directed to the halt-transfer signal. , 1994, Biochemistry.

[62]  J. Halpert,et al.  Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis. , 2001, Current drug metabolism.

[63]  M. J. Coon,et al.  Multiple mechanisms and multiple oxidants in P450-catalyzed hydroxylations. , 2003, Archives of biochemistry and biophysics.