1. Cytochrome P450 Mark Servos

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

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

4. Hydropathy Plot

5. Sequence Alignment

6. Structure E—R

7. Glu 362 Arg 365

8. Structure F—G-R-C

9. Gly 444 Gly 438 Cys 442 Phe 435 Arg 440

10. Mechanism RH + O 2 + NADPH + H + → ROH + H 2 O + NADP +

11. Xenobiotic Processing Main function in humans Found in liver Reason certain drugs and food cannot be mixed Furanocoumarin (Angelecin) Citrus paradisi (Grapefruit, pink)

12. 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

13. 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.svghttp://en.wikipedia.org/wiki/File:P450cycle.svg IMG: Angelecin. Wikipedia.org. http://en.wikipedia.org/wiki/File:Angelicin.pnghttp://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 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.