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Cytochrome P450 2D6 Center for BioMolecular Modeling Drugs: The Breakdown Kettle Moraine SMART Team …where teachers come first. Kyla Barr, Tristan Dudley, Madelyn Homuth, Talan Miller, Lindsay Swanson, and Brian Wenzler Instructors: Karen Deboer and Pete Nielsen What happens when a drug enters the body? Ingestion Liver Mentor: Dr. Daniel Sem, Marquette University The compounds work their way through the bloodstream and end up in the liver to be broken down. These compounds most often enter the body through the mouth (ingested) Liver Cell Prescription Drugs, as well as some other compounds are seen as pollutants to the body and must be destroyed. Cytochrome P450 Cells in the liver synthesize proteins, such as Cytochrome P450 2D6 to break down the compounds. Each protein has a specific type or shape of compound it can break down. Mutation Effects Abstract: Cytochrome P450 is a microsomal membrane-bound protein that metabolizes xenophobic compounds, mainly: pollutants, environmental compounds, and drugs; and is principally located in the liver. CYP2D6 is one of several P450s that primarily metabolizes 30% of pharmaceuticals such as anti- arrhythmics, anti-depressants and beta blockers. Research on P450s is extremely valuable to the pharmaceutical industry because CYP2D6 binds with, as substrates and inhibitors, drugs such as: codeine, quinidine, fluoxetine, and ritonavir. Regarding metabolism and inhibition, it is possible to predict how drugs will work by how they fit into the CYP2D6-binding site. CYP2D6 has a heme group and five amino acids that particularly impact binding. These five include: glutamate 216 which is part of the F-G helix, aspartate 301 which is along the I-helix, and phenylalanines 102, 481, and 483. The heme group in the binding site is responsible for carrying out the hydroxylation of substrates. Unluckily, if a drug can fit well into the site it may be metabolized before it has worked; if a drug fits, but not close enough to the heme to get hydroxylated, it can result in interactions because it will block the site when another drug molecule needs access. Therefore, the Cytochrome P450 system has a key role in pharmacology. Drug Design ? Most drug discovery screens include a test for CYP2D6 binding or metabolism ? Medicinal chemists need to understand the CYP2D6 binding site, to design drugs that will not be metabolized too fast Heme F/G Helix • Located at the base of the binding site • Extremely electronegative because of the four nitrogen atoms & the iron atom •attracts drug molecules into the binding site where they undergo destabilization. •Acts like a cap over CYP2D6 and determines if a substrate, such as a drug, will enter the protein or not. •Contains Aspartate 214 which mediates all interaction with the active part of the protein. Arginine Histidine • Mutations in CYP2D6 may result in certain problems with drug metabolism. • Some drugs may be rendered ineffective chemically or through metabolism that is too rapid. • Mutations such as the one below, Arginine mutating to Histidine can cause dangerous drug buildups. ? Diagnosing which mutant form of CYP2D6 a person may have, not everyone does, allows the tailoring of specific drugs and/or doses to a person’s genetic makeup – this is personalized medicine. This prevents a potentially toxic buildup of the drugs in the system. Also, it can predict if higher doses are needed due to faster breakdown by CYP2D6. Acknowledgements: •The Safety Management Corporation for the “Ingestion” picture found at http://www.safetymgmt.com/home_other/RiskTopics/HSChemical_Management.htm •Liver Picture is Public Domain taken from Gray’s Anatomy •Liver Cell Picture is Public Domain from ThinkQuest,org •Prescription bottle photo copyright of the National Drug Intelligence Center •All sidechain pictures are copyright of Jenna Library of Biological Macro Mole cules •We would also like to thank Aurora D. Costache, Doctor Sem’s graduate student at Marquette University for creating the original Cytochrome P450 PDB file for our project. Supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR -SEPA)