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Information on EC 4.2.1.152 - hydroperoxy icosatetraenoate dehydratase
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4.2.1.152 hydroperoxy icosatetraenoate dehydrataseIUBMB Comments
Binds Fe2+. The mammalian enzymes accept a range of hydroperoxyicosatetraenoates (HPETE). The human enzyme has highest activity with (12R)-HPETE, followed by (12S)-HPETE and (15R)-HPETE with much lower efficiency. The murine enzyme has highest activity with (8R)-HPETE followed by (8S)-HPETE. All HPETE isoforms are converted to the corresponding oxoicosatetraenoate forms (KETE) . The enzymes also catalyse the reaction of EC 5.4.4.7, hydroperoxy icosatetraenoate isomerase.
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Word Map
- 4.2.1.152
- alox12b
-
ichthyosiform
- erythroderma
-
lamellar
-
nipal4
-
abca12
- cyp4f22
- 12r-lox
- pnpla1
- harlequin
- 12r-lipoxygenase
- ichthyoses
-
hepoxilins
-
collodion
- lipoxygenase-3
-
sdr9c7
-
cornification
-
non-bullous
-
galicia
-
self-healing
-
corneocyte
-
self-improving
The enzyme appears in viruses and cellular organisms
Synonyms
aloxe3, elox-3, hepoxilin synthase, epidermis-type lipoxygenase 3, epidermal lox type 3, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ALOXE3
eLOX-3
eLOX3
epidermal lipoxygenase-3
eLOX3
-
-
ambiguous
-
epidermal lipoxygenase-3
-
-
ambiguous
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a hydroperoxyicosatetraenoate = an oxoicosatetraenoate + H2O
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
hydroperoxyicosatetraenoate hydro-lyase (oxoicosatetraenoate-forming)
Binds Fe2+. The mammalian enzymes accept a range of hydroperoxyicosatetraenoates (HPETE). The human enzyme has highest activity with (12R)-HPETE, followed by (12S)-HPETE and (15R)-HPETE with much lower efficiency. The murine enzyme has highest activity with (8R)-HPETE followed by (8S)-HPETE. All HPETE isoforms are converted to the corresponding oxoicosatetraenoate forms (KETE) [2]. The enzymes also catalyse the reaction of EC 5.4.4.7, hydroperoxy icosatetraenoate isomerase.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(12R)-HPETE
(8R)-hydroxy-(11R,12R)-epoxyeicosa-(5Z,9E,14Z)-trienoic acid + H2O
-
preferred substrate
-
-
?
(12R)-hydroperoxyeicosatetraenoic acid
(8R)-hydroxy-(11R,12R)-epoxyeicosa-(5Z,9E,14Z)-trienoic acid + 12-oxoeicosatetraenoic acid
-
preferred substrate
2:1 ratio, 2:1 product ratio
-
?
(12S)-hydroperoxyeicosatetraenoic acid
(10R)-hydroxy-(11S,12S)-epoxyeicosa-(5Z,8Z,14Z)-trienoic acid + (8R)-hydroxy-(11S,12S)-epoxyeicosa-(5Z,9E,14Z)-trienoic acid + 12-oxoeicosatetraenoic acid
-
-
-
-
?
(15S)-hydroperoxyeicosatetraenoic acid
(13R)-hydroxy-(14S,15S)-epoxyeicosa-(5Z,8Z,11Z)-trienoic acid + 12-oxoeicosatetraenoic acid
-
-
-
-
?
(5Z,8Z,10E,12R,14Z)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate
(8R)-hydroxy-(11R,12R)-epoxyeicosa-(5Z,9E,14Z)-trienoate + H2O
-
-
-
-
?
(8S)-HPETE
(10R)-hydroxy-(8S,9S)-epoxyeicosa-(5Z,11Z,14Z)-trienoic acid + H2O
-
-
-
-
?
(9E,11Z,14Z)-20:3omega6
(9S)-hydroperoxy-(10E,12E,14Z)-eicosatrienoic acid + H2O
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good substrate
-
-
?
arachidonic acid + O2
5-HPETE + 7-HPETE + 9-HPETE
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in the absence of fatty acid hydroperoxides, the enzyme shows only weak and slow activity with arachidonic acid
22%, 25%, and 29% yield, respectively
-
?
arachidonoyl-lysophosphatidic acid
15-HPETE-lysophosphatidic acid + 13-HPETE-lysophosphatidic acid + 11HPETE-lysophosphatidic acid + 5-HPETE-lysophosphatidic acid + H2O
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-
36%, 22%, 21%, and 13% yield, respectively
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?
additional information
?
-
-
linoleic, arachidonic, and eicosapentaenoic acids, the methyl esters of arachidonic acid and linoleic acid, arachidonyl phosphatidylcholine, anandamide, and the cholesteryl ester of arachidonic acid are no substrates
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-
?
(5S)-HPETE
(7R)-hydroxy-(5S,6S)-epoxyeicosa-(8Z,11Z,14Z)-trienoic acid + H2O
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-
-
-
?
(5S)-HPETE
(7R)-hydroxy-(5S,6S)-epoxyeicosa-(8Z,11Z,14Z)-trienoic acid + H2O
-
-
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(12R)-HPETE
(8R)-hydroxy-(11R,12R)-epoxyeicosa-(5Z,9E,14Z)-trienoic acid + H2O
-
preferred substrate
-
-
?
(12R)-hydroperoxyeicosatetraenoic acid
(8R)-hydroxy-(11R,12R)-epoxyeicosa-(5Z,9E,14Z)-trienoic acid + 12-oxoeicosatetraenoic acid
-
preferred substrate
2:1 ratio
-
?
(8S)-HPETE
(10R)-hydroxy-(8S,9S)-epoxyeicosa-(5Z,11Z,14Z)-trienoic acid + H2O
-
-
-
-
?
(5S)-HPETE
(7R)-hydroxy-(5S,6S)-epoxyeicosa-(8Z,11Z,14Z)-trienoic acid + H2O
-
-
-
-
?
(5S)-HPETE
(7R)-hydroxy-(5S,6S)-epoxyeicosa-(8Z,11Z,14Z)-trienoic acid + H2O
-
-
-
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
nordihydroguaiaretic acid
-
submicromolar concentrations of nordihydroguaiaretic acid cause a dose-dependent increase in reaction rate 83-4fold with 12R-HPETE and up to 6fold with 15S-HPETE
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
arachidonate 12-lipoxygenase deficiency
Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
Blister
Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
Dermatitis, Exfoliative
Congenital ichthyosiform erythroderma with a novel variant in ABCA12 in a Chinese patient.
Dermatitis, Exfoliative
Different TGM1 mutation spectra in Italian and Portuguese patients with autosomal recessive congenital ichthyosis: evidence of founder effects in Portugal.
Dermatitis, Exfoliative
Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.
Dermatitis, Exfoliative
Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.
Dermatitis, Exfoliative
Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.
Dermatitis, Exfoliative
Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
Epilepsies, Myoclonic
The ALOXE3 gene variants from patients with Dravet syndrome decrease gene expression and enzyme activity.
Epilepsy
The ALOXE3 gene variants from patients with Dravet syndrome decrease gene expression and enzyme activity.
Granuloma
Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.
hydroperoxy icosatetraenoate dehydratase deficiency
Aloxe3 Knockout Mice Reveal a Function of Epidermal Lipoxygenase-3 as Hepoxilin Synthase and Its Pivotal Role in Barrier Formation.
hydroperoxy icosatetraenoate dehydratase deficiency
Diminished protein-bound ?-hydroxylated ceramides in the skin of patients with ichthyosis with 12R-lipoxygenase (LOX) or eLOX-3 deficiency.
hydroperoxy icosatetraenoate dehydratase deficiency
miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities.
hydroperoxy icosatetraenoate dehydratase deficiency
Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis.
Hyperalgesia
Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia.
Ichthyosiform Erythroderma, Congenital
Congenital ichthyosiform erythroderma with a novel variant in ABCA12 in a Chinese patient.
Ichthyosiform Erythroderma, Congenital
Different TGM1 mutation spectra in Italian and Portuguese patients with autosomal recessive congenital ichthyosis: evidence of founder effects in Portugal.
Ichthyosiform Erythroderma, Congenital
Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.
Ichthyosiform Erythroderma, Congenital
Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.
Ichthyosiform Erythroderma, Congenital
Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
Ichthyosis
Aloxe3 Knockout Mice Reveal a Function of Epidermal Lipoxygenase-3 as Hepoxilin Synthase and Its Pivotal Role in Barrier Formation.
Ichthyosis
Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects.
Ichthyosis
Characterization of Epidermal Lipoxygenase Expression in Normal Human Skin and Tissue-Engineered Skin Substitutes.
Ichthyosis
Congenital Ichthyosis and Recurrent Eczema Associated with a Novel ALOXE3 Mutation.
Ichthyosis
Development of an ichthyosiform phenotype in Alox12b-deficient mouse skin transplants.
Ichthyosis
Diminished protein-bound ?-hydroxylated ceramides in the skin of patients with ichthyosis with 12R-lipoxygenase (LOX) or eLOX-3 deficiency.
Ichthyosis
Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients.
Ichthyosis
Identification of a novel PNPLA1 mutation in a Spanish family with autosomal recessive congenital ichthyosis.
Ichthyosis
Identification of Mutations in SDR9C7 in 6 Families with Autosomal Recessive Congenital Ichthyosis.
Ichthyosis
Increased cutaneous absorption reflects impaired barrier function of reconstructed skin models mimicking keratinisation disorders.
Ichthyosis
Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B.
Ichthyosis
Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis.
Ichthyosis
Novel insertion and a previously reported nonsense variant of ALOXE3 gene lead to autosomal recessive ichthyosis in two Balochi families.
Ichthyosis
Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13.
Ichthyosis
Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis.
Ichthyosis
Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
Ichthyosis
The role of lipoxygenases in pathophysiology; new insights and future perspectives.
Ichthyosis
Variants in NIPAL4 and ALOXE3 cause autosomal recessive congenital ichthyosis in Pakistani families.
Ichthyosis, Lamellar
Different TGM1 mutation spectra in Italian and Portuguese patients with autosomal recessive congenital ichthyosis: evidence of founder effects in Portugal.
Ichthyosis, Lamellar
Lamellar Ichthyosis Caused by a Previously Unreported Homozygous ALOXE3 Mutation in East Asia.
Insulin Resistance
Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPAR?.
Insulinoma
Biosynthesis of hepoxilins: evidence for the presence of a hepoxilin synthase activity in rat insulinoma cells.
Metabolic Diseases
Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPAR?.
Neoplasms
miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities.
Pulmonary Disease, Chronic Obstructive
The Perspective of Diagnostic and Prognostic Values of Lipoxygenases mRNA Expression in Colon Adenocarcinoma.
Seizures
Expression Pattern of ALOXE3 in Mouse Brain Suggests Its Relationship with Seizure Susceptibility.
Skin Diseases
ZNF750 Is a p63 Target Gene that Induces KLF4 to Drive Terminal Epidermal Differentiation.
Status Epilepticus
Expression Pattern of ALOXE3 in Mouse Brain Suggests Its Relationship with Seizure Susceptibility.
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression analysis of the enzyme in normal human skin and tissue-engineered skin substitutes, overview. Human TESS are models of epidermal differentiation expressing various epidermal markers. Normal human skin and TESS present the four expected epidermal layers: the basal, spinous, granular, and cornified layers. Enzyme eLOX3 is similarly expressed in TESS when compared with normal human skin
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
the lipoxygenase (LOX) family contains enzymes catalyzing dioxygenation or, for epidermis-type lipoxygenase 3 (eLOX-3), hydroperoxide isomerization of polyunsaturated fatty acids. Five LOX mRNAs are known to be expressed in human epidermal cells: eLOX-3, 12R-lipoxygenase (12RLOX), 12S-lipoxygenase (12S-LOX), 15-lipoxygenase 1 (15-LOX-1), and 15-lipoxygenase 2 (15-LOX-2), expression profiles, overview
malfunction
mutations in nine different genes are known to be responsible for ichthyoses. One of them is the lipoxygenase gene Aloxe3 encoding the epidermal lipoxygenase-3 (eLOX-3). eLOX-3-deficient mice decease rapidly after birth due to transepidermal water loss, short life-span of eLOX-3 null mice. For a prenatal gene therapy approach, intra-amniotic delivery of eLOX-3 to mice at gestational day 14.5, both via an adenoviral vector and as recombinant protein, is undertaken resulting in fetal growth restriction and intrauterine death. Periodic acid-Schiff staining and RT-PCR analysis of placentae from fetuses exposed to eLOX-3 indicate a lack of glycogen trophoblasts in the junctional zone, overview. Placenta-specific gene expression is altered. Thus, the observed prenatal toxicity of eLOX-3 can be due to a strong effect on placental development
physiological function
physiological function
the epidermal lipoxygenase-3 (eLOX-3) is involved in the conversion of fatty acids to specific epoxyalcohol derivatives such as ceramide precursors and hepoxilins and plays an important role in the generation of the permeability barrier of the skin, which protects against dehydration and physical injury. eLOX-3 appears to have some impact on the expression of genes that indirectly influence fetal development
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A451G
-
unlike wild type enzyme, the mutant reacts well with arachidonic acid even in the absence of fatty acid hydroperoxides, yet only after an unusually long lag phase of about 20 min
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA agarose column chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yu, Z.; Schneider, C.; Boeglin, W.E.; Marnett, L.J.; Brash, A.R.
The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase
Proc. Natl. Acad. Sci. USA
100
9162-9167
2003
Homo sapiens
brenda
Yu, Z.; Schneider, C.; Boeglin, W.E.; Brash, A.R.
Human and mouse eLOX3 have distinct substrate specificities: implications for their linkage with lipoxygenases in skin
Arch. Biochem. Biophys.
455
188-196
2006
Homo sapiens, Mus musculus
brenda
Yu, Z.; Schneider, C.; Boeglin, W.E.; Brash, A.R.
Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3
Biochim. Biophys. Acta
1686
238-247
2005
Homo sapiens
brenda
Zheng, Y.; Brash, A.R.
Dioxygenase activity of epidermal lipoxygenase-3 unveiled: typical and atypical features of its catalytic activity with natural and synthetic polyunsaturated fatty acids
J. Biol. Chem.
285
39866-39875
2010
Homo sapiens
brenda
Yu, Z.; Schneider, C.; Boeglin, W.E.; Brash, A.R.
Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha
Lipids
42
491-497
2007
Homo sapiens
brenda
Simard-Bisson, C.; Parent, L.A.; Moulin, V.J.; Fruteau de Laclos, B.
Characterization of epidermal lipoxygenase expression in normal human skin and tissue-engineered skin substitutes
J. Histochem. Cytochem.
66
813-824
2018
Homo sapiens (Q9BYJ1), Homo sapiens
brenda
Vierling, F.; Dick, A.; Wahlbuhl, M.; Krieg, P.; Henke, C.; Ruebner, M.; Schneider, H.
Surprising prenatal toxicity of epidermal lipoxygenase-3
Placenta
35
776-779
2014
Mus musculus (Q9WV07)
brenda
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Release 2023.1 (January 2023)
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