Cytochrome P450 Mark Servos. Introduction Superfamily o Found in all domains of life Monooxygenase Hemoprotein o Heme center.

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Cytochrome P450 Mark Servos

Introduction Superfamily o Found in all domains of life Monooxygenase Hemoprotein o Heme center

Overall Structure Structures will vary! CYP 3A4 17 alpha helixes 4 anti-parallel beta sheets PDB ID: 1W0E

Hydropathy Plot

Sequence Alignment

Structure E—R

Glu 362 Arg 365

Structure F—G-R-C

Gly 444 Gly 438 Cys 442 Phe 435 Arg 440

Mechanism RH + O 2 + NADPH + H + → ROH + H 2 O + 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 InhibitsMinorly 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 –90. IMG: The P450 catalytic cycle. Wikipedia.org. IMG: Angelecin. Wikipedia.org. IMG: Citrus paradisi (Grapefruit, pink). Wikipedia.org. 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) E 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)