Function of Ritonavir on CYP3A4

Unlike most designed drugs which aim to avoid CYP3A4 or be metabolized by it, ritonavir is a specific CYP3A4 inactivator. Specifically it is a type II ligand in that it causes inhibition by direct coordination to the heme iron atom. The large size of ritonavir allows for specificity to the binding pocket of CYP3A4. A drug binding all heme containing proteins in the body would be problematic. Ritonavir is given in conjunction with HIV protease inhibitors as a treatment of HIV. This is because CYP3A4 is the major human drug metabolizing enzyme and breaks down the drugs before they can be effective.

Sevrioukova IF, Poulos TL. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18422-7. doi: 10.1073/pnas.1010693107. Epub 2010 Oct 11. (PubMed)

3NXU(PDB)

 Nicotine bound to P450 2A13

CYP450 2A13 is the primary protein involved in the metabolism of nicotine, producing the tobacco procarcinogen NNK. The efficiency and specificity is not produced by the shape of the channel, as is normal with many Cytochrome P450s, but though residues that stabilize the nicotine-heme interaction. F300, N297, and A301 are shown in green wireframe. They sterically control the binding of nicotine and act as a key orienting feature.  These three residues when mutated, cause a 5 fold decrease in the affinity of 2A13 for nicotine. 

DeVore NM, Scott EE. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes.
J Biol Chem. 2012 Aug 3;287(32):26576-85. doi: 10.1074/jbc.M112.372813. Epub 2012 Jun 14. (PubMed)

4EJG (PDB)

Back to Links