CP2U1_HUMAN
ID CP2U1_HUMAN Reviewed; 544 AA.
AC Q7Z449; B2RMV7; Q96EQ6;
DT 26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2003, sequence version 1.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Cytochrome P450 2U1 {ECO:0000303|PubMed:24563460};
DE AltName: Full=Long-chain fatty acid omega-monooxygenase {ECO:0000305|PubMed:24563460};
DE EC=1.14.14.80 {ECO:0000269|PubMed:14660610, ECO:0000269|PubMed:24563460};
GN Name=CYP2U1 {ECO:0000303|PubMed:14660610, ECO:0000312|HGNC:HGNC:20582};
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 [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, CATALYTIC ACTIVITY, AND PATHWAY.
RC TISSUE=Thymus;
RX PubMed=14660610; DOI=10.1074/jbc.m311830200;
RA Chuang S.S., Helvig C., Taimi M., Ramshaw H.A., Collop A.H., Amad M.,
RA White J.A., Petkovich M., Jones G., Korczak B.;
RT "CYP2U1, a novel human thymus- and brain-specific cytochrome P450,
RT catalyzes omega- and (omega-1)-hydroxylation of fatty acids.";
RL J. Biol. Chem. 279:6305-6314(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Mammary gland;
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 [4]
RP TISSUE SPECIFICITY.
RX PubMed=14975754; DOI=10.1016/j.bbrc.2004.01.110;
RA Karlgren M., Backlund M., Johansson I., Oscarson M., Ingelman-Sundberg M.;
RT "Characterization and tissue distribution of a novel human cytochrome P450-
RT CYP2U1.";
RL Biochem. Biophys. Res. Commun. 315:679-685(2004).
RN [5]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=15752708; DOI=10.1016/j.abb.2005.02.001;
RA Choudhary D., Jansson I., Stoilov I., Sarfarazi M., Schenkman J.B.;
RT "Expression patterns of mouse and human CYP orthologs (families 1-4) during
RT development and in different adult tissues.";
RL Arch. Biochem. Biophys. 436:50-61(2005).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES,
RP PROTEIN SEQUENCE OF 60-544, AND PATHWAY.
RX PubMed=24563460; DOI=10.1074/jbc.m114.550004;
RA Siller M., Goyal S., Yoshimoto F.K., Xiao Y., Wei S., Guengerich F.P.;
RT "Oxidation of endogenous N-arachidonoylserotonin by human cytochrome P450
RT 2U1.";
RL J. Biol. Chem. 289:10476-10487(2014).
RN [7]
RP VARIANTS SPG56 ARG-262; VAL-316; GLY-380 AND TRP-488, AND SUBCELLULAR
RP LOCATION.
RX PubMed=23176821; DOI=10.1016/j.ajhg.2012.11.001;
RA Tesson C., Nawara M., Salih M.A., Rossignol R., Zaki M.S., Al Balwi M.,
RA Schule R., Mignot C., Obre E., Bouhouche A., Santorelli F.M., Durand C.M.,
RA Oteyza A.C., El-Hachimi K.H., Al Drees A., Bouslam N., Lamari F.,
RA Elmalik S.A., Kabiraj M.M., Seidahmed M.Z., Esteves T., Gaussen M.,
RA Monin M.L., Gyapay G., Lechner D., Gonzalez M., Depienne C., Mochel F.,
RA Lavie J., Schols L., Lacombe D., Yahyaoui M., Al Abdulkareem I.,
RA Zuchner S., Yamashita A., Benomar A., Goizet C., Durr A., Gleeson J.G.,
RA Darios F., Brice A., Stevanin G.;
RT "Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form
RT and function in hereditary spastic paraplegia.";
RL Am. J. Hum. Genet. 91:1051-1064(2012).
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC arachidonic acid and its conjugates (PubMed:14660610, PubMed:24563460).
CC Mechanistically, uses molecular oxygen inserting one oxygen atom into a
CC substrate, and reducing the second into a water molecule, with two
CC electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-
CC ferrihemoprotein reductase) (PubMed:14660610, PubMed:24563460). Acts as
CC an omega and omega-1 hydroxylase for arachidonic acid and possibly for
CC other long chain fatty acids. May modulate the arachidonic acid
CC signaling pathway and play a role in other fatty acid signaling
CC processes (PubMed:14660610, PubMed:24563460). May down-regulate the
CC biological activities of N-arachidonoyl-serotonin, an endocannabinoid
CC that has anti-nociceptive effects through inhibition of fatty acid
CC amide hydrolase FAAH, TRPV1 receptor and T-type calcium channels.
CC Catalyzes C-2 oxidation of the indole ring of N-arachidonoyl-serotonin
CC forming a less active product 2-oxo-N-arachidonoyl-serotonin
CC (PubMed:24563460). {ECO:0000269|PubMed:14660610,
CC ECO:0000269|PubMed:24563460}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an omega-methyl-long-chain fatty acid + O2 + reduced [NADPH--
CC hemoprotein reductase] = an omega-hydroxy-long-chain fatty acid +
CC H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:56748, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:140991,
CC ChEBI:CHEBI:140992; EC=1.14.14.80;
CC Evidence={ECO:0000269|PubMed:14660610, ECO:0000269|PubMed:24563460};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56749;
CC Evidence={ECO:0000305|PubMed:14660610, ECO:0000305|PubMed:24563460};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = 19-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate
CC + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:39759, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:32395, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:76627; Evidence={ECO:0000269|PubMed:14660610,
CC ECO:0000269|PubMed:24563460};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39760;
CC Evidence={ECO:0000305|PubMed:14660610, ECO:0000305|PubMed:24563460};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = 20-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate
CC + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:39755, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:32395, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:76624; Evidence={ECO:0000269|PubMed:14660610,
CC ECO:0000269|PubMed:24563460};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39756;
CC Evidence={ECO:0000305|PubMed:14660610, ECO:0000305|PubMed:24563460};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-[(5Z,8Z,11Z,14Z)-eicosatetraenoyl]-serotonin + O2 + reduced
CC [NADPH--hemoprotein reductase] = 2-oxo-N-[(5Z,8Z,11Z,14Z)-
CC eicosatetraenoyl]-serotonin + H(+) + H2O + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:50296, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:132255, ChEBI:CHEBI:132256;
CC Evidence={ECO:0000269|PubMed:24563460};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50297;
CC Evidence={ECO:0000305|PubMed:24563460};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:24563460};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.7 uM for arachidonic acid;
CC KM=82 uM for N-arachidonoylserotonin {ECO:0000269|PubMed:24563460};
CC -!- PATHWAY: Lipid metabolism; arachidonate metabolism.
CC {ECO:0000305|PubMed:14660610, ECO:0000305|PubMed:24563460}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14660610}; Multi-pass membrane protein
CC {ECO:0000255}. Microsome membrane {ECO:0000269|PubMed:14660610}; Multi-
CC pass membrane protein {ECO:0000255}. Mitochondrion inner membrane
CC {ECO:0000269|PubMed:23176821}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q7Z449-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7Z449-2; Sequence=VSP_026222, VSP_026223;
CC -!- TISSUE SPECIFICITY: Widely expressed with stronger expression in
CC thymus, heart and cerebellum. {ECO:0000269|PubMed:14660610,
CC ECO:0000269|PubMed:14975754, ECO:0000269|PubMed:15752708}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal thymus.
CC {ECO:0000269|PubMed:14660610, ECO:0000269|PubMed:15752708}.
CC -!- DISEASE: Spastic paraplegia 56, autosomal recessive (SPG56)
CC [MIM:615030]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. Complicated forms are recognized by
CC additional variable features including spastic quadriparesis, seizures,
CC dementia, amyotrophy, extrapyramidal disturbance, cerebral or
CC cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well
CC as by extra neurological manifestations. In SPG56, upper limbs are
CC often also affected. Some SPG56 patients may have a subclinical axonal
CC neuropathy. {ECO:0000269|PubMed:23176821}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AY343323; AAQ21380.1; -; mRNA.
DR EMBL; CH471057; EAX06216.1; -; Genomic_DNA.
DR EMBL; BC012027; AAH12027.1; -; mRNA.
DR EMBL; BC132767; AAI32768.1; -; mRNA.
DR EMBL; BC136483; AAI36484.1; -; mRNA.
DR CCDS; CCDS34047.1; -. [Q7Z449-1]
DR RefSeq; NP_898898.1; NM_183075.2. [Q7Z449-1]
DR AlphaFoldDB; Q7Z449; -.
DR SMR; Q7Z449; -.
DR BioGRID; 125252; 6.
DR IntAct; Q7Z449; 3.
DR STRING; 9606.ENSP00000333212; -.
DR BindingDB; Q7Z449; -.
DR ChEMBL; CHEMBL4523986; -.
DR SwissLipids; SLP:000001048; -.
DR iPTMnet; Q7Z449; -.
DR PhosphoSitePlus; Q7Z449; -.
DR BioMuta; CYP2U1; -.
DR DMDM; 74762432; -.
DR EPD; Q7Z449; -.
DR jPOST; Q7Z449; -.
DR MassIVE; Q7Z449; -.
DR MaxQB; Q7Z449; -.
DR PaxDb; Q7Z449; -.
DR PeptideAtlas; Q7Z449; -.
DR PRIDE; Q7Z449; -.
DR ProteomicsDB; 69149; -. [Q7Z449-1]
DR ProteomicsDB; 69150; -. [Q7Z449-2]
DR Antibodypedia; 26251; 149 antibodies from 25 providers.
DR DNASU; 113612; -.
DR Ensembl; ENST00000332884.11; ENSP00000333212.6; ENSG00000155016.18. [Q7Z449-1]
DR GeneID; 113612; -.
DR KEGG; hsa:113612; -.
DR MANE-Select; ENST00000332884.11; ENSP00000333212.6; NM_183075.3; NP_898898.1.
DR UCSC; uc003hyp.4; human. [Q7Z449-1]
DR CTD; 113612; -.
DR DisGeNET; 113612; -.
DR GeneCards; CYP2U1; -.
DR HGNC; HGNC:20582; CYP2U1.
DR HPA; ENSG00000155016; Tissue enriched (lymphoid).
DR MalaCards; CYP2U1; -.
DR MIM; 610670; gene.
DR MIM; 615030; phenotype.
DR neXtProt; NX_Q7Z449; -.
DR OpenTargets; ENSG00000155016; -.
DR Orphanet; 320411; Autosomal recessive spastic paraplegia type 56.
DR PharmGKB; PA134924269; -.
DR VEuPathDB; HostDB:ENSG00000155016; -.
DR eggNOG; KOG0156; Eukaryota.
DR GeneTree; ENSGT00940000157714; -.
DR HOGENOM; CLU_001570_22_3_1; -.
DR InParanoid; Q7Z449; -.
DR OMA; EPCIQQG; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; Q7Z449; -.
DR TreeFam; TF352043; -.
DR PathwayCommons; Q7Z449; -.
DR Reactome; R-HSA-211958; Miscellaneous substrates.
DR Reactome; R-HSA-2142816; Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE).
DR Reactome; R-HSA-5579011; Defective CYP2U1 causes SPG56.
DR SABIO-RK; Q7Z449; -.
DR SignaLink; Q7Z449; -.
DR UniPathway; UPA00383; -.
DR BioGRID-ORCS; 113612; 11 hits in 1075 CRISPR screens.
DR ChiTaRS; CYP2U1; human.
DR GeneWiki; CYP2U1; -.
DR GenomeRNAi; 113612; -.
DR Pharos; Q7Z449; Tbio.
DR PRO; PR:Q7Z449; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q7Z449; protein.
DR Bgee; ENSG00000155016; Expressed in thymus and 179 other tissues.
DR ExpressionAtlas; Q7Z449; baseline and differential.
DR Genevisible; Q7Z449; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0052869; F:arachidonic acid omega-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IBA:GO_Central.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0102033; F:long-chain fatty acid omega-hydroxylase activity; IEA:UniProtKB-EC.
DR GO; GO:0004497; F:monooxygenase activity; TAS:Reactome.
DR GO; GO:0016712; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; IBA:GO_Central.
DR GO; GO:0008395; F:steroid hydroxylase activity; IBA:GO_Central.
DR GO; GO:0097267; P:omega-hydroxylase P450 pathway; IDA:UniProtKB.
DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central.
DR GO; GO:0006805; P:xenobiotic metabolic process; IBA:GO_Central.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR008069; Cyt_P450_E_grp-I_CYP2D-like.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR01686; EP450ICYP2D.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Direct protein sequencing; Disease variant;
KW Endoplasmic reticulum; Heme; Hereditary spastic paraplegia; Iron;
KW Lipid metabolism; Membrane; Metal-binding; Microsome; Mitochondrion;
KW Mitochondrion inner membrane; Monooxygenase; Neurodegeneration;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..544
FT /note="Cytochrome P450 2U1"
FT /id="PRO_0000291756"
FT TRANSMEM 30..50
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 113..133
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 261..281
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 342..362
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 495..515
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 490
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250"
FT VAR_SEQ 164..168
FT /note="GVVFA -> ELFQE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026222"
FT VAR_SEQ 169..544
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026223"
FT VARIANT 262
FT /note="C -> R (in SPG56; dbSNP:rs397514515)"
FT /evidence="ECO:0000269|PubMed:23176821"
FT /id="VAR_069575"
FT VARIANT 316
FT /note="D -> V (in SPG56; dbSNP:rs397514513)"
FT /evidence="ECO:0000269|PubMed:23176821"
FT /id="VAR_069576"
FT VARIANT 380
FT /note="E -> G (in SPG56; dbSNP:rs397514514)"
FT /evidence="ECO:0000269|PubMed:23176821"
FT /id="VAR_069577"
FT VARIANT 488
FT /note="R -> W (in SPG56; dbSNP:rs141431913)"
FT /evidence="ECO:0000269|PubMed:23176821"
FT /id="VAR_069578"
SQ SEQUENCE 544 AA; 61987 MW; 01A0729318605770 CRC64;
MSSPGPSQPP AEDPPWPARL LRAPLGLLRL DPSGGALLLC GLVALLGWSW LRRRRARGIP
PGPTPWPLVG NFGHVLLPPF LRRRSWLSSR TRAAGIDPSV IGPQVLLAHL ARVYGSIFSF
FIGHYLVVVL SDFHSVREAL VQQAEVFSDR PRVPLISIVT KEKGVVFAHY GPVWRQQRKF
SHSTLRHFGL GKLSLEPKII EEFKYVKAEM QKHGEDPFCP FSIISNAVSN IICSLCFGQR
FDYTNSEFKK MLGFMSRGLE ICLNSQVLLV NICPWLYYLP FGPFKELRQI EKDITSFLKK
IIKDHQESLD RENPQDFIDM YLLHMEEERK NNSNSSFDEE YLFYIIGDLF IAGTDTTTNS
LLWCLLYMSL NPDVQEKVHE EIERVIGANR APSLTDKAQM PYTEATIMEV QRLTVVVPLA
IPHMTSENTV LQGYTIPKGT LILPNLWSVH RDPAIWEKPE DFYPNRFLDD QGQLIKKETF
IPFGIGKRVC MGEQLAKMEL FLMFVSLMQS FAFALPEDSK KPLLTGRFGL TLAPHPFNIT
ISRR
