Epoxide hydrolase

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microsomal epoxide hydrolase
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MetaCycmetabolic pathway
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soluble epoxide hydrolase
ExPASy
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KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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PMCarticles
PubMedarticles
NCBIproteins

Epoxide hydrolases (EHs), also known as epoxide hydratases, are

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.

Classification

mEH (EH1), sEH (EH2), EH3, and EH4 isozymes

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

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.

Chr. 1 q42.1
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Chr. 8 p21
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Chr. 19 p13.13
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epoxide hydrolase 4
Identifiers
SymbolEPHX4
Alt. symbolsABHD7
Chr. 1 p22.1
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mEH

mEH is widely expressed in virtually all mammalian cells as an

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

sEH is widely expressed in mammalian cells as a

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

Human EH3 is a recently characterized protein with epoxy hydrolase activity for metabolizing

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

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

Leukotriene A4 hydrolase

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

(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).[14] The function of ChEH is unknown.[2]

Peg1/MEST

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

MEST (gene)).[2][15][16][17]

Hepoxilin-epoxide hydrolase

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

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

  1. ^
    PMID 18585390.; rendered via PyMOL
  2. ^
    PMID 22722082
    .
  3. ^
    S2CID 16885502
    .
  4. PMID 26216302
    .
  5. S2CID 42452896
    .
  6. PMID 26621325
    .
  7. ^
    PMID 22798687
    .
  8. PMID 24718283
    .
  9. S2CID 35078536
    .
  10. PMID 16778180
    .
  11. PMID 24771855
    .
  12. S2CID 19117041
    .
  13. S2CID 19151713
    .
  14. PMID 11154734
    .
  15. PMID 12023987
    .
  16. S2CID 33234162
    .
  17. PMID 23775149
    .
  18. ^
    PMID 5240838
    .
  19. PMID 21217101
    .
  20. PMID 26256802
    .

External links
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