FA2H_MACFA
ID FA2H_MACFA Reviewed; 372 AA.
AC Q4R4P4;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=Fatty acid 2-hydroxylase {ECO:0000250|UniProtKB:Q7L5A8};
DE EC=1.14.18.- {ECO:0000250|UniProtKB:Q7L5A8};
DE AltName: Full=Fatty acid alpha-hydroxylase {ECO:0000250|UniProtKB:Q7L5A8};
GN Name=FA2H; Synonyms=FAAH; ORFNames=QtrA-13193;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Temporal cortex;
RG International consortium for macaque cDNA sequencing and analysis;
RT "DNA sequences of macaque genes expressed in brain or testis and its
RT evolutionary implications.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Catalyzes the hydroxylation of free fatty acids at the C-2
CC position to produce 2-hydroxy fatty acids, which are building blocks of
CC sphingolipids and glycosphingolipids common in neural tissue and
CC epidermis. FA2H is stereospecific for the production of (R)-2-hydroxy
CC fatty acids (By similarity). Plays an essential role in the synthesis
CC of galactosphingolipids of the myelin sheath (By similarity).
CC Responsible for the synthesis of sphingolipids and glycosphingolipids
CC involved in the formation of epidermal lamellar bodies critical for
CC skin permeability barrier (By similarity). Participates in the
CC synthesis of glycosphingolipids and a fraction of type II wax diesters
CC in sebaceous gland, specifically regulating hair follicle homeostasis.
CC Involved in the synthesis of sphingolipids of plasma membrane rafts,
CC controlling lipid raft mobility and trafficking of raft-associated
CC proteins (By similarity). {ECO:0000250|UniProtKB:Q5MPP0,
CC ECO:0000250|UniProtKB:Q7L5A8}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-saturated fatty acid + 2 Fe(II)-[cytochrome b5] + 2 H(+)
CC + O2 = a (R)-2-hydroxy fatty acid + 2 Fe(III)-[cytochrome b5] + H2O;
CC Xref=Rhea:RHEA:38855, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:29033, ChEBI:CHEBI:29034, ChEBI:CHEBI:76177,
CC ChEBI:CHEBI:83955; Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38856;
CC Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 Fe(II)-[cytochrome b5] + 2 H(+) + hexadecanoate + O2 = (R)-
CC 2-hydroxyhexadecanoate + 2 Fe(III)-[cytochrome b5] + H2O;
CC Xref=Rhea:RHEA:38551, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:75927; Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38552;
CC Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 Fe(II)-[cytochrome b5] + 2 H(+) + O2 + octadecanoate = (R)-
CC 2-hydroxyoctadecanoate + 2 Fe(III)-[cytochrome b5] + H2O;
CC Xref=Rhea:RHEA:39815, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:25629, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:57562; Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39816;
CC Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=docosanoate + 2 Fe(II)-[cytochrome b5] + 2 H(+) + O2 = 2-
CC hydroxydocosanoate + 2 Fe(III)-[cytochrome b5] + H2O;
CC Xref=Rhea:RHEA:39819, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:23858, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:76722; Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39820;
CC Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 Fe(II)-[cytochrome b5] + 2 H(+) + O2 + tetracosanoate = (R)-
CC 2-hydroxytetracosanoate + 2 Fe(III)-[cytochrome b5] + H2O;
CC Xref=Rhea:RHEA:38559, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:29033, ChEBI:CHEBI:29034, ChEBI:CHEBI:31014,
CC ChEBI:CHEBI:75935; Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38560;
CC Evidence={ECO:0000250|UniProtKB:Q7L5A8};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q03529};
CC Note=Binds 2 Zn(2+) ions per subunit that likely form a catalytic
CC dimetal center. {ECO:0000250|UniProtKB:Q03529};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000250|UniProtKB:Q7L5A8}.
CC -!- PATHWAY: Sphingolipid metabolism; galactosylceramide biosynthesis.
CC {ECO:0000250|UniProtKB:Q7L5A8}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q7L5A8}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q7L5A8}. Microsome membrane
CC {ECO:0000250|UniProtKB:Q7L5A8}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q7L5A8}.
CC -!- DOMAIN: The histidine box domains may contain the active site and/or be
CC involved in metal ion binding.
CC -!- DOMAIN: The N-terminal cytochrome b5 heme-binding domain is essential
CC for catalytic activity. {ECO:0000250|UniProtKB:Q7L5A8}.
CC -!- SIMILARITY: Belongs to the sterol desaturase family. SCS7 subfamily.
CC {ECO:0000305}.
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DR EMBL; AB169850; BAE01931.1; -; mRNA.
DR RefSeq; NP_001270612.1; NM_001283683.1.
DR AlphaFoldDB; Q4R4P4; -.
DR SMR; Q4R4P4; -.
DR STRING; 9541.XP_005592603.1; -.
DR GeneID; 101865555; -.
DR CTD; 79152; -.
DR VEuPathDB; HostDB:ENSMFAG00000026134; -.
DR eggNOG; KOG0537; Eukaryota.
DR eggNOG; KOG0539; Eukaryota.
DR OMA; HFADYEN; -.
DR OrthoDB; 1049908at2759; -.
DR UniPathway; UPA00199; -.
DR UniPathway; UPA00787; -.
DR Proteomes; UP000233100; Chromosome 20.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0080132; F:fatty acid alpha-hydroxylase activity; ISS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0046513; P:ceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0061436; P:establishment of skin barrier; ISS:UniProtKB.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006682; P:galactosylceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006679; P:glucosylceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0044857; P:plasma membrane raft organization; ISS:UniProtKB.
DR Gene3D; 3.10.120.10; -; 1.
DR InterPro; IPR001199; Cyt_B5-like_heme/steroid-bd.
DR InterPro; IPR036400; Cyt_B5-like_heme/steroid_sf.
DR InterPro; IPR018506; Cyt_B5_heme-BS.
DR InterPro; IPR006694; Fatty_acid_hydroxylase.
DR InterPro; IPR014430; Scs7.
DR PANTHER; PTHR12863; PTHR12863; 1.
DR Pfam; PF00173; Cyt-b5; 1.
DR Pfam; PF04116; FA_hydroxylase; 1.
DR PIRSF; PIRSF005149; IPC-B_HD; 1.
DR PRINTS; PR00363; CYTOCHROMEB5.
DR SMART; SM01117; Cyt-b5; 1.
DR SUPFAM; SSF55856; SSF55856; 1.
DR PROSITE; PS00191; CYTOCHROME_B5_1; 1.
DR PROSITE; PS50255; CYTOCHROME_B5_2; 1.
PE 2: Evidence at transcript level;
KW Endoplasmic reticulum; Fatty acid biosynthesis; Fatty acid metabolism;
KW Heme; Iron; Lipid biosynthesis; Lipid metabolism; Membrane; Metal-binding;
KW Microsome; Oxidoreductase; Reference proteome; Sphingolipid metabolism;
KW Transmembrane; Transmembrane helix; Zinc.
FT CHAIN 1..372
FT /note="Fatty acid 2-hydroxylase"
FT /id="PRO_0000312350"
FT TRANSMEM 168..188
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 213..233
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 271..291
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 292..312
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 8..86
FT /note="Cytochrome b5 heme-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00279"
FT DOMAIN 219..361
FT /note="Fatty acid hydroxylase"
FT /evidence="ECO:0000255"
FT BINDING 43
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:0000255|PROSITE-ProRule:PRU00279"
FT BINDING 69
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:0000255|PROSITE-ProRule:PRU00279"
FT BINDING 234
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 239
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 257
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 260
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 261
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 315
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 319
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 336
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 339
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
FT BINDING 340
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q03529"
SQ SEQUENCE 372 AA; 42782 MW; C1FEA2286C31955A CRC64;
MAPAPPPAAS FSPSEVQRRL AAGACWVRRG ARLYDLSSFV RHHPGGEQLL RARAGQDISA
DLDGPPHRHS ANARRWLEQY YVGELRGEQQ GSMENEAVAL EETQKTDPAM EPRFKVVDWD
KDLVDWQKPL LWQVGHLGEK YDEWVHQPVT RPIRLFHSDL IEGLSKTVWY SVPIIWVPLV
LYLSWSYYRT FAQGNVRLFT SFTTEYALAV PKSMFPGLFM LGIFLWSLIE YLIHRFLFHM
KPPSDSYYLI MLHFVMHGQH HKAPFDGSRL VFPPVPASLV IGVFYLCLQL ILPEAVGGTV
FAGGLLGYVL YDMTHYYLHF GSPHRGSYLY NLKAHHVKHH FAHQKSGFGI STKLWDYCFH
TLIPEKPHLK TQ
