CP4AE_RAT
ID CP4AE_RAT Reviewed; 507 AA.
AC P20817;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 2.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Cytochrome P450 4A14;
DE AltName: Full=CYPIVA14;
DE AltName: Full=Cytochrome P450-LA-omega 3;
DE AltName: Full=Lauric acid omega-hydroxylase;
DE AltName: Full=Long-chain fatty acid omega-monooxygenase;
DE EC=1.14.14.80 {ECO:0000250|UniProtKB:Q02928};
DE Flags: Precursor;
GN Name=Cyp4a14 {ECO:0000312|RGD:631356};
GN Synonyms=Cyp4a-3, Cyp4a3 {ECO:0000303|PubMed:10869363};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=2766933; DOI=10.1089/dna.1.1989.8.517;
RA Kimura S., Hardwick J.P., Kozak C.A., Gonzalez F.J.;
RT "The rat clofibrate-inducible CYP4A subfamily. II. cDNA sequence of IVA3,
RT mapping of the Cyp4a locus to mouse chromosome 4, and coordinate and
RT tissue-specific regulation of the CYP4A genes.";
RL DNA 8:517-525(1989).
RN [2]
RP PROTEIN SEQUENCE OF 5-19.
RX PubMed=3365247; DOI=10.1016/s0006-291x(88)80092-5;
RA Imaoka S., Shimojo N., Funae Y.;
RT "Induction of renal cytochrome P-450 in hepatic microsomes of diabetic
RT rats.";
RL Biochem. Biophys. Res. Commun. 152:680-687(1988).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-63; LYS-91; THR-92;
RP ALA-113; 114-SER--ILE-116 AND PHE-119, AND PATHWAY.
RX PubMed=10869363; DOI=10.1074/jbc.m004841200;
RA Hoch U., Falck J.R., de Montellano P.R.;
RT "Molecular basis for the omega-regiospecificity of the CYP4A2 and CYP4A3
RT fatty acid hydroxylases.";
RL J. Biol. Chem. 275:26952-26958(2000).
RN [4]
RP COVALENT HEME ATTACHMENT.
RX PubMed=11139583; DOI=10.1074/jbc.m009969200;
RA Hoch U., Ortiz de Montellano P.R.;
RT "Covalently linked heme in cytochrome P4504A fatty acid hydroxylases.";
RL J. Biol. Chem. 276:11339-11346(2001).
RN [5]
RP COVALENT HEME ATTACHMENT, AND MUTAGENESIS OF GLU-318.
RX PubMed=11821421; DOI=10.1074/jbc.m112155200;
RA LeBrun L.A., Hoch U., Ortiz de Montellano P.R.;
RT "Autocatalytic mechanism and consequences of covalent heme attachment in
RT the cytochrome P4504A family.";
RL J. Biol. Chem. 277:12755-12761(2002).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-437, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: A cytochrome P450 monooxygenase that catalyzes omega and
CC omega-1 hydroxylation of saturated fatty acids. Exhibits preferential
CC omega versus omega-1 regioselectivity and (R) versus (S)
CC stereoselectivity for hydroxylation of dodecanoic (lauric) acid.
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). {ECO:0000269|PubMed:10869363}.
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:10869363};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dodecanoate + O2 + reduced [NADPH--hemoprotein reductase] =
CC (11R)-hydroxydodecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:41724, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18262, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:78423; Evidence={ECO:0000269|PubMed:10869363};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41725;
CC Evidence={ECO:0000305|PubMed:10869363};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dodecanoate + O2 + reduced [NADPH--hemoprotein reductase] =
CC 12-hydroxydodecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:38947, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18262, ChEBI:CHEBI:36204, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:10869363};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38948;
CC Evidence={ECO:0000305|PubMed:10869363};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + tetradecanoate =
CC 14-hydroxytetradecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:40203, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:30807, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:77033; Evidence={ECO:0000269|PubMed:10869363};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40204;
CC Evidence={ECO:0000305|PubMed:10869363};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:11139583, ECO:0000269|PubMed:11821421};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000305|PubMed:10869363}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- INDUCTION: By clofibrate.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; M33936; AAA41458.1; -; mRNA.
DR PIR; A32966; A32966.
DR PIR; PC4351; PC4351.
DR RefSeq; NP_786936.1; NM_175760.2.
DR AlphaFoldDB; P20817; -.
DR SMR; P20817; -.
DR SwissLipids; SLP:000000744; -.
DR iPTMnet; P20817; -.
DR PhosphoSitePlus; P20817; -.
DR PRIDE; P20817; -.
DR GeneID; 298423; -.
DR KEGG; rno:298423; -.
DR UCSC; RGD:631356; rat.
DR CTD; 298423; -.
DR RGD; 631356; Cyp4a3.
DR InParanoid; P20817; -.
DR OrthoDB; 1247045at2759; -.
DR PhylomeDB; P20817; -.
DR BRENDA; 1.14.14.80; 5301.
DR Reactome; R-RNO-211935; Fatty acids.
DR Reactome; R-RNO-211958; Miscellaneous substrates.
DR Reactome; R-RNO-211979; Eicosanoids.
DR Reactome; R-RNO-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR UniPathway; UPA00199; -.
DR PRO; PR:P20817; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0018685; F:alkane 1-monooxygenase activity; IMP:RGD.
DR GO; GO:0008391; F:arachidonic acid monooxygenase activity; IMP:RGD.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
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:0019369; P:arachidonic acid metabolic process; IMP:RGD.
DR GO; GO:0046456; P:icosanoid biosynthetic process; IMP:RGD.
DR GO; GO:0001822; P:kidney development; IEP:RGD.
DR GO; GO:0048252; P:lauric acid metabolic process; IDA:RGD.
DR GO; GO:0043651; P:linoleic acid metabolic process; IDA:RGD.
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; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Endoplasmic reticulum; Heme; Iron; Membrane;
KW Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome.
FT PROPEP 1..4
FT /note="Removed in mature form"
FT /evidence="ECO:0000269|PubMed:3365247"
FT /id="PRO_0000003569"
FT CHAIN 5..507
FT /note="Cytochrome P450 4A14"
FT /id="PRO_0000003570"
FT BINDING 318
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /note="covalent"
FT /evidence="ECO:0000269|PubMed:11139583,
FT ECO:0000269|PubMed:11821421"
FT BINDING 454
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:0000269|PubMed:11139583,
FT ECO:0000269|PubMed:11821421"
FT MOD_RES 437
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MUTAGEN 63
FT /note="D->N: Has no significant effect on the catalytic
FT activity toward lauric and myristic acids."
FT /evidence="ECO:0000269|PubMed:10869363"
FT MUTAGEN 91
FT /note="K->T: Impairs substrate binding."
FT /evidence="ECO:0000269|PubMed:10869363"
FT MUTAGEN 92
FT /note="T->A: Has no significant effect on the catalytic
FT activity toward lauric and myristic acids."
FT MUTAGEN 113
FT /note="A->P: 70-fold increase of the binding constant for
FT lauric acid associated with higher catalytic activity."
FT /evidence="ECO:0000269|PubMed:10869363"
FT MUTAGEN 114..116
FT /note="Missing: Higher kcat for hydroxylation of lauric
FT acid. 2-fold increase of omega/(omega-1) hydroxylation
FT ratio for lauric and myristic acids; when associated with
FT S-119."
FT /evidence="ECO:0000269|PubMed:10869363"
FT MUTAGEN 119
FT /note="F->S: 7-fold increase of the binding constant for
FT lauric acid associated with higher catalytic activity. 2-
FT fold increase of omega/omega-1 hydroxylation ratio for
FT lauric and myristic acids; when associated with
FT S114_I116del."
FT /evidence="ECO:0000269|PubMed:10869363"
FT MUTAGEN 318
FT /note="E->A: Loss of covalent heme binding."
FT /evidence="ECO:0000269|PubMed:11821421"
FT MUTAGEN 318
FT /note="E->D: Significant reduction in covalent heme
FT binding."
FT /evidence="ECO:0000269|PubMed:11821421"
FT MUTAGEN 318
FT /note="E->Q: Significant reduction in covalent heme
FT binding."
FT /evidence="ECO:0000269|PubMed:11821421"
SQ SEQUENCE 507 AA; 58232 MW; 1A972C6F967BF1AB CRC64;
MGFSVFTPTR SLDGVSGFFQ GAFLLSLFLV LFKAVQFYLR RQWLLKALEK FPSTPSHWLW
GHDLKDREFQ QVLTWVEKFP GACLQWLSGS KTRVLLYDPD YVKVVLGRSD PKASGIYQFL
APWIGYGLLL LNGKKWFQHR RMLTPAFHYG ILKPYVKIMA DSVNIMLDKW EKLDDQDHPL
EIFHYVSLMT LDTVMKCAFS HQGSVQLDVN SRSYTKAVED LNNLTFFRVR SAFYGNSIIY
NMSSDGRLSR RACQIAHEHT DGVIKMRKAQ LQNEEELQKA RKKRHLDFLD ILLFAKMEDG
KSLSDEDLRA EVDTFMFEGH DTTASGISWV FYALATHPEH QERCREEVQS ILGDGTSVTW
DHLDQIPYTT MCIKEALRLY PPVPSVSREL SSPVTFPDGR SIPKGITTTI LIYGLHHNPS
YWPNPKVFDP SRFSPDSPRH SHAYLPFSGG ARNCIGKQFA MNELKVAVAL TLLRFELLPD
PTRIPVPMAR LVLKSKNGIH LRLKKLR
