Epoxide hydrolase

Humans express four epoxide hydrolase isozymes: mEH, sEH, EH3, and EH4. These isozymes are known (mEH and sEH) or presumed (EH3 and EH4) to share a common structure that includes containing an Alpha/beta hydrolase fold and a common reaction mechanism wherein they add water to epoxides to form vicinal cis (see (cis-trans isomerism); see (epoxide#Olefin (alkene) oxidation using organic peroxides and metal catalysts)) diol products. They differ, however, in subcellular location, substrate preferences, tissue expression, and/or function.

mEH is widely expressed in virtually all mammalian cells as an endoplasmic reticulum-bound (i.e. microsomal-bound) enzyme with its C terminal catalytic domain facing the cytoplasm; in some tissues, however, mEH has been found bound to the cell surface plasma membrane with its catalytic domain facing the extracellular space.{{cite journal | vauthors = El-Sherbeni AA, El-Kadi AO | title = The role of epoxide hydrolases in health and disease | journal = Archives of Toxicology | volume = 88 | issue = 11 | pages = 2013–32 | date = November 2014 | pmid = 25248500 | doi = 10.1007/s00204-014-1371-y | s2cid = 16885502 }} The primary function of mEH is to convert potentially toxic xenobiotics and other compounds that possess epoxide residues (which is often due to their initial metabolism by cytochrome P450 enzymes to epoxides) to diols. Epoxides are highly reactive electrophilic compounds that form adducts with DNA and proteins and also cause strand breaks in DHA; in consequence, epoxides can cause gene mutations, cancer, and the inactivation of critical proteins. The diols thereby formed are usually not toxic or far less toxic than their epoxide predecessors, are readily further metabolized, and ultimately excreted in the urine.{{cite journal | vauthors = Václavíková R, Hughes DJ, Souček P | title = Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease | journal = Gene | volume = 571 | issue = 1 | pages = 1–8 | date = October 2015 | pmid = 26216302 | pmc = 4544754 | doi = 10.1016/j.gene.2015.07.071 }} mEH also metabolizes certain epoxides of polyunsaturated fatty acids such as the epoxyeicosatrienoic acids (EETs) but its activity in doing this is far less than that of sEH; mEH therefore may play a minor role, compared to sEH, in limiting the bioactivity of these cell signaling compounds (see microsomal epoxide hydrolase).

sEH is widely expressed in mammalian cells as a cytosolic enzyme where it primarily serves the function of converting epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EQAs), and epoxydocosapentaenoic acids (DPAs) to their corresponding diols, thereby limiting or ending their cell signaling actions; in this capacity, sEH appears to play a critical in vivo role in limiting the effects of these epoxides in animal models and possibly humans.{{cite journal | vauthors = Bellien J, Joannides R | title = Epoxyeicosatrienoic acid pathway in human health and diseases | journal = Journal of Cardiovascular Pharmacology | volume = 61 | issue = 3 | pages = 188–96 | date = March 2013 | pmid = 23011468 | doi = 10.1097/FJC.0b013e318273b007 | s2cid = 42452896 }}{{cite journal | vauthors = He J, Wang C, Zhu Y, Ai D | title = Soluble epoxide hydrolase: A potential target for metabolic diseases | journal = Journal of Diabetes | volume = 8 | issue = 3 | pages = 305–13 | date = May 2016 | pmid = 26621325 | doi = 10.1111/1753-0407.12358 | doi-access = free }} However, sEH also metabolizes the epoxides of linoleic acid viz., Vernolic acid (leukotoxins) and Coronaric acids (isoleukotoxins) to their corresponding diols which are highly toxic in animal models and possibly humans (see Vernolic acid#Toxicity, Coronaric acid#toxicity, and soluble epoxide hydrolase). sEH also possesses hepoxilin-epoxide hydrolase activity, converting bioactive hepoxilins to their inactive trioxilin products (see below section "Hepoxilin-epoxide hydrolase").

Human EH3 is a recently characterized protein with epoxy hydrolase activity for metabolizing epoxyeicosatrienoic acids (EETs) and vernolic acids (leukotoxins) to their corresponding diols; in these capacities they may thereby limit the cell signaling activity of the EETs and contribute to the toxicity of the leukotoxins.{{cite journal|author7-link=John R. Falck| vauthors = 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 | title = EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides | journal = Journal of Lipid Research | volume = 53 | issue = 10 | pages = 2038–45 | date = October 2012 | pmid = 22798687 | doi = 10.1194/jlr.M024448 |doi-access=free | pmc=3435537}} mRNA for EH3 is most strongly expressed in the lung, skin, and upper gastrointestinal tract tissues of mice. The function of EH3 in humans, mice, or other mammals has not yet been determined although the gene for EH3 has been validated as being hypermethylated on CpG sites in its promoter region in human prostate cancer tissue, particularly in the tissues of more advanced or morphologically-based (i.e. Gleason score) more aggressive cancers; this suggests that the gene silencing of EH3 due to this hypermethylation may contribute to the onset and/or progression of prostate cancer.{{cite journal | vauthors = Stott-Miller M, Zhao S, Wright JL, Kolb S, Bibikova M, Klotzle B, Ostrander EA, Fan JB, Feng Z, Stanford JL | title = Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 23 | issue = 7 | pages = 1331–9 | date = July 2014 | pmid = 24718283 | pmc = 4082437 | doi = 10.1158/1055-9965.EPI-13-1000 }} Similar CpG site hypermethylations in the promoter of for the EH3 gene have been validated for other cancers.{{cite journal | vauthors = Oster B, Thorsen K, Lamy P, Wojdacz TK, Hansen LL, Birkenkamp-Demtröder K, Sørensen KD, Laurberg S, Orntoft TF, Andersen CL | title = Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas | journal = International Journal of Cancer | volume = 129 | issue = 12 | pages = 2855–66 | date = December 2011 | pmid = 21400501 | doi = 10.1002/ijc.25951 | s2cid = 35078536 | doi-access = free }} This promoter methylation pattern, although not yet validated, was also found in human malignant melanoma.{{cite journal | vauthors = Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T | title = Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas | journal = Cancer Research | volume = 66 | issue = 12 | pages = 6080–6 | date = June 2006 | pmid = 16778180 | doi = 10.1158/0008-5472.CAN-06-0157 | doi-access = free }}

The gene for EH4, EPHX4, is projected to encode an epoxide hydrolase closely related in amino acid sequence and structure to mEH, sEH, and EH3. The activity and function of EH4 has not yet been defined.

Leukotriene A4 hydrolase (LTA4H) acts primarily, if not exclusively, to hydrolyze leukotriene A4 (LTA4, i.e. 5S,6S-oxido-7E,9E,11Z,14Z-eicosatetetraenoic acid; IUPAC name 4-{(2S,3S)-3-[(1E,3E,5Z,8Z)-1,3,5,8-Tetradecatetraen-1-yl]-2-oxiranyl}butanoic acid) to its diol metabolite, leukotriene B4 (LTB4, i.e. 5S,12R-dihydroxy-6Z,8E,10E,14Z-icosatetraenoic acid; IUPA name 5S,6Z,8E,10E,12R,14Z)-5,12-Dihydroxy-6,8,10,14-icosatetraenoic acid). LTB4 is an important recruiter and activator of leukocytes involved in mediation in inflammatory responses and diseases. The enzyme also possess aminopeptidase activity, degrading, for example, the leukocyte chemotactic factor tripeptide, Pro-Gly-Pro (PGP); the function of the aminopeptidase activity of LTA4AH is unknown but has been proposed to be involved in limiting inflammatory reactions caused by this or other aminopeptidase-susceptible peptides.{{cite journal | vauthors = Paige M, Wang K, Burdick M, Park S, Cha J, Jeffery E, Sherman N, Shim YM | title = Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema | journal = Journal of Immunology | volume = 192 | issue = 11 | pages = 5059–68 | date = June 2014 | pmid = 24771855 | doi = 10.4049/jimmunol.1400452 | pmc=4083682}}{{cite journal | vauthors = Appiah-Kubi P, Soliman ME | title = Dual anti-inflammatory and selective inhibition mechanism of leukotriene A4 hydrolase/aminopeptidase: insights from comparative molecular dynamics and binding free energy analyses | journal = Journal of Biomolecular Structure & Dynamics | volume = 34 | issue = 11 | pages = 2418–2433 | date = January 2016 | pmid = 26555301 | doi = 10.1080/07391102.2015.1117991 | s2cid = 19117041 | url = https://figshare.com/articles/journal_contribution/1598113 | url-access = subscription }}{{cite journal | vauthors = Calışkan B, Banoglu E | title = Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors | journal = Expert Opinion on Drug Discovery | volume = 8 | issue = 1 | pages = 49–63 | date = January 2013 | pmid = 23095029 | doi = 10.1517/17460441.2013.735228 | s2cid = 19151713 }}

(Cholesterol epoxide hydrolase or ChEH), is located in the endoplasmic reticulum and to a lesser extent plasma membrane of various cell types but most highly express in liver. The enzyme catalyzes the conversion of certain 3-hydroxyl-5,6-epoxides of cholesterol to their 3,5,6-trihydroxy products (see Cholesterol-5,6-oxide hydrolase).{{cite journal | vauthors = Fretland AJ, Omiecinski CJ | title = Epoxide hydrolases: biochemistry and molecular biology | journal = Chemico-Biological Interactions | volume = 129 | issue = 1–2 | pages = 41–59 | date = December 2000 | pmid = 11154734 | doi=10.1016/s0009-2797(00)00197-6| bibcode = 2000CBI...129...41F | citeseerx = 10.1.1.462.3157 }} The function of ChEH is unknown.

The substrate(s) and physiological function of Peg1/MEST are not known; however, the protein may play a role in mammalian development and abnormalities in its expression by its gene (PEG1/MEST)by, for example, loss of Genomic imprinting, overexpression, or promoter switching, has been linked to certain types of cancer and tumors in humans such as invasive cervical cancer, uterine leiomyomas, and cancers of the breast, lung, and colon (see MEST (gene)).{{cite journal | vauthors = Pedersen IS, Dervan P, McGoldrick A, Harrison M, Ponchel F, Speirs V, Isaacs JD, Gorey T, McCann A | title = Promoter switch: a novel mechanism causing biallelic PEG1/MEST expression in invasive breast cancer | journal = Human Molecular Genetics | volume = 11 | issue = 12 | pages = 1449–53 | date = 2002 | pmid = 12023987 | doi=10.1093/hmg/11.12.1449| doi-access = free }}{{cite journal | vauthors = Moon YS, Park SK, Kim HT, Lee TS, Kim JH, Choi YS | title = Imprinting and expression status of isoforms 1 and 2 of PEG1/MEST gene in uterine leiomyoma | journal = Gynecologic and Obstetric Investigation | volume = 70 | issue = 2 | pages = 120–5 | year = 2010 | pmid = 20339302 | doi = 10.1159/000301555 | s2cid = 33234162 }}{{cite journal | vauthors = Vidal AC, Henry NM, Murphy SK, Oneko O, Nye M, Bartlett JA, Overcash F, Huang Z, Wang F, Mlay P, Obure J, Smith J, Vasquez B, Swai B, Hernandez B, Hoyo C | title = PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer | journal = Clinical & Translational Oncology | volume = 16 | issue = 3 | pages = 266–72 | date = March 2014 | pmid = 23775149 | pmc = 3924020 | doi = 10.1007/s12094-013-1067-4 }}

Hepoxilin-epoxide hydrolase or hepoxilin hydrolase is currently best defined as an enzyme activity that converts the biologically active monohydroxy-epoxide metabolites of arachidonic acid hepoxilin A3s and hepoxilin B3s to essentially inactive trihydroxy products, the trioxilins. That is, hepoxilin A3s (8-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) are metabolized to trioxilin A3s (8,11,12-trihydroxy-5Z,9E,14Z-eicosatrienoic acids) and hepoxilins B3s (10-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acids) are metabolized to trioxilin B3s (10,11,12-trihydroxy-5Z,8Z,14Z-eicosatrienoic acids).{{cite journal | vauthors = Thompson RD | title = Extra-oral nerve blocks | journal = Anesthesia Progress | volume = 15 | issue = 3 | pages = 65–8 | date = March 1968 | pmid = 5240838 | pmc = 2235474 }} However, this activity has not been characterized at the purified protein or gene level and recent work indicate that sEH readily metabolizes an hepoxilin A3 to a trioxilin A3 and that hepoxilin-epoxide hydrolase activity is due to sEH, at least as it is detected in mouse liver.{{cite journal | vauthors = Cronin A, Decker M, Arand M | title = Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase | journal = Journal of Lipid Research | volume = 52 | issue = 4 | pages = 712–9 | date = April 2011 | pmid = 21217101 | doi = 10.1194/jlr.M009639 |doi-access=free | pmc=3284163}}

Mycobacterium tuberculosis, the causative agent of tuberculosis, expresses at least six different forms of epoxide hydrolase (forms A-F). The structure of epoxide hydrolase B reveals that the enzyme is a monomer and contains an alpha/beta hydrolase fold. In addition to providing insights into the enzyme mechanism, this hydrolase currently serves as a platform for rational drug design of potent inhibitors. In particular, urea based inhibitors have been developed. These inhibitors directly target the catalytic cavity. It is hypothesized that the structure of epoxide hydrolase B may allow for drug design to inhibit all other Mycobacterium tuberculosis hydrolases as long as they contain similar alpha/beta folds. The structure of hydrolase B contains a cap domain, which is hypothesized to regulate the active site of the hydrolase. Furthermore, Asp104, His333, and Asp302 form the catalytic triad of the protein and is critical to function of the protein. At present, other structures of Mycobacterium tuberculosis hydrolase have not been solved. Model studies on pharmacological susceptibility of these epoxide hydrolases continue.{{cite journal | vauthors = Selvan A, Anishetty S | title = Cavities create a potential back door in epoxide hydrolase Rv1938 from Mycobacterium tuberculosis-A molecular dynamics simulation study | journal = Computational Biology and Chemistry | volume = 58 | pages = 222–30 | date = October 2015 | pmid = 26256802 | doi = 10.1016/j.compbiolchem.2015.07.008 }}

{{reflist}}

• {{MeshName|Epoxide+hydrolases}}
• [https://web.archive.org/web/20110714021140/http://www.epoxyde.hydrolase.mahjoubi.com/ Epoxide hydrolase characterization and purification]

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Category:EC 3.3.2

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