CYP3A
Human gene From Wikipedia, the free encyclopedia
Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus.[2][3] A homologous locus is found in mice.[4]
The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. These genes encode monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The CYP3A cluster consists of four genes:
The region also contains four pseudogenes:
as well as several extra exons which may or may not be included in transcripts produced from this region. Previously another CYP3A member, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4.[2]
Structure and function
Summarize
Perspective
The CYP3A subfamily plays a central role in the metabolism of various drugs. Specifically, they play a major role in the phase I metabolism, which introduces polar functional groups, enhancing water solubility, promoting excretion from the body. CYP3A enzymes account for the oxidative metabolism of approximately 30% of clinical drugs, like statins and chemotherapeutics.[5] The activity of the CYP3A enzyme subfamily is important to medicinal chemistry, influencing drug efficiency, half life, and theoretical toxicity.[5]
Structurally, the key to the CYP3A enzyme’s large range of activity is the heme cofactor and the P450 protein fold, an oxidation reaction through molecular oxygen and NADPH.[6] The enzyme binds to the substrate, where electrons are accepted from NADPH, and a reactive iron-oxo species inserts an oxygen atom into the substrate, making the metabolized drug more polar.[6] The active site is large and flexible allowing it to bind to a wide variety of substrates, and this specifically occurs due to secondary structure elements like helices and loops that can accommodate bulky ligands.[7] Another important feature of the active site is its ability to accommodate multiple substrates at once leading to cooperative interactions, making the CYP3A family often more potent than other types of CYP450 isoforms.[8]
CYP3A enzymes are essential when studying pharmacokinetics, where the inhibition and induction of CYP450s are major mechanisms that cause drug-drug interactions.[9] For instance, Paxlovid’s dosing contains both Nirmatrelvir, a Mpro-protease inhibitor, and Ritonavir, a CYP3A enzyme inhibitor, which decreases the breakdown of Nirmatrelvir.[10]
References
Further reading
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