LOXE3_HUMAN
ID LOXE3_HUMAN Reviewed; 711 AA.
AC Q9BYJ1; B2R981; B7Z3W0; Q3ZB74; Q9H4F2; Q9HC22;
DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Hydroperoxide isomerase ALOXE3 {ECO:0000305};
DE AltName: Full=Epidermis-type lipoxygenase 3 {ECO:0000250|UniProtKB:Q9WV07};
DE Short=Epidermal LOX-3;
DE Short=e-LOX-3 {ECO:0000250|UniProtKB:Q9WV07};
DE Short=eLOX-3;
DE AltName: Full=Hydroperoxy dehydratase ALOXE3 {ECO:0000305};
DE AltName: Full=Hydroperoxy icosatetraenoate dehydratase;
DE EC=4.2.1.152 {ECO:0000269|PubMed:12881489, ECO:0000269|PubMed:21558561};
DE AltName: Full=Hydroperoxy icosatetraenoate isomerase;
DE EC=5.4.4.7 {ECO:0000269|PubMed:12881489, ECO:0000269|PubMed:17045234, ECO:0000269|PubMed:21558561};
GN Name=ALOXE3 {ECO:0000312|HGNC:HGNC:13743};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=11350124; DOI=10.1006/geno.2001.6519;
RA Krieg P., Marks F., Fuerstenberger G.;
RT "A gene cluster encoding human epidermis-type lipoxygenases at chromosome
RT 17p13.1: cloning, physical mapping, and expression.";
RL Genomics 73:323-330(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN HEPOXILIN A3 SYNTHESIS,
RP CATALYTIC ACTIVITY, PATHWAY, REACTION MECHANISM, AND KINETIC PARAMETERS.
RX PubMed=12881489; DOI=10.1073/pnas.1633612100;
RA Yu Z., Schneider C., Boeglin W.E., Marnett L.J., Brash A.R.;
RT "The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a
RT hydroperoxide isomerase.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:9162-9167(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION AS A HYDROPEROXIDE ISOMERASE, CATALYTIC ACTIVITY, KINETIC
RP PARAMETERS, AND PATHWAY.
RX PubMed=17045234; DOI=10.1016/j.abb.2006.09.002;
RA Yu Z., Schneider C., Boeglin W.E., Brash A.R.;
RT "Human and mouse eLOX3 have distinct substrate specificities: implications
RT for their linkage with lipoxygenases in skin.";
RL Arch. Biochem. Biophys. 455:188-196(2006).
RN [7]
RP FUNCTION AS A DIOXYGENASE, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, MUTAGENESIS OF ALA-451, AND ACTIVITY REGULATION.
RX PubMed=20921226; DOI=10.1074/jbc.m110.155374;
RA Zheng Y., Brash A.R.;
RT "Dioxygenase activity of epidermal lipoxygenase-3 unveiled: typical and
RT atypical features of its catalytic activity with natural and synthetic
RT polyunsaturated fatty acids.";
RL J. Biol. Chem. 285:39866-39875(2010).
RN [8]
RP FUNCTION AS A DIOXYGENASE, CATALYTIC ACTIVITY, MUTAGENESIS OF ALA-451, AND
RP ACTIVITY REGULATION.
RX PubMed=20923767; DOI=10.1074/jbc.m110.180794;
RA Zheng Y., Brash A.R.;
RT "On the role of molecular oxygen in lipoxygenase activation: comparison and
RT contrast of epidermal lipoxygenase-3 with soybean lipoxygenase-1.";
RL J. Biol. Chem. 285:39876-39887(2010).
RN [9]
RP FUNCTION IN CERAMIDE METABOLISM, AND CATALYTIC ACTIVITY.
RX PubMed=21558561; DOI=10.1074/jbc.m111.251496;
RA Zheng Y., Yin H., Boeglin W.E., Elias P.M., Crumrine D., Beier D.R.,
RA Brash A.R.;
RT "Lipoxygenases mediate the effect of essential fatty acid in skin barrier
RT formation: a proposed role in releasing omega-hydroxyceramide for
RT construction of the corneocyte lipid envelope.";
RL J. Biol. Chem. 286:24046-24056(2011).
RN [10]
RP VARIANTS ARCI3 SER-396 AND PHE-500.
RX PubMed=11773004; DOI=10.1093/hmg/11.1.107;
RA Jobard F., Lefevre C., Karaduman A., Blanchet-Bardon C., Emre S.,
RA Weissenbach J., Ozguc M., Lathrop M., Prud'homme J.-F., Fischer J.;
RT "Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in
RT non-bullous congenital ichthyosiform erythroderma (NCIE) linked to
RT chromosome 17p13.1.";
RL Hum. Mol. Genet. 11:107-113(2002).
RN [11]
RP CHARACTERIZATION OF VARIANTS ARCI3 SER-396 AND PHE-500.
RX PubMed=15629692; DOI=10.1016/j.bbalip.2004.10.007;
RA Yu Z., Schneider C., Boeglin W.E., Brash A.R.;
RT "Mutations associated with a congenital form of ichthyosis (NCIE)
RT inactivate the epidermal lipoxygenases 12R-LOX and eLOX3.";
RL Biochim. Biophys. Acta 1686:238-247(2005).
RN [12]
RP VARIANTS ARCI3 MET-237; VAL-281 AND LEU-630, AND CHARACTERIZATION OF
RP VARIANTS ARCI3 MET-237; VAL-281 AND LEU-630.
RX PubMed=16116617; DOI=10.1002/humu.20236;
RA Eckl K.M., Krieg P., Kuester W., Traupe H., Andre F., Wittstruck N.,
RA Fuerstenberger G., Hennies H.C.;
RT "Mutation spectrum and functional analysis of epidermis-type lipoxygenases
RT in patients with autosomal recessive congenital ichthyosis.";
RL Hum. Mutat. 26:351-361(2005).
RN [13]
RP VARIANTS ARCI3 MET-237; 344-GLN--ALA-347 DELINS PRO AND LEU-630, AND
RP CHARACTERIZATION OF VARIANT 344-GLN--ALA-347 DELINS PRO.
RX PubMed=19131948; DOI=10.1038/jid.2008.409;
RA Eckl K.M., de Juanes S., Kurtenbach J., Naetebus M., Lugassy J., Oji V.,
RA Traupe H., Preil M.L., Martinez F., Smolle J., Harel A., Krieg P.,
RA Sprecher E., Hennies H.C.;
RT "Molecular analysis of 250 patients with autosomal recessive congenital
RT ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic
RT heterogeneity in ALOX12B.";
RL J. Invest. Dermatol. 129:1421-1428(2009).
RN [14]
RP VARIANTS ARCI3 PRO-427 AND LEU-630.
RX PubMed=19890349; DOI=10.1038/jid.2009.346;
RA Vahlquist A., Bygum A., Gaanemo A., Virtanen M., Hellstroem-Pigg M.,
RA Strauss G., Brandrup F., Fischer J.;
RT "Genotypic and clinical spectrum of self-improving collodion ichthyosis:
RT ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients.";
RL J. Invest. Dermatol. 130:438-443(2010).
CC -!- FUNCTION: Non-heme iron-containing lipoxygenase which is atypical in
CC that it displays a prominent hydroperoxide isomerase activity and a
CC reduced lipoxygenases activity (PubMed:12881489, PubMed:17045234,
CC PubMed:20921226, PubMed:20923767). The hydroperoxide isomerase activity
CC catalyzes the isomerization of hydroperoxides, derived from arachidonic
CC and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and
CC ketones (PubMed:12881489, PubMed:17045234, PubMed:20923767). In
CC presence of oxygen, oxygenates polyunsaturated fatty acids, including
CC arachidonic acid, to produce fatty acid hydroperoxides
CC (PubMed:20921226). In the skin, acts downstream of ALOX12B on the
CC linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS)
CC ceramides to produce an epoxy-ketone derivative, a crucial step in the
CC conjugation of omega-hydroxyceramide to membrane proteins
CC (PubMed:21558561). Therefore plays a crucial role in the synthesis of
CC corneocytes lipid envelope and the establishment of the skin barrier to
CC water loss (PubMed:21558561). In parallel, it may have a signaling
CC function in barrier formation through the production of hepoxilins
CC metabolites (PubMed:21558561). Also plays a role in adipocyte
CC differentiation through hepoxilin A3 and hepoxilin B3 production which
CC in turn activate PPARG (By similarity). Through the production of
CC hepoxilins in the spinal cord, it may regulate inflammatory tactile
CC allodynia (By similarity). {ECO:0000250|UniProtKB:D3ZKX9,
CC ECO:0000250|UniProtKB:Q9WV07, ECO:0000269|PubMed:12881489,
CC ECO:0000269|PubMed:17045234, ECO:0000269|PubMed:20921226,
CC ECO:0000269|PubMed:20923767, ECO:0000269|PubMed:21558561}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxyeicosatetraenoate = a hydroxy-epoxy-
CC eicosatetraenoate; Xref=Rhea:RHEA:55560, ChEBI:CHEBI:59720,
CC ChEBI:CHEBI:137328; EC=5.4.4.7;
CC Evidence={ECO:0000269|PubMed:12881489, ECO:0000269|PubMed:17045234,
CC ECO:0000269|PubMed:21558561};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55561;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (8R)-
CC hydroxy-(11R,12R)-epoxy-(5Z,9E,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:37939, ChEBI:CHEBI:75230, ChEBI:CHEBI:75232;
CC EC=5.4.4.7; Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37940;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (8R)-
CC hydroxy-(11S,12S)-epoxy-(5Z,9E,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:37955, ChEBI:CHEBI:57444, ChEBI:CHEBI:75233;
CC EC=5.4.4.7; Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37956;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (10R)-
CC hydroxy-(11S,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:37951, ChEBI:CHEBI:57444, ChEBI:CHEBI:75234;
CC EC=5.4.4.7; Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37952;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate = (13R)-
CC hydroxy-(14S,15S)-epoxy-(5Z,8Z,11Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:37959, ChEBI:CHEBI:57446, ChEBI:CHEBI:75235;
CC EC=5.4.4.7; Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37960;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate = 7R-
CC hydroxy-5S,6S-epoxy-(8Z,11Z,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:41251, ChEBI:CHEBI:57450, ChEBI:CHEBI:77919;
CC Evidence={ECO:0000269|PubMed:17045234};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41252;
CC Evidence={ECO:0000305|PubMed:17045234};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(13S)-hydroperoxy-(9Z,11E)-octadecadienoate = 11-hydroxy-
CC (12S,13S)-epoxy-(9Z)-octadecenoate; Xref=Rhea:RHEA:50212,
CC ChEBI:CHEBI:57466, ChEBI:CHEBI:132064;
CC Evidence={ECO:0000269|PubMed:20923767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50213;
CC Evidence={ECO:0000305|PubMed:20923767};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-[omega-(9R)-hydroperoxy-(10E,12Z)-octadecadienoyloxy]acyl-
CC beta-D-glucosyl-(1<->1)-octadecasphing-4E-enine = N-[omega-(9R,10R)-
CC epoxy-(13R)-hydroxy-(11E)-octadecadienoyloxy]acyl-beta-D-glucosyl-
CC (1<->1)-octadecasphing-4E-enine; Xref=Rhea:RHEA:40503,
CC ChEBI:CHEBI:134624, ChEBI:CHEBI:134626;
CC Evidence={ECO:0000269|PubMed:21558561};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40504;
CC Evidence={ECO:0000305|PubMed:21558561};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-acyl (9R)-hydroperoxy-(10E,12Z)-octadecadienoate
CC octadecasphing-4E-enine = N-acyl-(9R,10R)-epoxy-(13R)-hydroxy-(11E)-
CC octadecenoate (4E)-octadecasphin-4-enine; Xref=Rhea:RHEA:41243,
CC ChEBI:CHEBI:77889, ChEBI:CHEBI:77891;
CC Evidence={ECO:0000269|PubMed:21558561};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41244;
CC Evidence={ECO:0000305|PubMed:21558561};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a hydroperoxyeicosatetraenoate = an oxoeicosatetraenoate +
CC H2O; Xref=Rhea:RHEA:55556, ChEBI:CHEBI:15377, ChEBI:CHEBI:59720,
CC ChEBI:CHEBI:131859; EC=4.2.1.152;
CC Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55557;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = 12-oxo-
CC (5Z,8Z,10E,14Z)-eicosatetraenoate + H2O; Xref=Rhea:RHEA:37943,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:75230, ChEBI:CHEBI:75231;
CC EC=4.2.1.152; Evidence={ECO:0000269|PubMed:12881489,
CC ECO:0000269|PubMed:21558561};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37944;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = 12-oxo-
CC (5Z,8Z,10E,14Z)-eicosatetraenoate + H2O; Xref=Rhea:RHEA:37947,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57444, ChEBI:CHEBI:75231;
CC EC=4.2.1.152; Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37948;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate = 15-oxo-
CC (5Z,8Z,11Z,13E)-eicosatetraenoate + H2O; Xref=Rhea:RHEA:48636,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57410, ChEBI:CHEBI:57446;
CC Evidence={ECO:0000269|PubMed:12881489};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48637;
CC Evidence={ECO:0000305|PubMed:12881489};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(13S)-hydroperoxy-(9Z,11E)-octadecadienoate = 13-oxo-(9Z,11E)-
CC octadecadienoate + H2O; Xref=Rhea:RHEA:48716, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57466, ChEBI:CHEBI:90781;
CC Evidence={ECO:0000269|PubMed:20923767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48717;
CC Evidence={ECO:0000305|PubMed:20923767};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(8S)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = (10R)-
CC hydroxy-(8S,9S)-epoxy-(5Z,11Z,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:37931, ChEBI:CHEBI:75322, ChEBI:CHEBI:75327;
CC EC=5.4.4.7; Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37932;
CC Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(8R)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = 8-oxo-
CC (5Z,9E,11Z,14Z)-eicosatetraenoate + H2O; Xref=Rhea:RHEA:37935,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:57447, ChEBI:CHEBI:75326;
CC EC=4.2.1.152; Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37936;
CC Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(8S)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = 8-oxo-
CC (5Z,9E,11Z,14Z)-eicosatetraenoate + H2O; Xref=Rhea:RHEA:37927,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:75322, ChEBI:CHEBI:75326;
CC EC=4.2.1.152; Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37928;
CC Evidence={ECO:0000250|UniProtKB:Q9WV07};
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00726};
CC Note=Binds 1 Fe cation per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00726};
CC -!- ACTIVITY REGULATION: Lipoxygenase activity is activated by 13(S)-HPODE
CC leading to an active free ferric enzyme (PubMed:20921226). The
CC lipoxygenase and hydroperoxide isomerase activities are in competition
CC and are reciprocally regulated by oxygen (PubMed:20923767). The oxygen
CC reacts with an epoxyallylic radical intermediate leading to an
CC epoxyallylic peroxyl radical, which, due to its limited reactivity
CC within the enzyme active site, it dissociates and leaves the enzyme in
CC the activated free ferric state (PubMed:20923767).
CC {ECO:0000269|PubMed:20921226, ECO:0000269|PubMed:20923767}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=46 uM for (12R)-HPETE {ECO:0000269|PubMed:12881489};
CC KM=28 uM for (12S)-HPETE {ECO:0000269|PubMed:12881489};
CC KM=32 uM for (15S)-HPETE {ECO:0000269|PubMed:12881489};
CC KM=50 uM for synthetic fatty acid 9E,11Z,14Z-20:3omega6 (at pH 7.5)
CC {ECO:0000269|PubMed:20921226};
CC Vmax=3.256 umol/min/mg enzyme for (12R)-HPETE (at pH 7.5)
CC {ECO:0000269|PubMed:12881489};
CC Vmax=0.858 umol/min/mg enzyme for (12S)-HPETE (at pH 7.5)
CC {ECO:0000269|PubMed:12881489};
CC Vmax=0.484 umol/min/mg enzyme for (15S)-HPETE (at pH 7.5)
CC {ECO:0000269|PubMed:12881489};
CC Note=Has a 5 to 10 fold higher activity toward (12R)-HPETE
CC (hydroperoxyeicosatetraenoic acid) compared to (12S)-HPETE and (15S)-
CC HPETE (PubMed:12881489). From (12R)-HPETE produces a stereoisomer of
CC hepoxilin A3 (PubMed:12881489). More active on hydroperoxides with an
CC R configuration than an S one (PubMed:17045234).
CC {ECO:0000269|PubMed:12881489, ECO:0000269|PubMed:17045234};
CC -!- PATHWAY: Lipid metabolism; hydroperoxy eicosatetraenoic acid
CC biosynthesis. {ECO:0000269|PubMed:12881489}.
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC -!- INTERACTION:
CC Q9BYJ1; P25490: YY1; NbExp=3; IntAct=EBI-6925949, EBI-765538;
CC Q9BYJ1; P36508: ZNF76; NbExp=3; IntAct=EBI-6925949, EBI-7254550;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|PROSITE-ProRule:PRU00726}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9BYJ1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BYJ1-2; Sequence=VSP_043287;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in skin.
CC -!- DISEASE: Ichthyosis, congenital, autosomal recessive 3 (ARCI3)
CC [MIM:606545]: A form of autosomal recessive congenital ichthyosis, a
CC disorder of keratinization with abnormal differentiation and
CC desquamation of the epidermis, resulting in abnormal skin scaling over
CC the whole body. The main skin phenotypes are lamellar ichthyosis (LI)
CC and non-bullous congenital ichthyosiform erythroderma (NCIE), although
CC phenotypic overlap within the same patient or among patients from the
CC same family can occur. Lamellar ichthyosis is a condition often
CC associated with an embedment in a collodion-like membrane at birth;
CC skin scales later develop, covering the entire body surface. Non-
CC bullous congenital ichthyosiform erythroderma characterized by fine
CC whitish scaling on an erythrodermal background; larger brownish scales
CC are present on the buttocks, neck and legs.
CC {ECO:0000269|PubMed:11773004, ECO:0000269|PubMed:15629692,
CC ECO:0000269|PubMed:16116617, ECO:0000269|PubMed:19131948,
CC ECO:0000269|PubMed:19890349}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the lipoxygenase family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=about water - Issue 153 of
CC September 2013;
CC URL="https://web.expasy.org/spotlight/back_issues/153/";
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DR EMBL; AJ269499; CAC12843.1; -; mRNA.
DR EMBL; AJ305020; CAC34518.1; -; Genomic_DNA.
DR EMBL; AJ305021; CAC34518.1; JOINED; Genomic_DNA.
DR EMBL; AJ305023; CAC34518.1; JOINED; Genomic_DNA.
DR EMBL; AJ305025; CAC34518.1; JOINED; Genomic_DNA.
DR EMBL; AF182218; AAG16899.1; -; mRNA.
DR EMBL; AK296416; BAH12346.1; -; mRNA.
DR EMBL; AK313677; BAG36428.1; -; mRNA.
DR EMBL; CH471108; EAW90094.1; -; Genomic_DNA.
DR EMBL; BC101938; AAI01939.1; -; mRNA.
DR EMBL; BC101939; AAI01940.1; -; mRNA.
DR EMBL; BC103508; AAI03509.1; -; mRNA.
DR EMBL; BC104724; AAI04725.1; -; mRNA.
DR CCDS; CCDS11130.1; -. [Q9BYJ1-1]
DR CCDS; CCDS54084.1; -. [Q9BYJ1-2]
DR RefSeq; NP_001159432.1; NM_001165960.1. [Q9BYJ1-2]
DR RefSeq; NP_067641.2; NM_021628.2. [Q9BYJ1-1]
DR PDB; 6VB2; X-ray; 1.41 A; C=136-144.
DR PDBsum; 6VB2; -.
DR AlphaFoldDB; Q9BYJ1; -.
DR SMR; Q9BYJ1; -.
DR BioGRID; 121886; 65.
DR IntAct; Q9BYJ1; 21.
DR STRING; 9606.ENSP00000314879; -.
DR SwissLipids; SLP:000000656; -.
DR iPTMnet; Q9BYJ1; -.
DR PhosphoSitePlus; Q9BYJ1; -.
DR BioMuta; ALOXE3; -.
DR DMDM; 27923803; -.
DR MassIVE; Q9BYJ1; -.
DR PaxDb; Q9BYJ1; -.
DR PeptideAtlas; Q9BYJ1; -.
DR PRIDE; Q9BYJ1; -.
DR ProteomicsDB; 79655; -. [Q9BYJ1-1]
DR ProteomicsDB; 79656; -. [Q9BYJ1-2]
DR Antibodypedia; 24534; 164 antibodies from 21 providers.
DR DNASU; 59344; -.
DR Ensembl; ENST00000318227.4; ENSP00000314879.4; ENSG00000179148.10. [Q9BYJ1-1]
DR Ensembl; ENST00000380149.6; ENSP00000369494.2; ENSG00000179148.10. [Q9BYJ1-1]
DR Ensembl; ENST00000448843.7; ENSP00000400581.2; ENSG00000179148.10. [Q9BYJ1-1]
DR GeneID; 59344; -.
DR KEGG; hsa:59344; -.
DR MANE-Select; ENST00000448843.7; ENSP00000400581.2; NM_021628.3; NP_067641.2.
DR UCSC; uc010cnr.4; human. [Q9BYJ1-1]
DR CTD; 59344; -.
DR DisGeNET; 59344; -.
DR GeneCards; ALOXE3; -.
DR GeneReviews; ALOXE3; -.
DR HGNC; HGNC:13743; ALOXE3.
DR HPA; ENSG00000179148; Tissue enriched (skin).
DR MalaCards; ALOXE3; -.
DR MIM; 606545; phenotype.
DR MIM; 607206; gene.
DR neXtProt; NX_Q9BYJ1; -.
DR OpenTargets; ENSG00000179148; -.
DR Orphanet; 79394; Congenital non-bullous ichthyosiform erythroderma.
DR Orphanet; 313; Lamellar ichthyosis.
DR Orphanet; 281122; Self-improving collodion baby.
DR PharmGKB; PA24727; -.
DR VEuPathDB; HostDB:ENSG00000179148; -.
DR eggNOG; ENOG502QQSP; Eukaryota.
DR GeneTree; ENSGT00940000156796; -.
DR HOGENOM; CLU_004282_3_3_1; -.
DR InParanoid; Q9BYJ1; -.
DR OMA; LCEAFSM; -.
DR OrthoDB; 385042at2759; -.
DR PhylomeDB; Q9BYJ1; -.
DR TreeFam; TF105320; -.
DR BRENDA; 4.2.1.152; 2681.
DR PathwayCommons; Q9BYJ1; -.
DR Reactome; R-HSA-2142712; Synthesis of 12-eicosatetraenoic acid derivatives.
DR SignaLink; Q9BYJ1; -.
DR UniPathway; UPA00222; -.
DR UniPathway; UPA00881; -.
DR BioGRID-ORCS; 59344; 5 hits in 1062 CRISPR screens.
DR ChiTaRS; ALOXE3; human.
DR GeneWiki; ALOXE3; -.
DR GenomeRNAi; 59344; -.
DR Pharos; Q9BYJ1; Tbio.
DR PRO; PR:Q9BYJ1; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9BYJ1; protein.
DR Bgee; ENSG00000179148; Expressed in skin of leg and 105 other tissues.
DR ExpressionAtlas; Q9BYJ1; baseline and differential.
DR Genevisible; Q9BYJ1; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0051120; F:hepoxilin A3 synthase activity; IDA:UniProtKB.
DR GO; GO:0106256; F:hydroperoxy icosatetraenoate dehydratase activity; IEA:UniProtKB-EC.
DR GO; GO:0106255; F:hydroperoxy icosatetraenoate isomerase activity; IEA:UniProtKB-EC.
DR GO; GO:0050486; F:intramolecular transferase activity, transferring hydroxy groups; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0016702; F:oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; IDA:UniProtKB.
DR GO; GO:0019369; P:arachidonic acid metabolic process; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0061436; P:establishment of skin barrier; ISS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0051122; P:hepoxilin biosynthetic process; IDA:UniProtKB.
DR GO; GO:0043651; P:linoleic acid metabolic process; IDA:UniProtKB.
DR GO; GO:0019372; P:lipoxygenase pathway; IDA:UniProtKB.
DR GO; GO:0035357; P:peroxisome proliferator activated receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB.
DR GO; GO:0006665; P:sphingolipid metabolic process; IDA:UniProtKB.
DR CDD; cd01753; PLAT_LOX; 1.
DR InterPro; IPR000907; LipOase.
DR InterPro; IPR013819; LipOase_C.
DR InterPro; IPR036226; LipOase_C_sf.
DR InterPro; IPR020834; LipOase_CS.
DR InterPro; IPR020833; LipOase_Fe_BS.
DR InterPro; IPR001885; LipOase_mml.
DR InterPro; IPR001024; PLAT/LH2_dom.
DR InterPro; IPR036392; PLAT/LH2_dom_sf.
DR InterPro; IPR042062; PLAT_LOX_verte.
DR PANTHER; PTHR11771; PTHR11771; 2.
DR Pfam; PF00305; Lipoxygenase; 1.
DR Pfam; PF01477; PLAT; 1.
DR PRINTS; PR00087; LIPOXYGENASE.
DR PRINTS; PR00467; MAMLPOXGNASE.
DR SMART; SM00308; LH2; 1.
DR SUPFAM; SSF48484; SSF48484; 1.
DR SUPFAM; SSF49723; SSF49723; 1.
DR PROSITE; PS00711; LIPOXYGENASE_1; 1.
DR PROSITE; PS00081; LIPOXYGENASE_2; 1.
DR PROSITE; PS51393; LIPOXYGENASE_3; 1.
DR PROSITE; PS50095; PLAT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Dioxygenase;
KW Disease variant; Fatty acid metabolism; Ichthyosis; Iron; Isomerase;
KW Lipid metabolism; Lyase; Metal-binding; Oxidoreductase; Reference proteome.
FT CHAIN 1..711
FT /note="Hydroperoxide isomerase ALOXE3"
FT /id="PRO_0000220691"
FT DOMAIN 2..119
FT /note="PLAT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00152"
FT DOMAIN 120..711
FT /note="Lipoxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT BINDING 408
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT BINDING 413
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT BINDING 588
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT BINDING 592
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT BINDING 711
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00726"
FT VAR_SEQ 1
FT /note="M -> MPRGAFRPCLPALYFAFLTCPTPEQRMSGTQAPDIHLGEPARGTGCV
FT RGKQTSIRVQDCGRREEARAASRELRREKAQEHPRESWAHPQPYPAPQPLALRPETQPC
FT PACRSSPPGRLLLRPALPGHPFLLPIM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043287"
FT VARIANT 237
FT /note="L -> M (in ARCI3; no effect on enzyme activity;
FT dbSNP:rs121434235)"
FT /evidence="ECO:0000269|PubMed:16116617,
FT ECO:0000269|PubMed:19131948"
FT /id="VAR_069561"
FT VARIANT 281
FT /note="G -> V (in ARCI3; complete loss of the enzyme
FT activity; dbSNP:rs786205120)"
FT /evidence="ECO:0000269|PubMed:16116617"
FT /id="VAR_069562"
FT VARIANT 344..347
FT /note="QYVA -> P (in ARCI3; complete loss of the enzyme
FT activity)"
FT /evidence="ECO:0000269|PubMed:19131948"
FT /id="VAR_069563"
FT VARIANT 396
FT /note="R -> S (in ARCI3; complete loss of the enzyme
FT activity; dbSNP:rs121434234)"
FT /evidence="ECO:0000269|PubMed:11773004,
FT ECO:0000269|PubMed:15629692"
FT /id="VAR_015175"
FT VARIANT 427
FT /note="L -> P (in ARCI3; dbSNP:rs1355284797)"
FT /evidence="ECO:0000269|PubMed:19890349"
FT /id="VAR_069564"
FT VARIANT 500
FT /note="V -> F (in ARCI3; complete loss of the enzyme
FT activity; dbSNP:rs121434232)"
FT /evidence="ECO:0000269|PubMed:11773004,
FT ECO:0000269|PubMed:15629692"
FT /id="VAR_015176"
FT VARIANT 630
FT /note="P -> L (in ARCI3; complete loss of the enzyme
FT activity; dbSNP:rs147149459)"
FT /evidence="ECO:0000269|PubMed:16116617,
FT ECO:0000269|PubMed:19131948, ECO:0000269|PubMed:19890349"
FT /id="VAR_069565"
FT MUTAGEN 451
FT /note="A->G: Increases the O2-dependent dioxygenase
FT activity."
FT /evidence="ECO:0000269|PubMed:20921226,
FT ECO:0000269|PubMed:20923767"
FT CONFLICT 155
FT /note="C -> R (in Ref. 1; CAC12843)"
FT /evidence="ECO:0000305"
FT CONFLICT 194
FT /note="F -> L (in Ref. 2; AAG16899)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 711 AA; 80543 MW; BDED1E4ED5CF6783 CRC64;
MAVYRLCVTT GPYLRAGTLD NISVTLVGTC GESPKQRLDR MGRDFAPGSV QKYKVRCTAE
LGELLLLRVH KERYAFFRKD SWYCSRICVT EPDGSVSHFP CYQWIEGYCT VELRPGTART
ICQDSLPLLL DHRTRELRAR QECYRWKIYA PGFPCMVDVN SFQEMESDKK FALTKTTTCV
DQGDSSGNRY LPGFPMKIDI PSLMYMEPNV RYSATKTISL LFNAIPASLG MKLRGLLDRK
GSWKKLDDMQ NIFWCHKTFT TKYVTEHWCE DHFFGYQYLN GVNPVMLHCI SSLPSKLPVT
NDMVAPLLGQ DTCLQTELER GNIFLADYWI LAEAPTHCLN GRQQYVAAPL CLLWLSPQGA
LVPLAIQLSQ TPGPDSPIFL PTDSEWDWLL AKTWVRNSEF LVHENNTHFL CTHLLCEAFA
MATLRQLPLC HPIYKLLLPH TRYTLQVNTI ARATLLNPEG LVDQVTSIGR QGLIYLMSTG
LAHFTYTNFC LPDSLRARGV LAIPNYHYRD DGLKIWAAIE SFVSEIVGYY YPSDASVQQD
SELQAWTGEI FAQAFLGRES SGFPSRLCTP GEMVKFLTAI IFNCSAQHAA VNSGQHDFGA
WMPNAPSSMR QPPPQTKGTT TLKTYLDTLP EVNISCNNLL LFWLVSQEPK DQRPLGTYPD
EHFTEEAPRR SIAAFQSRLA QISRDIQERN QGLALPYTYL DPPLIENSVS I
