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Information on EC 1.13.11.33 - arachidonate 15-lipoxygenase and Organism(s) Oryctolagus cuniculus and UniProt Accession P12530
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1.13.11.33 arachidonate 15-lipoxygenaseIUBMB Comments
The product is rapidly reduced to the corresponding 15S-hydroxy compound.
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Word Map
- 1.13.11.33
- lipoxygenases
- cox-2
- 15-hete
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polyunsaturated
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leukotriene
-
eicosanoids
- hydroperoxide
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12-lipoxygenase
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cyclooxygenases
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lipoxins
-
15s-hydroxyeicosatetraenoic
- ndga
- alox15b
- 12/15-lipoxygenase
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nordihydroguaiaretic
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pro-resolving
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lipoxygenation
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resolvins
-
hodes
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13-hydroxyoctadecadienoic
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lipid-peroxidating
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leukocyte-type
- oxylipins
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platelet-type
- medicine
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protectins
- drug development
The taxonomic range for the selected organisms is: Oryctolagus cuniculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Synonyms
15-lox, 15-lo-1, 15-lox-2, 15-lox2, arachidonate 15-lipoxygenase, soybean 15-lipoxygenase, 15-lipoxygenase-2, 15lo1, 15-hlo, 15-lipoxygenase 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
15-lipoxygenase
15-LOX
arachidonic acid 15-lipoxygenase
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linoleic acid omega-6-lipoxygenase
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omega-6 lipoxygenase
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oxygenase, arachidonate 15-lip-
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15-lipoxygenase
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15-LOX
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
arachidonate + O2 = (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
important role of Leu597 in the mechanism of lipoxygenases
arachidonate + O2 = (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
the reaction proceeds via hydrogen abstraction, peroxide cleavage, radical rearrangement, and epoxide formation. To initiate the reaction the ferrous LOX is first activated by peroxide-dependent oxidation to a ferric form. The lipohydroperoxidase activity is initiatedwhen a lipid hydroperoxide (ROOH) is bound at the active site of the enzyme. The enzyme then catalyzes a homolytic cleavage of the hydroperoxy bond, which leads to the formation of an oxygen-centered alkoxy radical, a hydroxyl and oxidizes the ferrous iron to a ferric form. Then the enzyme binds a linoleic acid molecule (or an alterative reductant such as guaiacol) and releases a carbon-centered linoleic radical. This reaction reduces the ferric LOX back to its ferrous form to start the next catalytic cycle. The released radical intermediates may then initiate free radical secondary reactions leading to the formation of mixed oxygenated and non-oxygenated linoleic acid dimer
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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dioxygenation
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
arachidonate:oxygen 15-oxidoreductase
The product is rapidly reduced to the corresponding 15S-hydroxy compound.
CAS REGISTRY NUMBER
COMMENTARY
82249-77-2
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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
(16(R),5Z,8Z,11Z,14Z)-16-fluoroeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme: 78% of the 15,16(R) product and 22% of the 12,16(R) product
-
?
(16(R),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme and mutant enzyme I593A prouce small amounts of unspecific products. Mutant enzyme F353L produces 6% of 15,16(R) product and 94% of the 12,16(R) product
-
?
(16(S),5Z,8Z,11Z,14Z)-16-fluoroeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme: 69% of the 15,16(S) product and 31% of the 12,16(S) product
-
?
(16(S)5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme: 93% of the 15,16(S) product and 7% of the 12,16(S) product
-
?
(17(R),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme: 1% of the 15,17(R) product and 99% of the 12,17(R) product
-
?
(17(S),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
-
wild-type enzyme: 3% of the 15,17(S) product and 97% of the 12,17(S) product
-
?
(18(R),5Z,8Z,11Z,14Z)-18-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
oxygenation proceeds with little if any enantioselectivity
-
-
?
(18(S),5Z,8Z,11Z,14Z)-18-hydroxyeicosa-5,8,11,14-tetraenoic acid + O2
?
oxygenation proceeds with little if any enantioselectivity
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-
?
1-palmitoyl-2-arachidonyl phosphatidyl choline + O2
15S-HpETE + ?
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-
-
?
1-palmitoyl-2-docosahexaenoyl phosphatidyl choline + O2
17S-HpDHE + ?
-
-
-
?
1-palmitoyl-2-eicosapentaenoyl phosphatidyl choline + O2
15S-HpEPE + ?
-
-
-
?
1-palmitoyl-2-linoleoyl phosphatidyl choline + O2
13S-HpODE + ?
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
-
-
?
arachidonic acid + O2
(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid + (12S,5Z,8Z,10E,14Z)-12-hydroperoxyeicosa-5,8,10,14-tetraenoic acid
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93% (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid and 7% (12S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid
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?
1-linoleoyl lysophosphatidic acid + O2
(S)-hydroperoxy 1-linoleoyl lysophosphatidic acid
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i.e. linoleoyl-lysoPA
major product
-
?
1-linoleoyl lysophosphatidylcholine + O2
(S)-hydroperoxy 1-linoleoyl lysophosphatidylcholine
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i.e. linoleoyl-lysoPC
major product
-
?
11,14,17-eicosatrienoic acid + O2
15-hydroperoxy-11,13,17-eicosatrienoic acid
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-
-
?
8,11,14-eicosatrienoic acid + O2
15-hydroperoxy-8,11,13-eicosatrienoic acid
-
-
-
?
arachidonic acid + O2
(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid + (12S,5Z,8Z,10E,14Z)-12-hydroperoxyeicosa-5,8,10,14-tetraenoic acid
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the ratio of (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid to (12S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid is 20 for the wild-type enzyme
-
?
dilinoleoyl phosphatidic acid + O2
(S)-hydroperoxy dilinoleoyl phosphatidic acid
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i.e. dilinoleoylPA
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?
dilinoleoyl phosphatidylcholine + O2
(S)-hydroperoxy dilinoleoyl phosphatidylcholine
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i.e. dilinoleoylPC
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?
linoleic acid + O2
(9Z,11E)-(13S)-13-hydroperoxyoctadeca-9,11-dienoate
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
best substrate
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-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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-
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?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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and nonenzymatic production of 15-hydroxy-5,8,11,13-eicosatetraenoic acid, 15-keto-5,8,11,13-eicosatetraenoic acid, 13-hydroxy-14,15-epoxy-5,8,11-eicosatrienoic acid and 11,14,15-trihydroxy-5,8,12-eicosatrienoic acid
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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is further metabolized by hydroperoxide isomerase to the acid-sensitive metabolite 15(S)-hydroxy-11,12-epoxyeicosatrienoic acid, which is hydrolyzed to 11,12,15-trihydroxyeicosatrienoic acid, by a soluble epoxid hydrolase, causing endothelium-dependent smooth muscle hyperpolarization and relaxations, mass spectrometrical metabolite analysis and pathway, overview
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
the enzyme is regulated pretranslational, translational and posttranslational
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
catalyzes enzymatic lipid peroxidation in complex biological structures via direct dioxygenation of phospholipids and cholesterol esters of biomembranes and plasma lipoproteins
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
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first step in biotransformation of arachidonic acid to the 15-series of leukotrienes, reaction is involved in inactivation of slow-reacting substrances of anaphylaxis
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
high oxygen affinity is important for effective catalysis, L367 is involved in oxygen access, channel structure, overview, arachidonic acid closes the substrate-binding pocket for oxygen diffusion but opens a fourth oxygen access channel
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
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15-H(p)ETE is the major reaction product independent of the pH
-
?
arachidonic acid + O2
(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid
-
-
-
-
?
arachidonic acid + O2
(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid
-
an atomic-level study of the binding modes of linoleic acid to rabbit reticulocyte 15-rLO-1 is presented. Results are compared with binding of arachidonic acid to 15-rLO-1. Linoleic acid seems to adapt more easily to the enzyme structure and differs from arachidonic acid on some dynamical aspects that could introduce kinetic differences, as observed experimentally
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-
?
linoleic acid + O2
?
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an atomic-level study of the binding modes of linoleic acid to rabbit reticulocyte 15-rLO-1 is presented. Results are compared with binding of arachidonic acid to 15-rLO-1. Linoleic acid seems to adapt more easily to the enzyme structure and differs from arachidonic acid on some dynamical aspects that could introduce kinetic differences, as observed experimentally
-
-
?
additional information
?
-
15-lipoxygenating ALOX15 orthologs exhibit significantly higher lipoxin-synthesizing capacities than 12-lipoxygenating. The wild-type animal produces 3% 12-hydroperoxyicosatetraenoate and 97% 15-hydroperoxyicosatetraenoate
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-
?
additional information
?
-
the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
-
-
?
additional information
?
-
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the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
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-
?
additional information
?
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enzyme substrate specificity, overview. The ALOX15 enzyme activity is not restricted to free polyenoic fatty acids since phospholipids and even biomembranes and lipoproteins are suitable ALOX15 substrates. The ALOX15 orthologue is capable of converting hydroperoxy fatty acids to epoxy leukotrienes. Molecular docking studies of a phospholipid molecule at the active site of rabbit ALOX15. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement
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-
?
additional information
?
-
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enzyme substrate specificity, overview. The ALOX15 enzyme activity is not restricted to free polyenoic fatty acids since phospholipids and even biomembranes and lipoproteins are suitable ALOX15 substrates. The ALOX15 orthologue is capable of converting hydroperoxy fatty acids to epoxy leukotrienes. Molecular docking studies of a phospholipid molecule at the active site of rabbit ALOX15. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement
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?
additional information
?
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prediction of reaction specificity of mammalian ALOX15 orthologues, and reaction specificity of ALOX15 orthologues during late primate evolution
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?
additional information
?
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15-lipoxygenase is capable of disrupting the pH gradient maintained by mitochondria in living cells without additional factors specific for red blood cell development. Ectopic expression of 15-lipoxygenase leads to the collaps of the mitochondrial pH gradient in nonerythroid cells
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?
additional information
?
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activation of the enzyme at the protein and product levels and increased sensitivity to constriction of pulmonary arteries by the product 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid may contribute to pulmonary hypoxic vasoconstriction in neonatal rabbits
-
-
?
additional information
?
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the enzyme may be involved in the development of atherosclerosis
-
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?
additional information
?
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stereo-selectivity in LOX-catalyzed oxygenation of lysophospholipids, overview
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?
additional information
?
-
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the bifunctional enzyme also forms (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyeicosa-5,8,10,14-tetraenoate, the product of 12-LO activity, EC 1.13.11.31, in a ratio of 9:1 15(S)-HPETE to 12(S)HPETE
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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
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
best substrate
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
-
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
-
is further metabolized by hydroperoxide isomerase to the acid-sensitive metabolite 15(S)-hydroxy-11,12-epoxyeicosatrienoic acid, which is hydrolyzed to 11,12,15-trihydroxyeicosatrienoic acid, by a soluble epoxid hydrolase, causing endothelium-dependent smooth muscle hyperpolarization and relaxations, mass spectrometrical metabolite analysis and pathway, overview
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
the enzyme is regulated pretranslational, translational and posttranslational
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
catalyzes enzymatic lipid peroxidation in complex biological structures via direct dioxygenation of phospholipids and cholesterol esters of biomembranes and plasma lipoproteins
-
-
?
arachidonate + O2
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyeicosa-5,8,11,13-tetraenoate
-
first step in biotransformation of arachidonic acid to the 15-series of leukotrienes, reaction is involved in inactivation of slow-reacting substrances of anaphylaxis
-
-
?
additional information
?
-
15-lipoxygenating ALOX15 orthologs exhibit significantly higher lipoxin-synthesizing capacities than 12-lipoxygenating. The wild-type animal produces 3% 12-hydroperoxyicosatetraenoate and 97% 15-hydroperoxyicosatetraenoate
-
-
?
additional information
?
-
the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
-
-
?
additional information
?
-
-
the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
-
-
?
additional information
?
-
-
15-lipoxygenase is capable of disrupting the pH gradient maintained by mitochondria in living cells without additional factors specific for red blood cell development. Ectopic expression of 15-lipoxygenase leads to the collaps of the mitochondrial pH gradient in nonerythroid cells
-
-
?
additional information
?
-
-
activation of the enzyme at the protein and product levels and increased sensitivity to constriction of pulmonary arteries by the product 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid may contribute to pulmonary hypoxic vasoconstriction in neonatal rabbits
-
-
?
additional information
?
-
-
the enzyme may be involved in the development of atherosclerosis
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Iron
Ca2+
-
for maximal intracellular activity, 12/15-lipoxygenases require a rise in cytosolic calcium concentration inducing a translocation of the enzyme from the cytosol to cellular membranes
Iron
-
the iron is liganded by four histidines at positions 361, 366, 541 and 545 asell as the C-terminal isoleucine
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(-)-5,7-O-diacetyl-3',4',5'-O-triacetylepigallocatechin-3-O-(3'',4'',5''-O-triacetyl)gallate
-
IC50: 0.061 mM
(-)-5,7-O-dibutyryl-3',4',5'-O-tributyrylepigallocatechin-3-O-(3'',4'',5''-O-tributyryl) gallate
-
IC50: 0.033 mM
(-)-5,7-O-dimethyl-3',4',5'-O-trimethylepigallocatechin-3-O-(3'',4'',5''-O-trimethyl) gallate
-
IC50: 0.03 mM
(-)-5,7-O-dipropionyl-3',4',5'-O-tripropionylepigallocatechin-3-O-(3'',4'',5''-O-tripropionyl) gallate
-
IC50: 0.031 mM
1-(4-Methoxy-phenyl)-2,3-diphenyl-indolizine-7-carbonitrile
-
IC50: 0.037mM
1-(Hydroxy-phenyl-methyl)-2,3-diphenyl-indolizine-7-carbonitrile
-
IC50: 0.048 mM
1-(hydroxymethyl)-2,3-diphenylindolizine-7-carbonitrile
-
IC50: 0.034 mM
1-(methoxymethoxy)-2,3-diphenylindolizine-7-carbonitrile
-
IC50: 0.075 mM
1-benzyloxymethoxy-2,3-diphenyl-7-indolizinecarbonitrile
-
IC50: 0.039 mM
2-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione
-
-
3-(2-[[(4-pentylphenyl)sulfonyl]amino]ethyl)-1H-indole-6-carboxylic acid
-
-
4'-butyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
-
IC50: 0.00053 mM in the presence of arachidonate, IC50: 0.0002 mM in the presence of linoleic acid
4'-ethyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
-
IC50: 0.00026 mM in the presence of arachidonate, IC50: 0.00047 mM in the presence of linoleic acid
4'-tert-butyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
-
IC50: 0.00027 mM in the presence of arachidonate, IC50: 0.00023 mM in the presence of linoleic acid
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-(3-hydroxypropyl)benzamide
-
-
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-(4-methoxyphenyl)benzamide
-
-
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-butylbenzamide
-
-
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-cyclohexylbenzamide
-
-
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-phenylbenzamide
-
-
4-([2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]sulfamoyl)-N-[3-(dimethylamino)propyl]benzamide
-
-
4-([2-[2-(4-methoxyphenyl)-1H-indol-3-yl]ethyl]sulfamoyl)benzoic acid
-
-
4-butyl-N-[2-(1H-indol-3-yl)ethyl]benzenesulfonamide
-
IC50: 0.00307 mM in the presence of arachidonate, IC50: 0.004 mM in the presence of linoleic acid
4-butyl-N-[2-[2-(4-methoxyphenyl)-1H-indol-3-yl]ethyl]benzenesulfonamide
-
-
4-ethyl-N-[2-(1H-indol-3-yl)ethyl]benzenesulfonamide
-
IC50: 0.01 mM in the presence of arachidonate, IC50: 0.01 mM in the presence of linoleic acid
4-pentyl-N-(2-[2-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl]ethyl)benzenesulfonamide
-
-
4-pentyl-N-[2-(2-quinolin-3-yl-1H-indol-3-yl)ethyl]benzenesulfonamide
-
-
4-pentyl-N-[2-[5-(1H-pyrrol-2-yl)-1H-indol-3-yl]ethyl]benzenesulfonamide
-
-
5-(methoxymethoxy)-6,7-diphenylpyrrolo[1,2-b]pyridazine
-
IC50: 0.059 mM
7-cyano-2,3-diphenylindolizin-1-yl trifluoromethanesulfonate
-
IC50: 0.059 mM
BODIPY-D3825
-
competes with the substrate fatty acid for binding at the active site
methyl 3-(2-[[(4-pentylphenyl)sulfonyl]amino]ethyl)-1H-indole-6-carboxylate
-
-
N-[2-(1H-indol-3-yl)ethyl]-2'-methylbiphenyl-4-sulfonamide
-
IC50: 0.00092 mM in the presence of arachidonate, IC50: 0.00046 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-3'-methylbiphenyl-4-sulfonamide
-
IC50: 0.00045 mM in the presence of arachidonate, IC50: 0.00032 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4'-(1-methylethyl)biphenyl-4-sulfonamide
-
IC50: 0.00028 mM in the presence of arachidonate, IC50: 0.00014 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4'-(2-methylpropyl)biphenyl-4-sulfonamide
-
IC50: 0.00091 mM in the presence of arachidonate, IC50: 0.00017 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4'-methoxybiphenyl-4-sulfonamide
-
IC50: 0.0015 mM in the presence of arachidonate, IC50: 0.00109 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4'-methylbiphenyl-4-sulfonamide
-
IC50: 0.00047 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4-methylbenzenesulfonamide
-
IC50: 0.01 mM in the presence of arachidonate, IC50: 0.01 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4-pentylbenzenesulfonamide
-
IC50: 0.00042 mM in the presence of arachidonate, IC50: 0.00102 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]-4-propylbenzenesulfonamide
-
IC50: 0.00313 mM in the presence of arachidonate, IC50: 0.0032 mM in the presence of linoleic acid
N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
-
IC50: 0.0034 mM in the presence of arachidonate, IC50: 0.0042 mM in the presence of linoleic acid
N-[2-(2-dibenzo[b,d]furan-2-yl-1H-indol-3-yl)ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1-methyl-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-4-(hydrazinocarbonyl)benzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-4-bromobenzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-4-methylbenzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]ethyl]-4-pyridin-4-ylbenzenesulfonamide
-
-
N-[2-[2-(2,5-dimethoxyphenyl)-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(4-chlorophenyl)-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(4-ethoxyphenyl)-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(4-methoxyphenyl)-1H-indol-3-yl]ethyl]-4-methylbenzenesulfonamide
-
-
N-[2-[2-(4-methoxyphenyl)-1H-indol-3-yl]ethyl]-4-pentylbenzenesulfonamide
-
-
N-[2-[2-(4-methoxyphenyl)-1H-indol-3-yl]ethyl]biphenyl-4-sulfonamide
-
-
N-[3-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]propyl]-4-pentylbenzenesulfonamide
-
-
N-[3-[2-(1-benzofuran-2-yl)-1H-indol-3-yl]propyl]biphenyl-4-sulfonamide
-
-
RINKKIEK
-
68.1% inhibition at 0.25 mM, a beta-casein-derived octapeptide
Toluene-4-sulfonic acid 6,7-diphenyl-pyrrolo[1,2-b]pyridazin-5-yl ester
-
IC50: 0.028 mM
toluene-4-sulfonic acid 7-cyano-2,3-diphenyl-indolizin-1-yl ester
-
IC50: 0.025 mM
ebselen
-
i.e. 2-phenyl-1,2-benzisoselenazol-3(2H)-one, irreversible inhibition, IC50: 0.00006 mM
additional information
certain oxazole-4-carbonitrile based LOX inhibitors share a high inhibitory potency for human and mouse ALOX15 but hardly inhibit other mammalian LOX-isoforms
-
additional information
-
certain oxazole-4-carbonitrile based LOX inhibitors share a high inhibitory potency for human and mouse ALOX15 but hardly inhibit other mammalian LOX-isoforms
-
additional information
-
inhibitory and LOX binding abilities of diverse RINKKIEK peptide derivatives, overview
-
additional information
-
pH alterations in the near physiological range impact the iron content of LOX and thus the catalytic activity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
ALOX15 is usually present as catalytically silent ferrous enzyme. To initiate fatty acid oxygenation, the enzyme must first be oxidized to a ferric form capable of initiating hydrogen abstraction. Unfortunately, single activation of the enzyme is not sufficient to keep it running, since during catalysis small quantities of radical intermediates might escape from the active site leaving the enzyme in an inactive ferrous (Fe2+) form. To keep the reaction at quasistationary levels, repeated enzyme activation is required and the primary oxygenation products appear to serve as enzyme activators. In this sense, the LOX exhibits autocatalytic properties. Studying the oxygenation of 15S-HETE by pure rabbit ALOX15, it is found that the corresponding oxygenation product(s) does not activate the enzyme, while molecular dioxygen serves not only as a lipoxygenase substrate, but also impacts peroxide-dependent enzyme activation
-
additional information
-
ALOX15 is usually present as catalytically silent ferrous enzyme. To initiate fatty acid oxygenation, the enzyme must first be oxidized to a ferric form capable of initiating hydrogen abstraction. Unfortunately, single activation of the enzyme is not sufficient to keep it running, since during catalysis small quantities of radical intermediates might escape from the active site leaving the enzyme in an inactive ferrous (Fe2+) form. To keep the reaction at quasistationary levels, repeated enzyme activation is required and the primary oxygenation products appear to serve as enzyme activators. In this sense, the LOX exhibits autocatalytic properties. Studying the oxygenation of 15S-HETE by pure rabbit ALOX15, it is found that the corresponding oxygenation product(s) does not activate the enzyme, while molecular dioxygen serves not only as a lipoxygenase substrate, but also impacts peroxide-dependent enzyme activation
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0289
(16(R),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
0.136
(16(R),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme F353L
0.0227
(16(S),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme F353L
0.0236
(16(S),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
0.0368
(17(R),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme L353L
0.293
(17(R),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
0.0313
(17(S),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme L353L
0.236
(17(S),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
additional information
additional information
-
free-energy distribution for oxygen inside the substrate-free rabbit 12/15-LOX, containing four nested free-energy isosurfaces with different energy levels, overview
-
additional information
additional information
-
kinetics with lysophospholipid substrates
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.08
(16(R),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme F353L
0.2
(16(S),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme F353L
0.51
(16(S),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
0.18
(17(R),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
0.2
(17(R),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme L353L
0.24
(17(S),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, mutant enzyme L353L
1.24
(17(S),5Z,8Z,11Z,14Z)-17-hydroxyeicosa-5,8,11,14-tetraenoic acid
pH 7.4, wild-type enzyme
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.061
(-)-5,7-O-diacetyl-3',4',5'-O-triacetylepigallocatechin-3-O-(3'',4'',5''-O-triacetyl)gallate
Oryctolagus cuniculus
-
IC50: 0.061 mM
0.033
(-)-5,7-O-dibutyryl-3',4',5'-O-tributyrylepigallocatechin-3-O-(3'',4'',5''-O-tributyryl) gallate
Oryctolagus cuniculus
-
IC50: 0.033 mM
0.03
(-)-5,7-O-dimethyl-3',4',5'-O-trimethylepigallocatechin-3-O-(3'',4'',5''-O-trimethyl) gallate
Oryctolagus cuniculus
-
IC50: 0.03 mM
0.031
(-)-5,7-O-dipropionyl-3',4',5'-O-tripropionylepigallocatechin-3-O-(3'',4'',5''-O-tripropionyl) gallate
Oryctolagus cuniculus
-
IC50: 0.031 mM
0.037
1-(4-Methoxy-phenyl)-2,3-diphenyl-indolizine-7-carbonitrile
Oryctolagus cuniculus
-
IC50: 0.037mM
0.048
1-(Hydroxy-phenyl-methyl)-2,3-diphenyl-indolizine-7-carbonitrile
Oryctolagus cuniculus
-
IC50: 0.048 mM
0.034
1-(hydroxymethyl)-2,3-diphenylindolizine-7-carbonitrile
Oryctolagus cuniculus
-
IC50: 0.034 mM
0.075
1-(methoxymethoxy)-2,3-diphenylindolizine-7-carbonitrile
Oryctolagus cuniculus
-
IC50: 0.075 mM
0.039
1-benzyloxymethoxy-2,3-diphenyl-7-indolizinecarbonitrile
Oryctolagus cuniculus
-
IC50: 0.039 mM
0.015
3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one
Oryctolagus cuniculus
-
IC50: 0.015 mM
0.0002
4'-butyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00053 mM in the presence of arachidonate, IC50: 0.0002 mM in the presence of linoleic acid
0.00047
4'-ethyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00026 mM in the presence of arachidonate, IC50: 0.00047 mM in the presence of linoleic acid
0.00023
4'-tert-butyl-N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00027 mM in the presence of arachidonate, IC50: 0.00023 mM in the presence of linoleic acid
0.004
4-butyl-N-[2-(1H-indol-3-yl)ethyl]benzenesulfonamide
Oryctolagus cuniculus
-
IC50: 0.00307 mM in the presence of arachidonate, IC50: 0.004 mM in the presence of linoleic acid
0.01
4-ethyl-N-[2-(1H-indol-3-yl)ethyl]benzenesulfonamide
Oryctolagus cuniculus
-
IC50: 0.01 mM in the presence of arachidonate, IC50: 0.01 mM in the presence of linoleic acid
0.059
5-(methoxymethoxy)-6,7-diphenylpyrrolo[1,2-b]pyridazine
Oryctolagus cuniculus
-
IC50: 0.059 mM
0.059
7-cyano-2,3-diphenylindolizin-1-yl trifluoromethanesulfonate
Oryctolagus cuniculus
-
IC50: 0.059 mM
0.00006
ebselen
Oryctolagus cuniculus
-
i.e. 2-phenyl-1,2-benzisoselenazol-3(2H)-one, irreversible inhibition, IC50: 0.00006 mM
0.00046
N-[2-(1H-indol-3-yl)ethyl]-2'-methylbiphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00092 mM in the presence of arachidonate, IC50: 0.00046 mM in the presence of linoleic acid
0.00032
N-[2-(1H-indol-3-yl)ethyl]-3'-methylbiphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00045 mM in the presence of arachidonate, IC50: 0.00032 mM in the presence of linoleic acid
0.00014
N-[2-(1H-indol-3-yl)ethyl]-4'-(1-methylethyl)biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00028 mM in the presence of arachidonate, IC50: 0.00014 mM in the presence of linoleic acid
0.00017
N-[2-(1H-indol-3-yl)ethyl]-4'-(2-methylpropyl)biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00091 mM in the presence of arachidonate, IC50: 0.00017 mM in the presence of linoleic acid
0.00109
N-[2-(1H-indol-3-yl)ethyl]-4'-methoxybiphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.0015 mM in the presence of arachidonate, IC50: 0.00109 mM in the presence of linoleic acid
0.00047
N-[2-(1H-indol-3-yl)ethyl]-4'-methylbiphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.00047 mM in the presence of linoleic acid
0.01
N-[2-(1H-indol-3-yl)ethyl]-4-methylbenzenesulfonamide
Oryctolagus cuniculus
-
IC50: 0.01 mM in the presence of arachidonate, IC50: 0.01 mM in the presence of linoleic acid
0.00102
N-[2-(1H-indol-3-yl)ethyl]-4-pentylbenzenesulfonamide
Oryctolagus cuniculus
-
IC50: 0.00042 mM in the presence of arachidonate, IC50: 0.00102 mM in the presence of linoleic acid
0.0032
N-[2-(1H-indol-3-yl)ethyl]-4-propylbenzenesulfonamide
Oryctolagus cuniculus
-
IC50: 0.00313 mM in the presence of arachidonate, IC50: 0.0032 mM in the presence of linoleic acid
0.0042
N-[2-(1H-indol-3-yl)ethyl]biphenyl-4-sulfonamide
Oryctolagus cuniculus
-
IC50: 0.0034 mM in the presence of arachidonate, IC50: 0.0042 mM in the presence of linoleic acid
0.028
Toluene-4-sulfonic acid 6,7-diphenyl-pyrrolo[1,2-b]pyridazin-5-yl ester
Oryctolagus cuniculus
-
IC50: 0.028 mM
0.025
toluene-4-sulfonic acid 7-cyano-2,3-diphenyl-indolizin-1-yl ester
Oryctolagus cuniculus
-
IC50: 0.025 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
-
639237, 639238, 639239, 639244, 639255, 639258, 639259, 639266, 657880, 658046, 658263, 671666, 671670, 672574, 685330, 702247, 706579
additional information
stroma-free hemolysis supernatant of a reticulocyte-rich blood cell suspension
additional information
tissue specific expression of ALOX15 and transcriptional expression regulation, overview
additional information
-
tissue specific expression of ALOX15 and transcriptional expression regulation, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme associates to biomembranes primarily via hydrophobic interactions between surface-exposed apolar amino acid side chains and membrane lipids. Calcium supports membrane binding probably by forming salt bridges between the negatively charged head groups of membrane phospholipids and acidic surface amino acids of the membrane
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
physiological function
physiological function
additional information
evolution
mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologues. 15-lipoxygenating isoforms are found in primates (orangutans, humans), suggesting an evolution of ALOX15 specificity. Other primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity, an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins. Phylogenetic analysis
physiological function
ALOX15-encoded 12/15-lipoxygenase orthologs are implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids
physiological function
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview
physiological function
-
high degree of motional flexibility and a high membrane binding affinity
physiological function
-
is a regulator of angiogenesis, antiangiogenic action in skeletal muscle system. 15-LO-1 significantly decreases all angiogenic effects induced by vascular endothelial growth factor-A and placental growth factor, including capillary perfusion, vascular permeability, vasodilatation, and the increase in capillary number
additional information
molecular dynamics simulations and quantum mechanics/molecular mechanics calculations
additional information
quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to study the addition of O2 to the pentadienyl radical of arachidonic acid catalyzed by the Leu597Val and Leu597Ala mutants of rabbit 15-lipoxygenase, detailed overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LOX15_RABIT
663
0
75310
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
75000
78000
-
sucrose density gradient centrifugation, analytical ultracentrifugation
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
mammalian ALOX15 enzyme structure comparisons, overview. The single polypeptide chain of rabbit ALOX15 folds into a two-domain structure: a small N-terminal beta-barrel domain and a larger mostly helical catalytic domain. The small N-terminal domain comprises 110 amino acids and is composed of 8 beta-sheets. The C-terminal catalytic domain of ALOX15 (residues 114-663) consists of 21 helices, which are interrupted by a small beta-sheet subdomain. In the crystal structure of the rabbit ALOX15-inhibitor complex (PDB ID 2P0M) the enzyme is present as protein dimer, in which the hydrophobic Leu179, Leu183, Leu188, and Leu192 form a cluster, which resembles a leucine-zipper like motif
additional information
-
mammalian ALOX15 enzyme structure comparisons, overview. The single polypeptide chain of rabbit ALOX15 folds into a two-domain structure: a small N-terminal beta-barrel domain and a larger mostly helical catalytic domain. The small N-terminal domain comprises 110 amino acids and is composed of 8 beta-sheets. The C-terminal catalytic domain of ALOX15 (residues 114-663) consists of 21 helices, which are interrupted by a small beta-sheet subdomain. In the crystal structure of the rabbit ALOX15-inhibitor complex (PDB ID 2P0M) the enzyme is present as protein dimer, in which the hydrophobic Leu179, Leu183, Leu188, and Leu192 form a cluster, which resembles a leucine-zipper like motif
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of 15S-LOX1 in complex with inhibitor determined with a resolution of 2.4 A under PDB ID 1lox, reinterpretation of the crystallographic data, structure analysis and modelling, overview
X-ray diffraction crystal structure determination and analysis at 2.4 A resolution
crystals are grown by vapor diffusion method from concentrated solutions of the protein in sodium phosphate buffer, pH 7.0
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F353L
the ratio of turnover-number to KM-value is 4fold lower than the value for the wild-type enzyme. The mutation strongly alters the positional specificity of the oxygenation of most substrates in favor of 12-lipoxygenation except from (16(S),5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid
I418A
naturally occuring mutation, the mutant produces 92% 12-hydroperoxyicosatetraenoate and 8% 15-hydroperoxyicosatetraenoate, in contrast to the wild-type, that produces 3% 12-hydroperoxyicosatetraenoate and 97% 15-hydroperoxyicosatetraenoate
I593A
mutation induces alterations in the stereochemical characteristics of hydroxy fatty acid oxygenation
L597A
site-directed mutagenesis, regiospecificity favoring addition to C15 is sharper than that in the wild-type, but the stereochemistry is R. This is because the extra space created by the mutation to Ala is big enough for arachidonate to move so that it can adopt an alternative binding mode. The L597A mutant of 15r-LO works as an aspirin-acetylated cyclooxygenase-2, which synthesizes 15-(R)-hydroperoxyeicosatetraenoic acid
L597V
site-directed mutagenesis, the addition of O2 to C15 of arachidonate is the predominant path, although it reduces the C15/C11 product ratio by almost ten times with respect to the wild-type enzyme. The S stereochemistry is kept
Q548L
site-directed mutagenesis, the mutation disrupts the hydrogen bond network inducing a loss in catalytic activity suggesting that this mutation might alter the structure of the iron cluster
F412E
-
mutation slightly impairs membrane binding, mutant enzyme shows 29% of the arachidonic acid oxygenase activity of the wild-type enzyme
F70H
-
mutation impairs membrane binding, mutant enzyme shows 53% of the arachidonic acid oxygenase activity of the wild-type enzyme
L195E
-
mutation impairs membrane binding, mutant enzyme shows 42% of the arachidonic acid oxygenase activity of the wild-type enzyme
L367E
-
site-directed mutagenesis, site-directed mutagenesis, the mutant shows reduced activity with O2 compared to the wild-type enzyme, L367 is involved in oxygen access, overview
L367F
-
site-directed mutagenesis, site-directed mutagenesis, the mutant shows reduced activity with O2 compared to the wild-type enzyme, in silico mutagenesis and structural modeling, L367 is involved in oxygen access, overview
L367K
-
site-directed mutagenesis, site-directed mutagenesis, the mutant shows reduced activity with O2 compared to the wild-type enzyme, L367 is involved in oxygen access, overview
L367W
-
site-directed mutagenesis, site-directed mutagenesis, the mutant shows reduced activity with O2 compared to the wild-type enzyme, L367 is involved in oxygen access, overview
L71K
-
mutation impairs membrane binding, mutant enzyme shows 50% of the arachidonic acid oxygenase activity of the wild-type enzyme
W181E
-
mutation strongly impairs membrane binding, mutant enzyme shows 34% of the arachidonic acid oxygenase activity of the wild-type enzyme
Y15E
-
mutation impairs membrane binding, mutant enzyme shows 61% of the arachidonic acid oxygenase activity of the wild-type enzyme
Y292E
-
mutation slightly impairs membrane binding, mutant enzyme shows 112% of the arachidonic acid oxygenase activity of the wild-type enzyme
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
-
structural alterations induced by increasing the temperature to 30°C are completely reversible, loss of reversibility at 35°C, aggregates between 45-50°C. The enzyme is thermolabile and requires the presence of a lipid environment to be stabilized at higher temperatures
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
purified rabbit ALOX15 is surprisingly stable when digested with proteases in vitro. Even long-term incubations (up to two hours) of purified rabbit ALOX15 with 0.5% trypsin does only lead to minor impairment of the catalytic activity with absolute conservation of the product specificity
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by sequential fractionated ammonium sulfate precipitation, hydrophobic interaction chromatography and anion exchange chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the recombinant wild-type enzyme and various mutants are expressed in Escherichia coli as His-tagged fusion proteins
expression in the baculovirus/insect cell system, expression as intracellular enzyme and after fusion with a signal peptide as export protein in High Five cells
-
ligated into the pQE-9 plasmid and expressed as N-terminal His-tag fusion protein in Escherichia coli (XL-1 Blue)
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ford-Hutchinson, A.W.
Arachidonate 15-lipoxygenase; characteristics and potential biological significance
Eicosanoids
4
65-74
1991
Oryctolagus cuniculus, Homo sapiens
Kuehn, H.; Hayess, K.; Holzhuetter, H.G.; Zablotzki, D.A.; Myagkova, G.I.; Schewe, T.
Inactivation of 15-lipoxygenases by acetylenic fatty acids
Biomed. Biochim. Acta
50
835-839
1991
Oryctolagus cuniculus, Glycine max
Luther, H.; Jordanov, D.; Ludwig, P.; Schewe, T.
Inhibition of rabbit erythroid 15-lipoxygenase and sheep vesicular gland prostaglandin H synthase by gallic esters
Pharmazie
46
134-136
1991
Oryctolagus cuniculus
Sloane, D.L.; Browner, M.F.; Dauter, Z.; Wilson, K.; Fletterick, R.J.; Sigal, E.
Purification and crystallization of 15-lipoxygenase from rabbit reticulocytes
Biochem. Biophys. Res. Commun.
173
507-513
1990
Oryctolagus cuniculus
Rapoport, S.M.; Schewe, T.; Wiesner, R.; Halangk, W.; Ludwig, P.; Janicke-Hoehne, M.; Tannert, C.; Hiebsch, C.; Klatt, D.
The lipoxygenase of reticulocytes. Purification, characterization and biological dynamics of the lipoxygenase; its identity with the respiratory inhibitors of the reticulocyte
Eur. J. Biochem.
96
545-561
1979
Oryctolagus cuniculus
Narumiya, S.; Salmon, J.A.
Arachidonic acid-15-lipoxygenase from rabbit peritoneal polymorphonuclear leukocytes
Methods Enzymol.
86
45-48
1982
Oryctolagus cuniculus
Bryant, R.W.; Bailey, J.M.; Schewe, T.; Rapoport, S.M.
Positional specificity of a reticulocyte lipoxygenase. Conversion of arachidonic acid to 15-S-hydroperoxy-eicosatetraenoic acid
J. Biol. Chem.
257
6050-6055
1982
Oryctolagus cuniculus
Borngraber, S.; Grabenhorst, E.; Anton, M.; Conradt, H.; Kuhn, H.
Intra- and extracellular expression of rabbit reticulocyte 15-lipoxygenase in the baculovirus/insect cell system
Protein Expr. Purif.
14
237-246
1998
Oryctolagus cuniculus
Kuehn, H.; Heydeck, D.; Brinckman, R.; Trebus, F.
Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels
Lipids
34
S273-S279
1999
Oryctolagus cuniculus, Homo sapiens, Mus musculus, Rattus norvegicus
-
Walther, M.; Holzhutter, H.G.; Kuban, R.J.; Wiesner, R.; Rathmann, J.; Kuhn, H.
The inhibition of mammalian 15-lipoxygenases by the anti-inflammatory drug ebselen: dual-type mechanism involving covalent linkage and alteration of the iron ligand sphere
Mol. Pharmacol.
56
196-203
1999
Oryctolagus cuniculus
Schewe, T.
15-Lipoxygenase-1: A prooxidant enzyme
Biol. Chem.
383
365-374
2002
Oryctolagus cuniculus, Homo sapiens
Sadik, C.D.; Sies, H.; Schewe, T.
Inhibition of 15-lipoxygenases by flavonoids: structure-activity relations and mode of action
Biochem. Pharmacol.
65
773-781
2003
Oryctolagus cuniculus, Glycine max
Vijayvergiya, C.; De Angelis, D.; Walther, M.; Kuhn, H.; Duvoisin, R.M.; Smith, D.H.; Wiedmann, M.
High-level expression of rabbit 15-lipoxygenase induces collapse of the mitochondrial pH gradient in cell culture
Biochemistry
43
15296-15302
2004
Oryctolagus cuniculus
Ivanov, I.; Romanov, S.; Ozdoba, C.; Holzhutter, H.G.; Myagkova, G.; Kuhn, H.
Enantioselective substrate specificity of 15-lipoxygenase 1
Biochemistry
43
15720-15728
2004
Oryctolagus cuniculus (P12530)
Gundersen, L.L.; Malterud, K.E.; Negussie, A.H.; Rise, F.; Teklu, S.; Ostby, O.B.
Indolizines as novel potent inhibitors of 15-lipoxygenase
Bioorg. Med. Chem.
11
5409-5415
2003
Oryctolagus cuniculus, Glycine max
Zhu, D.; Medhora, M.; Campbell, W.B.; Spitzbarth, N.; Baker, J.E.; Jacobs, E.R.
Chronic hypoxia activates lung 15-lipoxygenase, which catalyzes production of 15-HETE and enhances constriction in neonatal rabbit pulmonary arteries
Circ. Res.
92
992-1000
2003
Oryctolagus cuniculus
Walther, M.; Wiesner, R.; Kuhn, H.
Investigations into calcium-dependent membrane association of 15-lipoxygenase-1. Mechanistic roles of surface-exposed hydrophobic amino acids and calcium
J. Biol. Chem.
279
3717-3725
2004
Oryctolagus cuniculus
Utenova, B.T.; Malterud, K.E.; Rise, F.
Antioxidant activity of O-protected derivatives of (-)-epigallocatechin-3-gallate: inhibition of soybean and rabbit 15-lipoxygenases
ARKIVOC
2007
6-16
2007
Oryctolagus cuniculus
-
Tang, X.; Holmes, B.B.; Nithipatikom, K.; Hillard, C.J.; Kuhn, H.; Campbell, W.B.
Reticulocyte 15-lipoxygenase-I is important in acetylcholine-induced endothelium-dependent vasorelaxation in rabbit aorta
Arterioscler. Thromb. Vasc. Biol.
26
78-84
2006
Oryctolagus cuniculus
Weinstein, D.S.; Liu, W.; Gu, Z.; Langevine, C.; Ngu, K.; Fadnis, L.; Combs, D.W.; Sitkoff, D.; Ahmad, S.; Zhuang, S.; Chen, X.; Wang, F.L.; Loughney, D.A.; Atwal, K.S.; Zahler, R.; Macor, J.E.; Madsen, C.S.; Murugesan, N.
Tryptamine and homotryptamine-based sulfonamides as potent and selective inhibitors of 15-lipoxygenase
Bioorg. Med. Chem. Lett.
15
1435-1440
2005
Oryctolagus cuniculus
Chawengsub, Y.; Aggarwal, N.T.; Nithipatikom, K.; Gauthier, K.M.; Anjaiah, S.; Hammock, B.D.; Falck, J.R.; Campbell, W.B.
Identification of 15-hydroxy-11,12-epoxyeicosatrienoic acid as a vasoactive 15-lipoxygenase metabolite in rabbit aorta
Am. J. Physiol. Heart Circ. Physiol.
294
H1348-H1356
2008
Oryctolagus cuniculus
Huang, L.S.; Kim, M.R.; Jeong, T.S.; Sok, D.E.
Linoleoyl lysophosphatidic acid and linoleoyl lysophosphatidylcholine are efficient substrates for mammalian lipoxygenases
Biochim. Biophys. Acta
1770
1062-1070
2007
Oryctolagus cuniculus
Schurink, M.; van Berkel, W.J.; Wichers, H.J.; Boeriu, C.G.
Improvement of lipoxygenase inhibition by octapeptides
Peptides
28
2268-2275
2007
Oryctolagus cuniculus
Saam, J.; Ivanov, I.; Walther, M.; Holzhuetter, H.G.; Kuhn, H.
Molecular dioxygen enters the active site of 12/15-lipoxygenase via dynamic oxygen access channels
Proc. Natl. Acad. Sci. USA
104
13319-13324
2007
Oryctolagus cuniculus
Choi, J.; Chon, J.K.; Kim, S.; Shin, W.
Conformational flexibility in mammalian 15S-lipoxygenase: Reinterpretation of the crystallographic data
Proteins
70
1023-1032
2008
Oryctolagus cuniculus (P12530), Oryctolagus cuniculus
Mei, G.; Di Venere, A.; Nicolai, E.; Angelucci, C.B.; Ivanov, I.; Sabatucci, A.; Dainese, E.; Kuhn, H.; Maccarrone, M.
Structural properties of plant and mammalian lipoxygenases. Temperature-dependent conformational alterations and membrane binding ability
Biochemistry
47
9234-9242
2008
Oryctolagus cuniculus, Glycine max
Walther, M.; Roffeis, J.; Jansen, C.; Anton, M.; Ivanov, I.; Kuhn, H.
Structural basis for pH-dependent alterations of reaction specificity of vertebrate lipoxygenase isoforms
Biochim. Biophys. Acta
1791
827-835
2009
Oryctolagus cuniculus, Homo sapiens, Mus musculus
Mochizuki, N.; Kwon, Y.
15-Lipoxygenase-1 in the vasculature: Expanding roles in angiogenesis
Circ. Res.
102
143-145
2008
Oryctolagus cuniculus, Homo sapiens
Claesson, H.E.
On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma
Prostaglandins Other Lipid Mediat.
89
120-125
2009
Homo sapiens, Mus musculus, Oryctolagus cuniculus, Sus scrofa
Toledo, L.; Masgrau, L.; Lluch, J.M.; Gonzalez-Lafont, A.
Substrate binding to mammalian 15-lipoxygenase
J. Comput. Aided Mol. Des.
25
825-835
2011
Oryctolagus cuniculus
Suardiaz, R.; Masgrau, L.; Lluch, J.M.; Gonzalez-Lafont, A.
Regio- and stereospecificity in the oxygenation of arachidonic acid catalyzed by Leu597 mutants of rabbit 15-lipoxygenase a QM/MM study
Chemphyschem
15
2303-2310
2014
Oryctolagus cuniculus (P12530)
Ivanov, I.; Kuhn, H.; Heydeck, D.
Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)
Gene
573
1-32
2015
Oryctolagus cuniculus (P12530), Oryctolagus cuniculus, Homo sapiens (P16050), Homo sapiens, Mus musculus (P39654), Mus musculus, Rattus norvegicus (Q02759)
Adel, S.; Karst, F.; Gonzalez-Lafont, A.; Pekarova, M.; Saura, P.; Masgrau, L.; Lluch, J.M.; Stehling, S.; Horn, T.; Kuhn, H.; Heydeck, D.
Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins
Proc. Natl. Acad. Sci. USA
113
E4266-E4275
2016
Homo sapiens (P16050), Homo sapiens neanderthalensis, Homo sapiens subsp. 'Denisova', Macaca mulatta (F7EPQ4), Nomascus leucogenys (G1S6D2), Oryctolagus cuniculus (P12530), Pan paniscus, Pan troglodytes (H2QBX9), Papio anubis (A0A096P2G1), Pongo abelii (Q5RBE8), Pongo pygmaeus (Q5RBE8)
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