Epoxide hydrolase 3
| EPHX3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | EPHX3, ABHD9, EH3, epoxide hydrolase 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 617400; MGI: 1919182; HomoloGene: 69386; GeneCards: EPHX3; OMA:EPHX3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Epoxide hydrolase 3 (ABHD9, EH3, EPHX3) is a protein that in humans is encoded by the EPHX3 gene. It is the third defined isozyme in a set of epoxide hydrolase isozymes, the epoxide hydrolases. This set includes the Microsomal epoxide hydrolase (also termed epoxide hydrolase 1, EPHX1, mEH, and EH1); the epoxide hydrolase 2 (also termed soluble epoxide hydrolase, EPHX2, sEH and EH2); and the far less well defined enzymatically, epoxide hydrolase 4 (also termed ABHD7 and EH4). All four enzyme contain an Alpha/beta hydrolase fold suggesting that they have Hydrolysis activity. EH1, EH2, and EH3 have been shown to have such activity in that they add water to epoxides of unsaturated fatty acids to form vicinal cis (see cis-trans isomerism) products; the activity of EH4 has not been reported. The former three EH's differ in subcellular location, tissue expression patterns, substrate preferences, and thereby functions. These functions include limiting the biologically actions of certain fatty acid epoxides, increasing the toxicity of other fatty acid epoxides, and contributing to the metabolism of drugs and other xenobiotics.
History
[edit]EH3 was first named ABHD9 owing to its possession of a particular Protein domain, the Alpha/beta hydrolase fold or α/β hydrolase fold domain. This domain is found in more than 30 other human hydrolytic enzymes including the four epoxide hydrolases. The gene for EH3 (EPHX3) was discovered on chromosome locus 19p13.13 in sequencing the human.genome[5] Based on its amino acid sequence, it was projected to encode a protein with an α/β hydrolase fold domain; the encoded protein was therefore dubbed ABHD9.[6] Some 10 years later, ABHD9 was defined to possess the ability to hydrolyze certain fatty acid epoxides.[7][8]
Expression
[edit]Similar to mEH but unlike sEH, EH3 is membrane-bound enzyme. Based on the expression of its mRNA in mouse tissue, EH3 has a very different distribution than mEH or sEH: EH3 expression is high in skin, lung, tongue, esophagus, and stomach; intermediate in pancreas and eye, visceral fat, lymph nodes, spleen, aortic arch, and heart; low in liver, kidney, testis, ovary intestine, and brain; and very low in skeletal muscle.[7][8] Its expression in human tissues has not yet been reported.
Activity and function
[edit]ABHD9 first drew attention is studies that validated that its gene, EPHX3, was hypermethylated on CpG sites in its Promoter (genetics) in human prostate cancer tissues, particularly in the tissues of more advanced or, base on morphological criteria (i.e. Gleason score), more aggressive diseases. This allows that the gene silencing of EPHX3 due to promoter hypermethylation may contribute to the onset and/or progression of prostate cancer.[9] Similar CpG site hypermethylations in the promoter of EPHX3 have been validated for colorectal adenocarcinomas.[10] As similar promoter methylation pattern, although not yet validated, was also found in human malignant melanoma tissues[11] and human gastric cancer cell lines.[12] These studies allow but certainly do not prove that the silencing of EPHX (i.e. failure to be expressed as ABHD9 protein) is involved in the development and/or progression of certain cancers in humans.
More recently, ABHD9 was characterized as possessing epoxy hydrolase activity for metabolizing epoxyeicosatrienoic acids (EETs) and epoxides of linoleic acid (i.e. vernolic acids [also termed leukotoxins] to their corresponding diols.[7] For example, it metabolizes one particular EET (14,15-epoxy-5Z,8Z,11Z-eicosatrienoic acid) as follows:
In this particular reaction, the enzyme inactivates the EET and thereby may function to limit the biological activity of this as well as the other EETs upon which it acts in, for example, regulating blood pressure (see epoxyeicosatrienoic acids. In its hydrolysis one isomer of vernolic acid (12S,13R-epoxy-cis-9-octadecenoic acid)
to a diol, however, the enzyme increases its toxicity in, for example, contributing to acute respiratory distress syndromes (see vernolic acid).[7][8] The enzyme thereby may function to limit the cell signaling activity of the EETs yet contribute to the toxic actions of linoleic acid epoxides.
While mEH and to a lesser extent sEH metabolize drugs, foreign toxic chemicals, and certain endogenous compounds that are not simple fatty acids (see Microsomal epoxide hydrolase and epoxide hydrolase 2), the activity of EH3 on such substrates, while likely, has not yet been reported.
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000105131 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037577 – 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.
- ^ "EPHX3 Symbol Report | HUGO Gene Nomenclature Committee". genenames.org. Retrieved 2016-04-30.
- ^ Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- ^ a b c d Decker M, Adamska M, Cronin A, Di Giallonardo F, Burgener J, Marowsky A, Falck JR, Morisseau C, Hammock BD, Gruzdev A, Zeldin DC, Arand M (October 2012). "EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides". Journal of Lipid Research. 53 (10): 2038–45. doi:10.1194/jlr.M024448. PMC 3435537. PMID 22798687.
- ^ a b c Morisseau C (January 2013). "Role of epoxide hydrolases in lipid metabolism". Biochimie. 95 (1): 91–5. doi:10.1016/j.biochi.2012.06.011. PMC 3495083. PMID 22722082.
- ^ Stott-Miller M, Zhao S, Wright JL, Kolb S, Bibikova M, Klotzle B, Ostrander EA, Fan JB, Feng Z, Stanford JL (July 2014). "Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence". Cancer Epidemiology, Biomarkers & Prevention. 23 (7): 1331–9. doi:10.1158/1055-9965.EPI-13-1000. PMC 4082437. PMID 24718283.
- ^ Oster B, Thorsen K, Lamy P, Wojdacz TK, Hansen LL, Birkenkamp-Demtröder K, Sørensen KD, Laurberg S, Orntoft TF, Andersen CL (December 2011). "Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas". International Journal of Cancer. 129 (12): 2855–66. doi:10.1002/ijc.25951. PMID 21400501. S2CID 35078536.
- ^ Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T (June 2006). "Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas". Cancer Research. 66 (12): 6080–6. doi:10.1158/0008-5472.CAN-06-0157. PMID 16778180.
- ^ Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T (January 2006). "Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray". Cancer Science. 97 (1): 64–71. doi:10.1111/j.1349-7006.2006.00136.x. PMC 11159443. PMID 16367923. S2CID 33738798.