CP2D6_PANTR
ID CP2D6_PANTR Reviewed; 497 AA.
AC Q2XNC8;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2005, sequence version 1.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=Cytochrome P450 2D6;
DE EC=1.14.14.- {ECO:0000250|UniProtKB:P10635};
DE AltName: Full=CYPIID6;
DE AltName: Full=Cholesterol 25-hydroxylase {ECO:0000250|UniProtKB:P10635};
DE AltName: Full=Cytochrome P450-DB1;
DE AltName: Full=Debrisoquine 4-hydroxylase;
GN Name=CYP2D6;
OS Pan troglodytes (Chimpanzee).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9598;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Koch W.H., Nikoloff D.M., Lu W., Pan R.M., deLeon J., Wedlund P.J.;
RT "CYP2D6 evolution and allele diversity among human races.";
RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC fatty acids, steroids and retinoids. Mechanistically, uses molecular
CC oxygen inserting one oxygen atom into a substrate, and reducing the
CC second into a water molecule, with two electrons provided by NADPH via
CC cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the
CC epoxidation of double bonds of polyunsaturated fatty acids (PUFA).
CC Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to
CC 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-,
CC 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs),
CC potentially modulating endocannabinoid system signaling. Catalyzes the
CC hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward
CC 25-hydroxycholesterol, a physiological regulator of cellular
CC cholesterol homeostasis. Catalyzes the oxidative transformations of
CC all-trans retinol to all-trans retinal, a precursor for the active form
CC all-trans-retinoic acid. Also involved in the oxidative metabolism of
CC drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic
CC antidepressants. {ECO:0000250|UniProtKB:P10635}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = (8R,9S)-epoxy-(5Z,11Z,14Z)-eicosatrienoate +
CC H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:49884, 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:131975; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49885;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = (11R,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate
CC + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:49880, 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:131970; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49881;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = (14S,15R)-epoxy-(5Z,8Z,11Z)-eicosatrienoate
CC + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:49856, 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:131964; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49857;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + O2 + reduced
CC [NADPH--hemoprotein reductase] = H(+) + H2O + N-(8,9-epoxy-
CC 5Z,11Z,14Z-eicosatrienoyl)-ethanolamine + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:53140, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:136989;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53141;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + O2 + reduced
CC [NADPH--hemoprotein reductase] = H(+) + H2O + N-(11,12-epoxy-
CC 5Z,8Z,14Z-eicosatrienoyl)-ethanolamine + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:53144, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:136990; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53145;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + O2 + reduced
CC [NADPH--hemoprotein reductase] = H(+) + H2O + N-(14,15-epoxy-
CC 5Z,8Z,11Z-eicosatrienoyl)-ethanolamine + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:53148, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:136991; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53149;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + O2 + reduced
CC [NADPH--hemoprotein reductase] = H(+) + H2O + N-(20-hydroxy-
CC 5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:53152, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210, ChEBI:CHEBI:136992;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53153;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 + reduced [NADPH--
CC hemoprotein reductase] = (17S,18R)-epoxy-(5Z,8Z,11Z,14Z)-
CC eicosatetraenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:39783, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:58562,
CC ChEBI:CHEBI:76635; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39784;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 + reduced
CC [NADPH--hemoprotein reductase] = (19R,20S)-epoxy-(4Z,7Z,10Z,13Z,16Z)-
CC docosapentaenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:52120, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:77016,
CC ChEBI:CHEBI:136410; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52121;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 + reduced
CC [NADPH--hemoprotein reductase] = (19S,20R)-epoxy-(4Z,7Z,10Z,13Z,16Z)-
CC docosapentaenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:52124, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:77016,
CC ChEBI:CHEBI:136411; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52125;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol + O2 + reduced [NADPH--hemoprotein reductase] =
CC 25-hydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:50256, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:42977, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50257;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=all-trans-retinol + O2 + reduced [NADPH--hemoprotein
CC reductase] = all-trans-retinal + H(+) + 2 H2O + oxidized [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:42092, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:17336, ChEBI:CHEBI:17898,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42093;
CC Evidence={ECO:0000250|UniProtKB:P10635};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000250};
CC -!- PATHWAY: Cofactor metabolism; retinol metabolism.
CC {ECO:0000250|UniProtKB:P10635}.
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000250|UniProtKB:P10635}.
CC -!- PATHWAY: Steroid metabolism; cholesterol metabolism.
CC {ECO:0000250|UniProtKB:P10635}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P10635}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P10635}. Microsome membrane
CC {ECO:0000250|UniProtKB:P10635}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P10635}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; DQ282164; ABB77911.1; -; Genomic_DNA.
DR RefSeq; NP_001035712.1; NM_001040622.1.
DR AlphaFoldDB; Q2XNC8; -.
DR BMRB; Q2XNC8; -.
DR SMR; Q2XNC8; -.
DR STRING; 9598.ENSPTRP00000024888; -.
DR PaxDb; Q2XNC8; -.
DR GeneID; 470228; -.
DR KEGG; ptr:470228; -.
DR CTD; 1565; -.
DR eggNOG; KOG0156; Eukaryota.
DR InParanoid; Q2XNC8; -.
DR OrthoDB; 702827at2759; -.
DR UniPathway; UPA00199; -.
DR UniPathway; UPA00296; -.
DR UniPathway; UPA00912; -.
DR Proteomes; UP000002277; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0062188; F:anandamide 11,12 epoxidase activity; IEA:RHEA.
DR GO; GO:0062189; F:anandamide 14,15 epoxidase activity; IEA:RHEA.
DR GO; GO:0062187; F:anandamide 8,9 epoxidase activity; IEA:RHEA.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
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:0019369; P:arachidonic acid metabolic process; IBA:GO_Central.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central.
DR GO; GO:0042572; P:retinol metabolic process; IEA:UniProtKB-UniPathway.
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 3: Inferred from homology;
KW Cholesterol metabolism; Endoplasmic reticulum; Fatty acid metabolism; Heme;
KW Iron; Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase;
KW Oxidoreductase; Reference proteome; Steroid metabolism; Sterol metabolism.
FT CHAIN 1..497
FT /note="Cytochrome P450 2D6"
FT /id="PRO_0000051733"
FT BINDING 301
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 443
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"
SQ SEQUENCE 497 AA; 55862 MW; 389387F955E2F4F6 CRC64;
MGLEALVPLA VIVTIFLLLV DLMHRRQRWA ARYPPGPLPL PGLGNLLHVD FQNTPYCFDQ
LRRRFGDVFS LQLAWTPVVV LNGLAAVREA LVTHGEDTAD RPPVPITQIL GFGPRSQGVF
LARYGPAWRE QRRFSVSTLR NLGLGKKSLE QWVTEEAACL CAAFANHSGR PFRPNGLLDK
AVSNVIASLT CGRRFEYDDP RFLRLLDLAQ EGLKEESGFL REVLNAIPVL LHIPALAGKV
LRFQKAFLTQ LDELLTEHRM TWDPAQPPRD LTEAFLAEME KAKGNPESSF NDENLRIVVA
DLFSAGIVTT STTLAWGLLL MILHPDVQRR VQQEIDDVIG QVRRPEMGDQ ARMPYTTAVI
HEVQRFGDIV PLGVTHMTSR DIEVQGFRIP KGTTLFTNLS SVLKDKAVWE KPFRFHPEHF
LDAQGHFVKP EAFLPFSAGR RACLGEPLAR MELFLFFTSL LQHFSFSVPT GQPRPSHHGV
FAFLVTPSPY ELCAVPR
