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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)