Functional analysis of CYP2D6.31 variant: Homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution

Proteins: Structure, Function and Genetics

Volumn 59, Issue 2, 2005, Pages 339-346

  Allorge, Delphine ^a   Bréant, Didier ^a   Harlow, Jacky ^b   Chowdry, Joey ^b   Lo Guidice, Jean Marc ^a   Chevalier, Dany ^a   Cauffiez, Christelle ^a   Lhermitte, Michel ^a   Blaney, Frank E ^c   Tucker, Geoffrey T ^b   Broly, Franck ^a   Ellis, S Wynne ^b,d  

^a UNIV LILLE   (France)

^b UNIVERSITY OF SHEFFIELD   (United Kingdom)

^c GLAXOSMITHKLINE   (United Kingdom)

^d ROYAL HALLAMSHIRE HOSPITAL   (United Kingdom)

Author keywords

CYP2D6.31; Diminished activity; Homology modeling; Reductase interaction

Indexed keywords

ARGININE; CYSTEINE; CYTOCHROME P450 2D6; CYTOCHROME P450 REDUCTASE; DEBRISOQUINE; DEXTROMETHORPHAN; DRUG METABOLIZING ENZYME; ENZYME VARIANT; HISTIDINE; METOPROLOL; THREONINE;

ALLELE; AMINO ACID SUBSTITUTION; ARTICLE; CONCENTRATION (PARAMETERS); CRYSTAL STRUCTURE; DEMETHYLATION; ENZYME KINETICS; ENZYME MECHANISM; GENE EXPRESSION; GENE EXPRESSION SYSTEM; GENE MUTATION; GENETIC POLYMORPHISM; HUMAN; HYDROXYLATION; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; OXIDATION REDUCTION REACTION; PHENOTYPE; PRIORITY JOURNAL; SURFACE PROPERTY; WILD TYPE; YEAST;

AMINO ACID SUBSTITUTION; ARGININE; CLONING, MOLECULAR; CYTOCHROME P-450 CYP2D6; DEBRISOQUIN; DEXTROMETHORPHAN; GENE FREQUENCY; GENOTYPE; HISTIDINE; HUMANS; KINETICS; MICROSOMES; OXIDATION-REDUCTION; PHENOTYPE; POLYMERASE CHAIN REACTION; RECOMBINANT PROTEINS; SACCHAROMYCES CEREVISIAE; SUBSTRATE SPECIFICITY; VARIATION (GENETICS);

ORYCTOLAGUS CUNICULUS;

EID: 20144387805     PISSN: 08873585     EISSN: None     Source Type: Journal    
DOI: 10.1002/prot.20399     Document Type: Article

References (43)

1. Wolf CR, Smith G. Pharmacogenetics. Br Med Bull 1999;55:366-386.
2. Gaedigk A. Interethnic differences of drug-metabolizing enzymes. Int J Clin Pharmacol Ther 2000;38:61-68.
3. Daly AK, Brockmöller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, Huang JD, Idle JR, Ingelman-Sundberg M, Ishizaki T, Jacqz-Aigrain E, Meyer UA, Nebert DW, Steen VM, Wolf CR, Zanger UM. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996;6:193-201.
4. Marez D, Legrand M, Sabbagh N, Lo-Guidice J-M, Spire C, Lafitte J-J, Meyer UA, Broly F. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997;7:193-202.
5. Evert B, Griese EU, Eichelbaum M. A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn-Schmiedeberg's Arch Pharmacol 1994;350:434-439.
6. 324Pro) expressed by recombinant baculovirus in insect cells. Naunyn-Schmiedeberg's Arch Pharmacol 1997;355:309-318.
7. Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation phenotype - a major determinant of metoprolol metabolism and response. N Engl J Med 1982;307:1558-1560.
8. McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF. Metoprolol metabolism and debrisoquine oxidation polymorphism: population and family studies. Br J Clin Pharmacol 1985;20:555-566.
9. Ellis SW, Rowland K, Ackland MJ, Rekka E, Simula AP, Lennard MS, Wolf CR, Tucker GT. Influence of amino acid residue 374 of cytochrome P-450 2D6 (CYP2D6) on the regio- and enantio-selective metabolism of metoprolol. Biochem J 1996;316:647-654.
10. Ellis SW, Hayhurst GP, Lightfoot T, Smith G, Harlow J, Rowland-Yeo K, Larsson C, Mahling J, Lim CK, Wolf CR, Blackburn MG, Lennard MS, Tucker GT. Evidence that serine 304 is not a key ligand-binding residue in the active site of cytochrome P450 2D6. Biochem J 2000;345:565-571.
11. Omura T, Sato R. The carbon monoxide-binding pigment of liver microsomes I. Evidence for its hemoprotein nature. J Biol Chem 1964;239:2370-2378.
12. Lowry OH, Rosebrough NJ, Fair AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-275.
13. Jeffcote CR. Measurement of substrate and inhibitor binding to microsomal cytochrome P-450 by optical-difference spectroscopy. Methods Enzymol 1978;52:258-279.
14. Lightfoot T, Ellis SW, Mahling J, Ackland MJ, Blaney FE, Biljoo GJ, de Groot MJ, Vermeulen NPE, Blackburn GN, Lennard MS, Tucker GT. Regioselective hydroxylation of debrisoquine by cytochrome P450 2D6: implications for active site modelling. Xenobiotica 2000;30:219-233.
15. Otton SV, Crewe HK, Lennard MS, Tucker GT, Woods HF. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther 1988;247:242-247.
16. Chen ZR, Somogyi AA, Bochner F. Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man. Ther Drug Monit 1990;12:97-104.
17. Williams PA, Cosme J, Stridhar V, Johnson EF, McRee DE. Mammalian microsomal cytochrome P450 monoxygenase: structural adaptations for membrane binding and functional diversity. Mol Cell 2000;5:121-131.
18. Modi S, Paine MJ, Sutcliffe MJ, Lian L-Y, Primrose WU, Wolf CR, Roberts GCK. A model for human cytochrome P450 2D6 based on modelling and NMR studies of substrate binding. Biochemistry 1996;35:4540-4550.
19. Lewis DFV, Eddershaw PJ, Goldfarb PS, Tarbit MH. Molecular modelling of cytochrome P450 2D6 (CYP2D6) based on alignment with CYP102: structural studies on specific CYP2D6 substrate metabolism. Xenobiotica 1997;27:319-340.
20. de Groot MJ, Ackland MJ, Home VA, Alex AA, Jones BC. Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6. J Med Chem 1999;42:1515-1524.
21. de Rienzo F, Fanelli F, Menziani C, de Benedetti PG. Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450IIIA4. J Comp Aided Mol Design 2000;14:93-116.
22. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ, Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 1997;25: 3389-3402.
23. Blaney FE, Raveglia LF, Artico M, Cavagnera S, Dartois C, Farina C, Grugni M, Gagliardi S, Luttmann MA, Martinelli M, Nadler GM, Parini C, Petrillo P, Sarau HM, Scheideier MA, Hay DWP, Giardina GAM. Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists. J Med Chem 2001;44:1675-1689.
24. Dunbrack RL Jr, Karplus M. Backbone-dependent rotamer library for proteins. Application to side-chain prediction. J Mol Biol 1993;230:543-574.
25. Paine MJ, McLaughlin LA, Flanagan JU, Kemp CA, Sutcliffe MJ, Roberts GCK, Wolf CR. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. J Biol Chem 2003;278: 4021-4027.
26. Zhao Q, Modi S, Smith G, Paine M, McDonagh PD, Wolf CR, Tew D, Lian L-Y, Roberts GCK, Driessen HPC. Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 Angresolution. Prot Sci 1999;8:298-306.
27. Sevrioukova IF, Li H, Zhang H, Peterson JA, Poulos TL. Structure of a cytochrome P450-redox partner electron-transfer complex. Proc Natl Acad Sci USA 1999;96:1863-1868.
28. Broly F, Meyer UA. Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. Pharmacogenetics 1993;3:123-130.
29. Ramamoorthy Y, Tyndale RF, Sellers EM. Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics 2001;11:477-487.
30. Yu A, Kneller BM, Rettie AE, Raining RL. Expression, purification, biochemical characterization, and comparative function of human cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 allelic isoforms. J Pharmacol Exp Ther 2002;303:1291-1300.
31. Johansson I, Oscarson M, Yue QY, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-459.
32. Fukuda T, Nishida Y, Imaoka S, Hiroi T, Naohara M, Funae Y, Azuma J. The decreased in vivo clearance of CYP2D6 substrates by CYP2D6*10 might be caused not only by the low-expression but also by low affinity of CYP2D6. Arch Biochem Biophys 2000;380: 303-308.
33. Zanger UM, Fischer J, Raimundo S, Stüven T, Evert BO, Schwab M, Eichelbaum M. Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 2001;11:573-585.
34. Morita S, Shimoda K, Someya T, Yoshimura Y, Kamijima K, Kato N. Steady-state plasma levels of nortriptyline and its hydroxy-lated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psychopharmacol 2000;20:141-149.
35. Wennerholm A, Johansson I, Hidestrand M, Bertilsson L, Gustafsson LL, Ingelman-Sundberg M. Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity. Pharmacogenetics 2001;11:417-427.
36. Tsuzuki D, Takemi C, Yamamoto S, Tamagake K, Imaoka S, Funae Y, Kataoka H, Shinoda S, Narimatsu S. Functional evaluation of cytochrome P450 2D6 with Gly42Arg substitution expressed in Saccharomyces cerevisiae. Pharmacogenetics 2001;11: 709-718.
37. Bapiro TE, Hasler JA, Ridderström M, Masimirembwa CM. The molecular and kinetic basis for the diminished activity of cytochrome P450 2D6.17 (CYP2D6.17) variant - potential implications for CYP2D6 phenotyping studies and the clinical use of CYP2D6 substrate drugs in some African populations. Biochem Pharmacol 2002;64:1387-1398.
38. Marcucci KA, Pearce RE, Crespi C, Steimel DT, Leeder JS, Gaedigk A. Characterisation of cytochrome P4502D6.1 (CYP2D6), CYP2D6.2, and CYP2D6.17 activities toward model substrates dextromethorphan, bufuralol, and debrisoquine. Drug Metab Dispos 2002;30:595-601.
39. Shimada T, Tsumura F, Yamazaki H, Guengerich FP, Inoue K. Characterization of (±)-bufuralol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6. Pharmacogenetics 2001;11:143-156.
40. bm3). Xenobiotica 1995;25:333-366.
41. d: catalytic activities toward benzphetamine and 7-ethoxycoumarin. Biochemistry 1989;28:6848-6857.
42. d wild type, proximal mutants, and distal mutants. Biochemistry 1991;30:1490-1496.
43. d by site-directed mutagenesis. J Biol Chem 1991;266: 3372-3375.