Cytochrome P450

Mark Servos

Introduction• SuperfamilyoFound in all domains of life

• Monooxygenase

• HemoproteinoHeme center

Overall Structure• Structures will

vary!

• CYP 3A4• 17 alpha

helixes• 4 anti-

parallel beta sheets

PDB ID: 1W0E

Hydropathy Plot

Sequence AlignmentMushr 368 SDRGSLPYIDAIVKEVLRWSPVAPLGLPHMTTK-ADEFRGYHIPA-GTLVVGNSW----- Maize 370 EDLSRMPYLKATIKESMRIHPPAPFLLPHFSTH-DCEINGYTIPA-GTRVIVNAWALARD Rice 338 EEYRSLKFSTQVMNEITRISNVTP-GVFRKTLT-DVQVKGYTIPS-GWLVMISPMAVHLN ActinM 259 ----DPSLLPGAIEEMLRWTAPVK-NMCRVLTA-DTEFHGTALCA-GEKMMLLFESANFD Rat 380 KDFAHMPLLKAVIKETLRLYPVVPTNSRIITEK-ETEINGFLFPK-NTQFVLCTYVVSRD Human 395 TDKAQMPYTEATIMEVQRLTVVVPLAIPHMTSE-NTVLQGYTIPK-GTLILPNLWSVHRD Boar 348 DALAQMEYLDMVVNEILRLYPIAA-RLERVCKK-DVEIHGVSVPK-GTVMMVPVFSIHRD Euryar 267 EQVRECEWLEQVIDESLRLYPPAY-SIFREPTT-DVTLGGYRVPA-GSIIALPQWAIHRD ActinS 344 EQVAKLRYVRRVLDESLRLWPTAP-GFAREARE-DTVLGGTHPMRRGAWALVLTGMLHRD Mushr ------------------------------------------------------------ Maize 428 PTCWDKA-EEFFPERFLEQGRDAEVDMYGKDIRFVPFGAGRRICAGATFAIATVEIMLAN Rice 395 PKLFEDP-LKFDPWRWREEKR-----S-SMLKNYMPFGGGVRLCLGAEFSKLFIALFLHI ActinM 312 EAVFCEP-EKFDV-------------Q-RNPNSHLAFGFGTHFCLGNQLARLELSLMTER Rat 438 PSVFPEP-ESFQPHRWLRKREDDNSGI-QHPFGSVPFGYGVRSCLGRRIAELEMQLLLSR Human 453 PAIWEKP-EDFYPNRFLDDQG----QL-IKKETFIPFGIGKRVCMGEQLAKMELFLMFVS Boar 405 PELWPEP-EEFRPERFSKKNK----DS-INPYTYLPFGTGPRNCIGMRFALMNMKLALVR Euryar 324 SDVFDAP-TEFRPSRWTNEFA----SS-VSPGAYFPFAAGPRRCIGERFAKLELKIVLGM ActinS 402 PEVWGADAERFDPDRFDAKAV----RS-RAPHTFKPFGTGARACIGRQFALHEATLVLGL

Structure E—R

Structure E—R

Glu 362

Arg 365

Structure F—G-R-C

Structure F—G-R-C

Gly 444

Gly 438

Cys 442

Phe 435

Arg 440

MechanismRH + O2 + NADPH + H+ → ROH + H2O + NADP+

Xenobiotic Processing• Main function in humans• Found in liver• Reason certain drugs and food cannot be mixed

Furanocoumarin (Angelecin)

Citrus paradisi (Grapefruit, pink)

Furanocoumarin/CYP Interaction

Majorly Inhibits Minorly Inhibits

• Amphetamines• Dextroampheatamine

(Dexedrine®)• Levoamphetamine (Adderall®)

• Antiarrythmics• Amiodarone (Cordarone®)• Dronedarone (Multaq®)

• Antihistimines• Diphenhydramine (Benadryl®)

• Statins• Simvastatin (Zocor®)• Lovastatin (Mevacor®)

• Anxiolytics• Diazepam (Valium®)• Alprazolam (Xanax®)

• Erectile Dysfunction• Sildenafil (Viagra®)• Tadalafil (Cialis®)• Vardenafil (Levitra®)

• HIV Protease Inhibitors• Saquinavir (Invirase®)• Ritonavir (Norvir®)

• Opiates/Opioids• Codeine• Methadone

References• Bailey, D. G., Dresser, G., Arnold, J. M. (2013). Grapefruit-medication interactions: forbidden fruit or

avoidable consequences?. CMAJ. 185 (4) 309–16.

• Gotoh, O. (1992) Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 267. 83–90.

• IMG: The P450 catalytic cycle. Wikipedia.org. http://en.wikipedia.org/wiki/File:P450cycle.svg

• IMG: Angelecin. Wikipedia.org. http://en.wikipedia.org/wiki/File:Angelicin.png

• IMG: Citrus paradisi (Grapefruit, pink). Wikipedia.org. http://en.wikipedia.org/wiki/Grapefruit#mediaviewer/File:Citrus_paradisi_(Grapefruit,_pink)_white_bg.jpg

• Syed, K., Mashele, S. S. (2014) Comparative Analysis of P450 Signature Motifs EXXR and CXG in the Large and Diverse Kingdom of Fungi: Identification of Evolutionarily Conserved Amino Acid Patterns Characteristic of P450 Family. PLoS ONE 9. (4) E95616.

• Williams, P. A., Cosme, J., Vinković, D. M., Ward, A., Angove, H. C., Day, P. J., Vonrhein, C., Tickle, I. J., Jhoti, H. (2004) Crystal structures of human cytochrome P-450 3A4 bound to metyrapone and progesterone. Science. 305 (5684) 683-6.