# CYP2B6

## Overview
CYP2B6 is a gene that encodes for the enzyme cytochrome P450 family 2 subfamily B member 6, a crucial component in the metabolism of various xenobiotics and endogenous compounds. This enzyme, primarily expressed in the liver, plays a significant role in the oxidative metabolism of numerous drugs and chemicals, thereby influencing their pharmacokinetics and dynamics (Wang2008CYP2B6:). The protein itself is part of the larger cytochrome P450 superfamily, known for its diverse roles in metabolizing potentially toxic compounds, synthesizing cholesterol, steroids, and other lipids (Nair2016Cytochrome). CYP2B6 is characterized by its ability to metabolize a wide array of substrates through reactions such as N-demethylation and ortho-hydroxylation, and its activity can be highly variable among individuals due to genetic polymorphisms (Zanger2013Pharmacogenetics). This variability is critical for personalized medicine, as it can significantly affect drug efficacy and safety (Turpeinen2012Cytochrome).

## Structure
The molecular structure of CYP2B6, a member of the cytochrome P450 family, has been extensively studied through various modeling techniques. The primary structure of CYP2B6, which refers to its amino acid sequence, aligns closely with that of CYP2C5, allowing for homology modeling based on the CYP2C5 crystal structure (Bathelt2002Regioselectivity). The secondary structure includes a series of helices, notably labeled from A to L, which are highly conserved across different species and crucial for the enzyme's function (Nair2016Cytochrome). 

Tertiary structure details, such as the three-dimensional folding, are derived from molecular dynamics simulations and homology modeling, indicating the presence of a missing 22-residue loop between helices F and G, which is significant for the enzyme's activity (Turpeinen2006The). The quaternary structure, which involves the assembly of multiple protein units, is not specifically detailed in the provided sources.

Notably, the enzyme features a heme group crucial for its catalytic activity, located between helices I and L (Nair2016Cytochrome). The substrate binding site is formed by three hydrophobic pockets adjacent to the catalytic heme, essential for the enzyme's function in metabolizing various substrates (Bathelt2002Regioselectivity). 

Information on specific domains, prominent folds, common post-translational modifications, or splice variant isoforms of CYP2B6 is not detailed in the provided sources, thus cannot be elaborated upon.

## Function
CYP2B6, encoded by the CYP2B6 gene, is a cytochrome P450 enzyme predominantly expressed in the liver, playing a crucial role in the metabolism of various xenobiotics, including drugs and environmental chemicals. This enzyme is involved in the biotransformation of these substances into more soluble compounds, facilitating their excretion and reducing their potential toxic effects on the body (Wang2008CYP2B6:). CYP2B6 is also expressed in extrahepatic tissues such as the brain, kidney, intestine, and skin, where it contributes to the local metabolism of xenobiotics and endogenous compounds (Zanger2013Pharmacogenetics).

The enzyme metabolizes a wide range of substrates, including clinically important pharmaceuticals like bupropion, efavirenz, and ketamine, through specific metabolic reactions such as N-demethylation and ortho-hydroxylation (Wang2008CYP2B6:). CYP2B6's activity is highly variable among individuals due to genetic polymorphisms, which can significantly affect drug metabolism efficiency and response (Zanger2013Pharmacogenetics). This variability is a critical factor in personalized medicine, as it influences drug efficacy and safety (Turpeinen2012Cytochrome).

Moreover, CYP2B6 is inducible by several drugs and chemicals, which can increase its expression and activity, further influencing drug metabolism and potential interactions (Zanger2013Pharmacogenetics). This inducibility involves interactions with nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), which enhance CYP2B6 gene expression (Zanger2013Pharmacogenetics).

## Clinical Significance
Mutations in the CYP2B6 gene and variations in its expression significantly impact the metabolism of various drugs, leading to altered drug efficacy and toxicity. The CYP2B6*6 allele, for instance, is associated with decreased enzyme activity and expression, particularly affecting the metabolism of HIV drugs such as efavirenz. This results in higher plasma drug concentrations, which can lead to neurotoxicity and other central nervous system side effects (Hofmann2008Aberrant; Hedrich2016Insights; Turpeinen2012Cytochrome). Additionally, the CYP2B6*6 variant impacts the metabolism of chemotherapeutic agents like cyclophosphamide and ifosfamide, influencing therapeutic outcomes and increasing the risk of toxicities (Hedrich2016Insights; Zanger2007Polymorphic).

Furthermore, polymorphisms such as CYP2B6*5 and CYP2B6*18 also affect drug metabolism. The CYP2B6*5 allele, despite its low protein levels, does not show a proportionate decrease in activity with certain drugs, leading to only moderately reduced activity in vivo (Zanger2013Pharmacogenetics). The CYP2B6*18 allele is described as functionally deficient, impacting the metabolism of drugs like bupropion and selegiline (Turpeinen2012Cytochrome).

These genetic variations necessitate personalized medicine approaches, including genotyping and therapeutic drug monitoring, to optimize drug dosages and reduce the risk of adverse drug reactions, thereby enhancing treatment efficacy (Hedrich2016Insights).

## Interactions
CYP2B6, a member of the cytochrome P450 superfamily, is involved in various protein-protein interactions that significantly influence its function in drug metabolism. Notably, CYP2B6 interacts with other cytochrome P450 isoforms, which can affect its enzymatic activity. For instance, studies have shown that CYP2B6 can form complexes with other CYP isoforms, such as CYP1A2 and CYP3A4, which may lead to altered metabolic activities due to competitive mechanisms for electron transfer from cytochrome P450 reductase (CPR) (Kandel2014Role). Additionally, interactions with non-enzymatic proteins like the progesterone receptor membrane component 1 (PGRMC1) are also significant, as PGRMC1 can modulate the activity of CYP2B6, potentially through mechanisms involving drug delivery or sequestration (Kandel2014Role).

Furthermore, CYP2B6 participates in interactions within the active site involving halogen-π bonds, particularly with halogenated substrates. These interactions are crucial for the substrate selectivity and orientation, influencing the metabolic processing of these compounds. Structural studies using X-ray crystallography have highlighted these interactions, demonstrating their role in the enzyme's function (Shah2017Halogen−π).

These interactions underline the complexity of CYP2B6's role in drug metabolism and its potential implications for pharmacokinetics and drug toxicity.


## References


[1. (Wang2008CYP2B6:) Hongbing Wang and Leslie Tompkins. Cyp2b6: new insights into a historically overlooked cytochrome p450 isozyme. Current Drug Metabolism, 9(7):598–610, September 2008. URL: http://dx.doi.org/10.2174/138920008785821710, doi:10.2174/138920008785821710. (348 citations) 10.2174/138920008785821710](https://doi.org/10.2174/138920008785821710)

[2. (Zanger2007Polymorphic) Ulrich M Zanger, Kathrin Klein, Tanja Saussele, Julia Blievernicht, Marco H Hofmann, and Matthias Schwab. Polymorphic cyp2b6: molecular mechanisms and emerging clinical significance. Pharmacogenomics, 8(7):743–759, July 2007. URL: http://dx.doi.org/10.2217/14622416.8.7.743, doi:10.2217/14622416.8.7.743. (309 citations) 10.2217/14622416.8.7.743](https://doi.org/10.2217/14622416.8.7.743)

[3. (Shah2017Halogen−π) Manish B. Shah, Jingbao Liu, Qinghai Zhang, C. David Stout, and James R. Halpert. Halogen−π interactions in the cytochrome p450 active site: structural insights into human cyp2b6 substrate selectivity. ACS Chemical Biology, 12(5):1204–1210, April 2017. URL: http://dx.doi.org/10.1021/acschembio.7b00056, doi:10.1021/acschembio.7b00056. (53 citations) 10.1021/acschembio.7b00056](https://doi.org/10.1021/acschembio.7b00056)

[4. (Turpeinen2012Cytochrome) Miia Turpeinen and Ulrich M. Zanger. Cytochrome p450 2b6: function, genetics, and clinical relevance. dmdi, 27(4):185–197, November 2012. URL: http://dx.doi.org/10.1515/dmdi-2012-0027, doi:10.1515/dmdi-2012-0027. (114 citations) 10.1515/dmdi-2012-0027](https://doi.org/10.1515/dmdi-2012-0027)

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[6. (Zanger2013Pharmacogenetics) Ulrich M. Zanger and Kathrin Klein. Pharmacogenetics of cytochrome p450 2b6 (cyp2b6): advances on polymorphisms, mechanisms, and clinical relevance. Frontiers in Genetics, 2013. URL: http://dx.doi.org/10.3389/fgene.2013.00024, doi:10.3389/fgene.2013.00024. (329 citations) 10.3389/fgene.2013.00024](https://doi.org/10.3389/fgene.2013.00024)

[7. (Bathelt2002Regioselectivity) Christine Bathelt, Rolf Schmid, and Jürgen Pleiss. Regioselectivity of cyp2b6: homology modeling, molecular dynamics simulation, docking. Journal of Molecular Modeling, 8(11):327–335, November 2002. URL: http://dx.doi.org/10.1007/s00894-002-0104-y, doi:10.1007/s00894-002-0104-y. (60 citations) 10.1007/s00894-002-0104-y](https://doi.org/10.1007/s00894-002-0104-y)

[8. (Hofmann2008Aberrant) Marco H. Hofmann, Julia K. Blievernicht, Kathrin Klein, Tanja Saussele, Elke Schaeffeler, Matthias Schwab, and Ulrich M. Zanger. Aberrant splicing caused by single nucleotide polymorphism c.516g>t [q172h], a marker of cyp2b6*6, is responsible for decreased expression and activity of cyp2b6 in liver. Journal of Pharmacology and Experimental Therapeutics, 325(1):284–292, January 2008. URL: http://dx.doi.org/10.1124/jpet.107.133306, doi:10.1124/jpet.107.133306. (268 citations) 10.1124/jpet.107.133306](https://doi.org/10.1124/jpet.107.133306)

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[10. (Turpeinen2006The) Miia Turpeinen, Hannu Raunio, and Olavi Pelkonen. The functional role of cyp2b6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Current Drug Metabolism, 7(7):705–714, October 2006. URL: http://dx.doi.org/10.2174/138920006778520633, doi:10.2174/138920006778520633. (161 citations) 10.2174/138920006778520633](https://doi.org/10.2174/138920006778520633)

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