Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene.[4][5] CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.
Protein structure
editThe CYP2J2 contains the following domains:[6]
• 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
editThe 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
editCYP2J2 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.[7]
Function
editCYP2J2 localizes to the endoplasmic reticulum and is thought to be a prominent enzyme responsible for metabolizing endogenous polyunsaturated fatty acids to signaling molecules.[8] 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).[9]
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.[10][11]
Animal studies
editAnimal 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).[11] Vernolic and coronaric acids are potentially toxic, causing multiple organ failure and respiratory distress when injected into animals.[11]
Human studies
editTissue 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.[12] 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.[12]
Clinical significance
editCYP2J2 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.[7]
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.[citation needed] 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.[7] There is still conflict in studies on the effects of EETs in relation to the cardiovascular system.[13][14] 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.[7] 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.[7]
References
edit- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000052914 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Ma J, Ramachandran S, Fiedorek FT, Zeldin DC (Apr 1998). "Mapping of the CYP2J cytochrome P450 genes to human chromosome 1 and mouse chromosome 4". Genomics. 49 (1): 152–5. doi:10.1006/geno.1998.5235. PMID 9570962.
- ^ "Entrez Gene: CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2".
- ^ McDougle DR, Baylon JL, Meling DD, Kambalyal A, Grinkova YV, Hammernik J, Tajkhorshid E, Das A (2015). "Incorporation of charged residues in the CYP2J2 F-G loop disrupts CYP2J2-lipid bilayer interactions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1848 (10 Pt A): 2460–2470. doi:10.1016/j.bbamem.2015.07.015. PMC 4559526. PMID 26232558.
- ^ a b c d e Karkhanis A, Hong Y, Chan EC (2017). "Inhibition and inactivation of human CYP2J2: Implications in cardiac pathophysiology and opportunities in cancer therapy". Biochemical Pharmacology. 135: 12–21. doi:10.1016/j.bcp.2017.02.017. PMID 28237650. S2CID 43456597. Archived from the original on 2017-11-12. Retrieved 2019-07-05.
- ^ Chen C, Wang DW (2013). "CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy". Current Topics in Medicinal Chemistry. 13 (12): 1454–69. doi:10.2174/1568026611313120007. PMID 23688135.
- ^ Westphal C, Konkel A, Schunck WH (2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326.
- ^ Wagner K, Vito S, Inceoglu B, Hammock BD (2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators. 113–115: 2–12. doi:10.1016/j.prostaglandins.2014.09.001. PMC 4254344. PMID 25240260.
- ^ a b c Spector AA, Kim HY (2015). "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 356–65. doi:10.1016/j.bbalip.2014.07.020. PMC 4314516. PMID 25093613.
- ^ a b Jiang, Jian-Gang; Chen, Chun-Lian; Card, Jeffrey W; Yang, Shilin; Chen, Ji-Xiong; Fu, Xiang-Ning; Ning, Yao-Gui; Zeldin, Darryl C; Wang, Dao Wen (2005). "Cytochrome P450 Promotes the neoplastic phenotype of carcinoma cells and is Up-regulated in Human Tumors". Cancer Research. 65 (11): 4707–4715. doi:10.1158/0008-5472.CAN-04-4173. PMID 15930289.
- ^ Xu M, Ju W, Hao H, Wang G, Li P (2013). "Cytochrome P450 2J2: distribution, function, regulation, genetic polymorphisms and clinical significance". Drug Metabolism Reviews. 45 (3): 311–52. doi:10.3109/03602532.2013.806537. PMID 23865864. S2CID 22721300.
- ^ Askari A, Thomson SJ, Edin ML, Zeldin DC, Bishop-Bailey D (2013). "Roles of the epoxygenase CYP2J2 in the endothelium". Prostaglandins & Other Lipid Mediators. 107: 56–63. doi:10.1016/j.prostaglandins.2013.02.003. PMC 3711961. PMID 23474289.
Further reading
edit- Scarborough PE, Ma J, Qu W, Zeldin DC (Feb 1999). "P450 subfamily CYP2J and their role in the bioactivation of arachidonic acid in extrahepatic tissues". Drug Metabolism Reviews. 31 (1): 205–34. doi:10.1081/DMR-100101915. PMID 10065373.
- Capdevila JH, Falck JR, Harris RC (Feb 2000). "Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase". Journal of Lipid Research. 41 (2): 163–81. doi:10.1016/S0022-2275(20)32049-6. PMID 10681399.
- Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC (Feb 1996). "Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart". The Journal of Biological Chemistry. 271 (7): 3460–8. doi:10.1074/jbc.271.7.3460. PMID 8631948.
- Zeldin DC, Foley J, Ma J, Boyle JE, Pascual JM, Moomaw CR, Tomer KB, Steenbergen C, Wu S (Nov 1996). "CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance". Molecular Pharmacology. 50 (5): 1111–7. PMID 8913342.
- Zeldin DC, Foley J, Boyle JE, Moomaw CR, Tomer KB, Parker C, Steenbergen C, Wu S (Mar 1997). "Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human and rat pancreas". Endocrinology. 138 (3): 1338–46. doi:10.1210/endo.138.3.4970. PMID 9048644.
- Zeldin DC, Foley J, Goldsworthy SM, Cook ME, Boyle JE, Ma J, Moomaw CR, Tomer KB, Steenbergen C, Wu S (Jun 1997). "CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance". Molecular Pharmacology. 51 (6): 931–43. doi:10.1124/mol.51.6.931. PMID 9187259.
- Bylund J, Finnström N, Oliw EH (Jul 1999). "Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles". Biochemical and Biophysical Research Communications. 261 (1): 169–74. doi:10.1006/bbrc.1999.1011. PMID 10405341.
- Gu J, Su T, Chen Y, Zhang QY, Ding X (Jun 2000). "Expression of biotransformation enzymes in human fetal olfactory mucosa: potential roles in developmental toxicity". Toxicology and Applied Pharmacology. 165 (2): 158–62. doi:10.1006/taap.2000.8923. PMID 10828211.
- King LM, Ma J, Srettabunjong S, Graves J, Bradbury JA, Li L, Spiecker M, Liao JK, Mohrenweiser H, Zeldin DC (Apr 2002). "Cloning of CYP2J2 gene and identification of functional polymorphisms". Molecular Pharmacology. 61 (4): 840–52. doi:10.1124/mol.61.4.840. PMID 11901223. S2CID 27031365.
- Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y (Nov 2002). "Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole". Drug Metabolism and Disposition. 30 (11): 1240–5. doi:10.1124/dmd.30.11.1240. PMID 12386130. S2CID 20029273.
- Marden NY, Fiala-Beer E, Xiang SH, Murray M (Aug 2003). "Role of activator protein-1 in the down-regulation of the human CYP2J2 gene in hypoxia". The Biochemical Journal. 373 (Pt 3): 669–80. doi:10.1042/BJ20021903. PMC 1223548. PMID 12737630.
- Pucci L, Lucchesi D, Chirulli V, Penno G, Johansson I, Gervasi P, Del Prato S, Longo V (2004). "Cytochrome P450 2J2 polymorphism in healthy Caucasians and those with diabetes mellitus". American Journal of Pharmacogenomics. 3 (5): 355–8. doi:10.2165/00129785-200303050-00006. PMID 14575523. S2CID 41947830.
- Seubert J, Yang B, Bradbury JA, Graves J, Degraff LM, Gabel S, Gooch R, Foley J, Newman J, Mao L, Rockman HA, Hammock BD, Murphy E, Zeldin DC (Sep 2004). "Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway". Circulation Research. 95 (5): 506–14. doi:10.1161/01.RES.0000139436.89654.c8. PMID 15256482.
- Xiao YF, Ke Q, Seubert JM, Bradbury JA, Graves J, Degraff LM, Falck JR, Krausz K, Gelboin HV, Morgan JP, Zeldin DC (Dec 2004). "Enhancement of cardiac L-type Ca2+ currents in transgenic mice with cardiac-specific overexpression of CYP2J2". Molecular Pharmacology. 66 (6): 1607–16. doi:10.1124/mol.104.004150. PMID 15361551. S2CID 17036714.
- Spiecker M, Darius H, Hankeln T, Soufi M, Sattler AM, Schaefer JR, Node K, Börgel J, Mügge A, Lindpaintner K, Huesing A, Maisch B, Zeldin DC, Liao JK (Oct 2004). "Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2". Circulation. 110 (15): 2132–6. doi:10.1161/01.CIR.0000143832.91812.60. PMC 2633457. PMID 15466638.
External links
edit- Human CYP2J2 genome location and CYP2J2 gene details page in the UCSC Genome Browser.