ID   CP2D6_PANPA             Reviewed;         497 AA.
AC   Q2XNC9;
DT   24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT   20-DEC-2005, sequence version 1.
DT   24-JAN-2024, entry version 73.
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 paniscus (Pygmy chimpanzee) (Bonobo).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pan.
OX   NCBI_TaxID=9597;
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
CC         [NADPH--hemoprotein reductase] = (8R,9S)-epoxy-(5Z,11Z,14Z)-
CC         eicosatrienoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:49884, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, 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
CC         [NADPH--hemoprotein reductase] = (11R,12S)-epoxy-(5Z,8Z,14Z)-
CC         eicosatrienoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:49880, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, 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
CC         [NADPH--hemoprotein reductase] = (14S,15R)-epoxy-(5Z,8Z,11Z)-
CC         eicosatrienoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:49856, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, 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
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53140, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:2700,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, 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
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53152, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:2700,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, 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
CC         [NADPH--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
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:42092, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17336,
CC         ChEBI:CHEBI:17898, 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; DQ282163; ABB77910.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q2XNC9; -.
DR   SMR; Q2XNC9; -.
DR   STRING; 9597.ENSPPAP00000027583; -.
DR   eggNOG; KOG0156; Eukaryota.
DR   OrthoDB; 2900138at2759; -.
DR   UniPathway; UPA00199; -.
DR   UniPathway; UPA00296; -.
DR   UniPathway; UPA00912; -.
DR   Proteomes; UP000240080; Unplaced.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
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; IEA:InterPro.
DR   GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0006631; P:fatty acid metabolic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0042572; P:retinol metabolic process; IEA:UniProtKB-UniPathway.
DR   CDD; cd20663; CYP2D; 1.
DR   Gene3D; 1.10.630.10; Cytochrome P450; 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   PANTHER; PTHR24300:SF1; CYTOCHROME P450 2D6-RELATED; 1.
DR   PANTHER; PTHR24300; CYTOCHROME P450 508A4-RELATED; 1.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR01686; EP450ICYP2D.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; Cytochrome P450; 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_0000051732"
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;  55867 MW;  B878B8B844EAD08E CRC64;
     MGLEALVPLA VIVTIFLLLV DLMHRRQRWA ARYPPGPLPL PGLGNLLHVD FQNTPYCFDQ
     LRRRFGDVFS LQLAWTPVVV LNGLAAVREA LVTHGEDTAD RPPVPITQIL GFGPRSQGVF
     LARYGPAWRE QRRFSVSTLR NLGLGKKSLE QWVTEEAACL CAAFANHSGR PFRPNGLLDK
     AVSNVIASLT CGRRFEYDDP RFLRLLDLAQ EGLKEESGFL REVLNAVPVL LHIPALAGKV
     LRFQKAFLTQ LDELLTEHRM TWDPAQPPRD LTEAFLAEME KAKGNPESSF NDENLRIVVA
     DLFSAGMVTT STTLAWGLLL MILHPDVQRR VQQEIDDVIG QVRRPEMGDQ ARMPYTTAVI
     HEVQRFGDIV PLGVTHMTSR DIEVQGFRIP KGTTLFTNLS SVLKDEAVWE KPFRFHPEHF
     LDAQGHFVKP EAFLPFSAGR RACLGEPLAR MELFLFFTSL LQHFSFSVPT GQPRPSHHGV
     FAFLVTPSPY ELCAVPR
//