Epoxide hydrolase

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microsomal epoxide hydrolase
Identifiers
EC number 3.3.2.9
CAS number 9048-63-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
soluble epoxide hydrolase
Epoxide Hydrolase B (2E3J).png
Epoxide hydrolase from Mycobacterium tuberculosis.[1]
Identifiers
EC number 3.3.2.10
CAS number 9048-63-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through a dihydroxylation reaction to form diol products. Several enzymes possess EH activity. Microsomal epoxide hydrolase (epoxide hydrolase 1, EH1, or mEH), soluble epoxide hydrolase (sEH, epoxide hydrolase 2, EH2, or cytoplasmic epoxide hydrolase), and the more recently discovered but not as yet well defined functionally, epoxide hydrolase 3 (EH3) and epoxide hydrolase 4 (EH4) are structurally closely related isozymes. Other enzymes with epoxide hydrolase activity include leukotriene A4 hydrolase, Cholesterol-5,6-oxide hydrolase, MEST (gene) (Peg1/MEST), and Hepoxilin-epoxide hydrolase.[2] The hydrolases are distinguished from each other by their substrate preferences and, directly related to this, their functions.

Epoxide hydrolase types[edit]

mEH (EH1), sEH (EH2), EH3, and EH4 isozymes[edit]

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 oxidation using organic peroxides and metal catalysts)) diol products. They differ, however, in subcellular location, substrate preferences, tissue expression, and/or function.

epoxide hydrolase 1, microsomal
Identifiers
Symbol EPHX1
Entrez 2052
HUGO 3401
OMIM 132810
RefSeq NM_000120
UniProt Q9NQV0
Other data
EC number 3.3.2.9
Locus Chr. 1 q42.1
epoxide hydrolase 2, cytoplasmic
Identifiers
Symbol EPHX2
Entrez 2053
HUGO 3402
OMIM 132811
RefSeq NM_001979
UniProt P34913
Other data
EC number 3.3.2.10
Locus Chr. 8 p21
epoxide hydrolase 3
Identifiers
Symbol EPHX3
Alt. symbols ABHD9
Entrez 79852
HUGO 23760
RefSeq NM_024794
UniProt Q9H6B9
Other data
EC number 3.3.-.-
Locus Chr. 19 p13.13
epoxide hydrolase 4
Identifiers
Symbol EPHX4
Alt. symbols ABHD7
Entrez 253152
HUGO 23758
RefSeq NM_173567
UniProt Q8IUS5
Other data
EC number 3.3.-.-
Locus Chr. 1 p22.1

mEH[edit]

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.[3] 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.[2] 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.[3][4] 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).[3]

sEH[edit]

sEH is widely expressed in mammalian cells as a cytosolic enzyme where it primarily serves the function of converting epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EPAs), and epoxydocosapentaenoic acids (DPAs) to there 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.[5][6] However, sEH also metabolizes the epoxides of linoleic acid viz., Vernolic acid (leukotoxins) and Coronaric acids (isoleukotoxins) to there 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").

EH3[edit]

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.[2][7] mRNA for EH3 is most strongly expressed in the lung, skin, and upper gastrointestinal tract tissues of mice.[7] 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.[8] Similar CpG site hypermethylations in the promoter of for the EH3 gene have been validated for other cancers.[9] This promoter methylation pattern, although not yet validated, was also found in human malignant melanoma.[10]

EH4[edit]

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.[7] The activity and function of EH4 has not yet been defined.[2]

Other epoxy hydrolases[edit]

Leukotriene A4 hydrolase[edit]

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.[11][12][13]

Cholesterol-5,6-oxide hydrolase[edit]

(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-hydoxyl-5,6-epoxides of cholesterol to their 3,5,6-trihydroxy products (see Cholesterol-5,6-oxide hydrolase).[14] The function of ChEH is unknown.[2]

Peg1/MEST[edit]

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)).[2][15][16][17]

Hepoxilin-epoxide hydrolase[edit]

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).[18] However, this activity has not been characterized at the purified protein or gene level[2] 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.[18][19]

Mycobacterium tuberculosis[edit]

This 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.[1] 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.[20]

References[edit]

  1. ^ a b PDB: 2E3J​; Biswal BK, Morisseau C, Garen G, Cherney MM, Garen C, Niu C, Hammock BD, James MN (September 2008). "The molecular structure of epoxide hydrolase B from Mycobacterium tuberculosis and its complex with a urea-based inhibitor". Journal of Molecular Biology. 381 (4): 897–912. doi:10.1016/j.jmb.2008.06.030. PMC 2866126Freely accessible. PMID 18585390. ; rendered via PyMOL
  2. ^ a b c d e f g 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 3495083Freely accessible. PMID 22722082. 
  3. ^ a b c El-Sherbeni AA, El-Kadi AO (November 2014). "The role of epoxide hydrolases in health and disease". Archives of Toxicology. 88 (11): 2013–32. doi:10.1007/s00204-014-1371-y. PMID 25248500. 
  4. ^ Václavíková R, Hughes DJ, Souček P (October 2015). "Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease". Gene. 571 (1): 1–8. doi:10.1016/j.gene.2015.07.071. PMC 4544754Freely accessible. PMID 26216302. 
  5. ^ Bellien J, Joannides R (March 2013). "Epoxyeicosatrienoic acid pathway in human health and diseases". Journal of Cardiovascular Pharmacology. 61 (3): 188–96. doi:10.1097/FJC.0b013e318273b007. PMID 23011468. 
  6. ^ He J, Wang C, Zhu Y, Ai D (May 2016). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. 8 (3): 305–13. doi:10.1111/1753-0407.12358. PMID 26621325. 
  7. ^ a b c 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 3435537Freely accessible. PMID 22798687. 
  8. ^ 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 4082437Freely accessible. PMID 24718283. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ Paige M, Wang K, Burdick M, Park S, Cha J, Jeffery E, Sherman N, Shim YM (June 2014). "Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema". Journal of Immunology. 192 (11): 5059–68. doi:10.4049/jimmunol.1400452. PMC 4083682Freely accessible. PMID 24771855. 
  12. ^ Appiah-Kubi P, Soliman ME (January 2016). "Dual anti-inflammatory and selective inhibition mechanism of leukotriene A4 hydrolase/aminopeptidase: insights from comparative molecular dynamics and binding free energy analyses". Journal of Biomolecular Structure & Dynamics: 1–16. doi:10.1080/07391102.2015.1117991. PMID 26555301. 
  13. ^ Calışkan B, Banoglu E (January 2013). "Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors". Expert Opinion on Drug Discovery. 8 (1): 49–63. doi:10.1517/17460441.2013.735228. PMID 23095029. 
  14. ^ Fretland AJ, Omiecinski CJ (December 2000). "Epoxide hydrolases: biochemistry and molecular biology". Chemico-Biological Interactions. 129 (1-2): 41–59. doi:10.1016/s0009-2797(00)00197-6. PMID 11154734. 
  15. ^ Pedersen IS, Dervan P, McGoldrick A, Harrison M, Ponchel F, Speirs V, Isaacs JD, Gorey T, McCann A (June 2002). "Promoter switch: a novel mechanism causing biallelic PEG1/MEST expression in invasive breast cancer". Human Molecular Genetics. 11 (12): 1449–53. doi:10.1093/hmg/11.12.1449. PMID 12023987. 
  16. ^ Moon YS, Park SK, Kim HT, Lee TS, Kim JH, Choi YS (2010). "Imprinting and expression status of isoforms 1 and 2 of PEG1/MEST gene in uterine leiomyoma". Gynecologic and Obstetric Investigation. 70 (2): 120–5. doi:10.1159/000301555. PMID 20339302. 
  17. ^ 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 (March 2014). "PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer". Clinical & Translational Oncology. 16 (3): 266–72. doi:10.1007/s12094-013-1067-4. PMC 3924020Freely accessible. PMID 23775149. 
  18. ^ a b Thompson RD (March 1968). "Extra-oral nerve blocks". Anesthesia Progress. 15 (3): 65–8. PMC 2235474Freely accessible. PMID 5240838. 
  19. ^ Cronin A, Decker M, Arand M (April 2011). "Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase". Journal of Lipid Research. 52 (4): 712–9. doi:10.1194/jlr.M009639. PMC 3284163Freely accessible. PMID 21217101. 
  20. ^ Selvan A, Anishetty S (October 2015). "Cavities create a potential back door in epoxide hydrolase Rv1938 from Mycobacterium tuberculosis-A molecular dynamics simulation study". Computational Biology and Chemistry. 58: 222–30. doi:10.1016/j.compbiolchem.2015.07.008. PMID 26256802. 

External links[edit]