Sandbox CYPMetabolism: Difference between revisions

As you rotate the molecule, look at how each of the amino acid residues at the active site is interacting with parts of the flavone. Can you predict what kinds of interactions (H-bonds, lipophilic, or ionic) might be made? Examine the hydrophobic portions of the inhibitor. What kind of residues would interact with these? Hover the cursor over each residue and examine the label that appears (you may have to re-size the molecule to pick the individual atoms). Is the label consistent with your expectations for these kinds of interactions? Since the CYPs largely metabolize hydrophobic substrates, hydrophobic interactions are very important for binding many substrates. That is clearly the case here.  

== CYP450 3A4 and Its Malleable Active Site ==

The CYP3A4 isoform, PDB entry [[1tqn]], is involved in metabolizing over 50% of marketed drugs, and accounts for approximately 40% of hepatic CYP enzymes. This helps to make sense of the fact that it is the enzyme most commonly associated with undesired drug-drug interactions. CYP3A4 differs from the CYP1A2 isoform considered above, as well as most other CYPs, because of the diversity of drugs it can metabolize. A number of these drugs are known to cause potentially dangerous or even fatal interactions. The reason that CYP3A4 is involved in the metabolism of so many drugs appears to be related to the size and flexibility of its binding pocket, which can accommodate a number of fairly large drugs. A few drugs considered to be "large" include macrolide antibiotic erythromycin, the anticancer drug taxol, the immunosuppressant cyclosporine, and several statins.

Examining the way drugs bind to CYP3A4 gives some insight into its selectivity and the way it may be influence the pharmacokinetics of the drug. In the crystal structure of CYP3A4 bound to erythromycin, the volume of the active site is notably different than the unbound protein. With erythromycin being a fairly large drug (MW 733.9), CYP450 isoforms with smaller binding pockets (e.g. CYP1A2) cannot accommodate it and therefore cannot metabolize it. Due to its flexible binding pocket, CYP3A4 can also accommodate a diversity of other, smaller substrates.

The following scene shows the ligand-free form of <scene name='60/609993/Cyp3a4/1'>CYP3A4</scene>. The next scene shows the <scene name='60/609993/Cyp3a4/15'>binding pocket</scene> of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule. Observe that the cavity extends within a short distance of the heme ring. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme.  

 

Rotate and re-size the molecule until you can clearly see that there are 2 regions open to the outside of the molecule. Note that the opening to the cavity does not seem large enough to allow a drug of any significant size to enter. In order for a larger drug to enter the inside of the enzyme, a change in its shape must occur.