CYP2J2

Protein structure

The CYP2J2 contains the following domains:

• Hydrophobic binding domains

• F-G loop (containing non-conservative mutations) primary membrane binding motif

The protein also contains an N-terminal anchor.

F-G loop

The F-G loop mediates the binding and passage of substrates, and its hydrophobic region containing residues Trp-235, Phe-239 and Ille-236 allows the enzyme to interact with cellular membranes. Mutations to hydrophilic residues in the F-G loop alter the binding mechanism by changing insertion depth of the enzyme into the membrane.

Tissue distribution

CYP2J2 is expressed predominately in the heart and, to a lesser extent, in other tissues such as the liver, gastrointestinal tract, pancreas, lung, and central nervous system.

Function

CYP2J2 localizes to the endoplasmic reticulum and is thought to be a prominent enzyme responsible for metabolizing endogenous polyunsaturated fatty acids to signaling molecules. It metabolizes arachidonic acid to the following eicosatrienoic acid epoxides (termed EETs): 5,6-epoxy-8Z,11Z,14Z-EET, 8,9-epoxy-8Z,11Z,14Z-EET, 11,12-epoxy-5Z,8Z,14Z-EET, and 14,15-epoxy-5Z,8Z,11Z-EET. CYP2J2 also metabolizes linoleic acid to 9,10-epoxy octadecenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).

CYP2J2, along with CYP219, CYP2C8, CYP2C9, and possibly CYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.

Animal studies

Animal model studies implicate the EETs, EDPs, and EEQs in regulating hypertension, the development of myocardial infarction and other damage to the heart, the growth of various cancers, inflammation, blood vessel formation, and pain perception; limited studies suggest but have not proven that these epoxides may function similarly in humans (see epoxyeicosatrienoic acid, epoxydocosapentaenoic acid, and epoxygenase pages). Vernolic and coronaric acids are potentially toxic, causing multiple organ failure and respiratory distress when injected into animals.

Human studies

Tissue samples containing carcinomas were obtained from 130 subjects and analyzed for expression of CYP2J2. Increased detection of CYP2J2 mRNA and protein were evident in 77% of patient carcinoma cell lines. Cell proliferation was positively regulated by CYP2J2 and furthermore CYP2J2 was shown to promote tumor progression. There was also a greater amount of CYP2J2 mRNA in various tumor types, including esophageal adenocarcinoma, breast carcinoma, and stomach carcinoma compared to that of surrounding normal tissue.

The overexpression of CYP2J2 and its effects on carcinoma cells are also evident when EETs are administered exogenously, suggesting a link between the production of EETs and cancer progression. Furthermore, tumor progression increases at a faster rate in cell lines with over-expression of CYP2J2 compared to control cancer cell lines.

Clinical significance

CYP2J2 is over-expressed in a number of cancers, and forced over-expression of CYP2J2 in human cancer cells lines accelerates proliferation and protects cells against apoptosis.

HETEs and EETs derived from CYP2J2 have also been shown to contribute to the proper functioning of the cardiovascular system and the regulation of the renal and pulmonary systems in humans. CYP2J2 is readily expressed in the cardiac myocytes and endothelial cells of the coronary artery where various EETs are produced. The presence of EETs relaxes vascular smooth muscle cells by hyperpolarizing the cell membrane, thus highlighting the protective anti-inflammatory function of CYP2J2 in the circulatory system. There is still conflict in studies on the effects of EETs in relation to the cardiovascular system. P450 enzymes have shown both positive and negative effects in the heart, and the production of EETs has been shown to produce vascular protective and vascular depressive mechanisms. The over-expression of CYP2J2 enhances the activation of mitoKATP, and is believed to confer a physiological benefit by altering the production of reactive oxygen species.

References

References

1. (Apr 1998). "Mapping of the CYP2J cytochrome P450 genes to human chromosome 1 and mouse chromosome 4". Genomics.
2. "Entrez Gene: CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2".
3. (Oct 2015). "Incorporation of charged residues in the CYP2J2 F-G loop disrupts CYP2J2-lipid bilayer interactions". Biochimica et Biophysica Acta (BBA) - Biomembranes.
4. (2013). "CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy". Current Topics in Medicinal Chemistry.
5. (Nov 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators.
6. (Oct 2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators.
7. (Apr 2015). "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
8. (2005). "Cytochrome P450 Promotes the neoplastic phenotype of carcinoma cells and is Up-regulated in Human Tumors". Cancer Research.
9. (Jul 2017). "Inhibition and inactivation of human CYP2J2: Implications in cardiac pathophysiology and opportunities in cancer therapy". Biochemical Pharmacology.
10. (Aug 2013). "Cytochrome P450 2J2: distribution, function, regulation, genetic polymorphisms and clinical significance". Drug Metabolism Reviews.
11. (Dec 2013). "Roles of the epoxygenase CYP2J2 in the endothelium". Prostaglandins & Other Lipid Mediators.