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Literature summary for 1.13.11.33 extracted from

  • Ivanov, I.; Kuhn, H.; Heydeck, D.
    Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15) (2015), Gene, 573, 1-32 .
    View publication on PubMedView publication on EuropePMC

Activating Compound

Activating Compound Comment Organism Structure
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 Rattus norvegicus
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 Homo sapiens
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 Mus musculus
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 Oryctolagus cuniculus

Crystallization (Commentary)

Crystallization (Comment) Organism
X-ray diffraction crystal structure determination and analysis at 2.4 A resolution Oryctolagus cuniculus

Protein Variants

Protein Variants Comment Organism
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 Oryctolagus cuniculus

General Stability

General Stability Organism
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 Oryctolagus cuniculus

Inhibitors

Inhibitors Comment Organism Structure
AA-861
-
Homo sapiens
AA-861
-
Mus musculus
AA-861
-
Oryctolagus cuniculus
AA-861
-
Rattus norvegicus
baicalein
-
Homo sapiens
baicalein
-
Mus musculus
baicalein
-
Oryctolagus cuniculus
baicalein
-
Rattus norvegicus
CDC CAS-No. 132465-11-3 Homo sapiens
CDC CAS-No. 132465-11-3 Mus musculus
CDC CAS-No. 132465-11-3 Oryctolagus cuniculus
CDC CAS-No. 132465-11-3 Rattus norvegicus
gallic acid
-
Homo sapiens
gallic acid
-
Mus musculus
gallic acid
-
Oryctolagus cuniculus
gallic acid
-
Rattus norvegicus
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 Homo sapiens
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 Mus musculus
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 Oryctolagus cuniculus
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 Rattus norvegicus
nordihydroguaiaretic acid
-
Homo sapiens
nordihydroguaiaretic acid
-
Mus musculus
nordihydroguaiaretic acid
-
Oryctolagus cuniculus
nordihydroguaiaretic acid
-
Rattus norvegicus
PD146176
-
Homo sapiens
PD146176
-
Mus musculus
PD146176
-
Oryctolagus cuniculus
PD146176
-
Rattus norvegicus

Metals/Ions

Metals/Ions Comment Organism Structure
Fe2+ enzyme-bound, required for catalysis Rattus norvegicus
Fe2+ enzyme-bound, required for catalysis Homo sapiens
Fe2+ enzyme-bound, required for catalysis Mus musculus
Fe2+ enzyme-bound, required for catalysis Oryctolagus cuniculus

Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
75000
-
-
Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
arachidonate + O2 Rattus norvegicus
-
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2 Homo sapiens
-
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2 Mus musculus
-
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2 Oryctolagus cuniculus
-
(5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
additional information Rattus norvegicus 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 Mus musculus 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 Oryctolagus cuniculus 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 Homo sapiens 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. Intraenzyme oxygen movement ?
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P16050
-
-
Mus musculus P39654
-
-
Oryctolagus cuniculus P12530
-
-
Rattus norvegicus Q02759
-
-

Reaction

Reaction Comment Organism Reaction ID
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 Rattus norvegicus
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 Homo sapiens
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 Mus musculus
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 Oryctolagus cuniculus

Source Tissue

Source Tissue Comment Organism Textmining
airway epithelial cell
-
Homo sapiens
-
brain
-
Homo sapiens
-
eosinophil
-
Homo sapiens
-
erythrocyte immature Homo sapiens
-
leukocyte
-
Homo sapiens
-
macrophage alveolar Homo sapiens
-
macrophage high level expression in peritoneal macrophages, while murine peripheral monocytes, alveolar macrophages and bone marrow-derived macrophages express alox15 only at low levels Mus musculus
-
additional information tissue specific expression of ALOX15 and transcriptional expression regulation, overview Rattus norvegicus
-
additional information tissue specific expression of ALOX15 and transcriptional expression regulation, overview Mus musculus
-
additional information tissue specific expression of ALOX15 and transcriptional expression regulation, overview Oryctolagus cuniculus
-
additional information tissue specific expression of ALOX15 and transcriptional expression regulation, overview. In humans ALOX15 is constitutively expressed at high levels in immature red blood cells, in eosinophils and in airway epithelial cells. Human peripheral blood monocytes do not express ALOX15 Homo sapiens
-
uterus
-
Homo sapiens
-
vascular cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1-palmitoyl-2-arachidonyl phosphatidyl choline + O2
-
Oryctolagus cuniculus 15S-HpETE + ?
-
?
1-palmitoyl-2-docosahexaenoyl phosphatidyl choline + O2
-
Oryctolagus cuniculus 17S-HpDHE + ?
-
?
1-palmitoyl-2-eicosapentaenoyl phosphatidyl choline + O2
-
Oryctolagus cuniculus 15S-HpEPE + ?
-
?
1-palmitoyl-2-linoleoyl phosphatidyl choline + O2
-
Oryctolagus cuniculus 13S-HpODE + ?
-
?
1-stearoyl-2-arachidonoyl glycerol + O2
-
Oryctolagus cuniculus 15-HETE + ?
-
?
1-stearoyl-2-linoleoyl glycerol + O2
-
Oryctolagus cuniculus 13S-HPODE + ?
-
?
arachidonate + O2
-
Rattus norvegicus (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2
-
Homo sapiens (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2
-
Mus musculus (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
arachidonate + O2
-
Oryctolagus cuniculus (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
-
?
cholesteryl arachidonate + O2
-
Oryctolagus cuniculus 15S-HpETE + ?
-
?
cholesteryl linoleate + O2
-
Oryctolagus cuniculus 13S-HpODE + ?
-
?
cholesteryl linolenate + O2
-
Oryctolagus cuniculus 13S-HpOTE + ?
-
?
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 Rattus norvegicus ?
-
?
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 Mus musculus ?
-
?
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 Oryctolagus cuniculus ?
-
?
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. Intraenzyme oxygen movement Homo sapiens ?
-
?
additional information 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 Oryctolagus cuniculus ?
-
?
additional information 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. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification Homo sapiens ?
-
?
additional information 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. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement Rattus norvegicus ?
-
?
additional information 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. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement Mus musculus ?
-
?

Subunits

Subunits Comment Organism
? x * 75000 Homo sapiens
More mammalian ALOX15 enzyme structure comparisons, overview Rattus norvegicus
More mammalian ALOX15 enzyme structure comparisons, overview Mus musculus
More mammalian ALOX15 enzyme structure comparisons, overview. The enzyme contains 11 cysteine residues but no disulfide bridge Homo sapiens
More 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 Oryctolagus cuniculus

Synonyms

Synonyms Comment Organism
Alox15
-
Rattus norvegicus
Alox15
-
Homo sapiens
Alox15
-
Mus musculus
Alox15
-
Oryctolagus cuniculus
arachidonic acid 15-lipoxygenase-1
-
Rattus norvegicus
arachidonic acid 15-lipoxygenase-1
-
Homo sapiens
arachidonic acid 15-lipoxygenase-1
-
Mus musculus
arachidonic acid 15-lipoxygenase-1
-
Oryctolagus cuniculus

pI Value

Organism Comment pI Value Maximum pI Value
Oryctolagus cuniculus
-
-
5.5

General Information

General Information Comment Organism
evolution LOX isozymes and classification systems, overview Rattus norvegicus
evolution LOX isozymes and classification systems, overview Homo sapiens
evolution LOX isozymes and classification systems, overview Mus musculus
evolution LOX isozymes and classification systems, overview Oryctolagus cuniculus
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 Rattus norvegicus
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 Homo sapiens
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 Mus musculus
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 Oryctolagus cuniculus