FA2H_HUMAN
ID FA2H_HUMAN Reviewed; 372 AA.
AC Q7L5A8; B7Z8T6; O75213; Q96DK1; Q9H1A5;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Fatty acid 2-hydroxylase {ECO:0000303|PubMed:15337768, ECO:0000303|PubMed:15863841, ECO:0000303|PubMed:17355976, ECO:0000303|PubMed:22517924};
DE EC=1.14.18.- {ECO:0000269|PubMed:15337768, ECO:0000269|PubMed:15863841, ECO:0000269|PubMed:17355976, ECO:0000269|PubMed:22517924};
DE AltName: Full=Fatty acid alpha-hydroxylase {ECO:0000303|PubMed:15863841};
DE AltName: Full=Fatty acid hydroxylase domain-containing protein 1 {ECO:0000312|HGNC:HGNC:21197};
GN Name=FA2H {ECO:0000303|PubMed:15337768, ECO:0000303|PubMed:15863841,
GN ECO:0000303|PubMed:17355976, ECO:0000303|PubMed:22517924,
GN ECO:0000312|HGNC:HGNC:21197};
GN Synonyms=FAAH, FAXDC1 {ECO:0000312|HGNC:HGNC:21197};
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 [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Gastric mucosa, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [3]
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 (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, and Pancreas;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 93-372 (ISOFORM 1).
RA Van Veldhoven P.P.;
RT "Cloning of human fatty acid hydroxylase.";
RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DOMAIN, AND CATALYTIC
RP ACTIVITY.
RX PubMed=15337768; DOI=10.1074/jbc.m406649200;
RA Alderson N.L., Rembiesa B.M., Walla M.D., Bielawska A., Bielawski J.,
RA Hama H.;
RT "The human FA2H gene encodes a fatty acid 2-hydroxylase.";
RL J. Biol. Chem. 279:48562-48568(2004).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=15863841; DOI=10.1194/jlr.d500013-jlr200;
RA Alderson N.L., Walla M.D., Hama H.;
RT "A novel method for the measurement of in vitro fatty acid 2-hydroxylase
RT activity by gas chromatography-mass spectrometry.";
RL J. Lipid Res. 46:1569-1575(2005).
RN [8]
RP FUNCTION, INDUCTION, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY.
RX PubMed=17355976; DOI=10.1074/jbc.m611562200;
RA Uchida Y., Hama H., Alderson N.L., Douangpanya S., Wang Y., Crumrine D.A.,
RA Elias P.M., Holleran W.M.;
RT "Fatty acid 2-hydroxylase, encoded by FA2H, accounts for differentiation-
RT associated increase in 2-OH ceramides during keratinocyte
RT differentiation.";
RL J. Biol. Chem. 282:13211-13219(2007).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=22517924; DOI=10.1194/jlr.m025742;
RA Guo L., Zhang X., Zhou D., Okunade A.L., Su X.;
RT "Stereospecificity of fatty acid 2-hydroxylase and differential functions
RT of 2-hydroxy fatty acid enantiomers.";
RL J. Lipid Res. 53:1327-1335(2012).
RN [10]
RP VARIANT SPG35 TYR-35.
RX PubMed=19068277; DOI=10.1016/j.ajhg.2008.10.010;
RA Edvardson S., Hama H., Shaag A., Gomori J.M., Berger I., Soffer D.,
RA Korman S.H., Taustein I., Saada A., Elpeleg O.;
RT "Mutations in the fatty acid 2-hydroxylase gene are associated with
RT leukodystrophy with spastic paraparesis and dystonia.";
RL Am. J. Hum. Genet. 83:643-648(2008).
RN [11]
RP VARIANT SPG35 CYS-154.
RX PubMed=20853438; DOI=10.1002/ana.22122;
RA Kruer M.C., Paisan-Ruiz C., Boddaert N., Yoon M.Y., Hama H., Gregory A.,
RA Malandrini A., Woltjer R.L., Munnich A., Gobin S., Polster B.J.,
RA Palmeri S., Edvardson S., Hardy J., Houlden H., Hayflick S.J.;
RT "Defective FA2H leads to a novel form of neurodegeneration with brain iron
RT accumulation (NBIA).";
RL Ann. Neurol. 68:611-618(2010).
RN [12]
RP VARIANTS SPG35 53-ARG--ILE-58 DEL AND CYS-235, AND CHARACTERIZATION OF
RP VARIANTS SPG35 53-ARG--ILE-58 DEL AND CYS-235.
RX PubMed=20104589; DOI=10.1002/humu.21205;
RA Dick K.J., Eckhardt M., Paisan-Ruiz C., Alshehhi A.A., Proukakis C.,
RA Sibtain N.A., Maier H., Sharifi R., Patton M.A., Bashir W., Koul R.,
RA Raeburn S., Gieselmann V., Houlden H., Crosby A.H.;
RT "Mutation of FA2H underlies a complicated form of hereditary spastic
RT paraplegia (SPG35).";
RL Hum. Mutat. 31:E1251-E1260(2010).
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 (PubMed:15337768, PubMed:15863841, PubMed:17355976,
CC PubMed:22517924). FA2H is stereospecific for the production of (R)-2-
CC hydroxy fatty acids (PubMed:22517924). Plays an essential role in the
CC synthesis 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 (PubMed:17355976). 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 (By similarity). Involved in the synthesis of sphingolipids of plasma
CC membrane rafts, controlling lipid raft mobility and trafficking of
CC raft-associated proteins (By similarity).
CC {ECO:0000250|UniProtKB:Q5MPP0, ECO:0000269|PubMed:15337768,
CC ECO:0000269|PubMed:15863841, ECO:0000269|PubMed:17355976,
CC ECO:0000269|PubMed:22517924}.
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:0000269|PubMed:22517924,
CC ECO:0000305|PubMed:15337768, ECO:0000305|PubMed:15863841,
CC ECO:0000305|PubMed:17355976};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38856;
CC Evidence={ECO:0000269|PubMed:22517924};
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:0000269|PubMed:22517924,
CC ECO:0000305|PubMed:15337768};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38552;
CC Evidence={ECO:0000269|PubMed:22517924};
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:0000269|PubMed:15337768};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39816;
CC Evidence={ECO:0000269|PubMed:15337768};
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:0000269|PubMed:15337768};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39820;
CC Evidence={ECO:0000269|PubMed:15337768};
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:0000269|PubMed:15337768,
CC ECO:0000269|PubMed:15863841, ECO:0000269|PubMed:17355976};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38560;
CC Evidence={ECO:0000269|PubMed:15337768, ECO:0000269|PubMed:17355976};
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Note=KM<0.18 uM for tetracosanoic acid.
CC {ECO:0000269|PubMed:15863841};
CC pH dependence:
CC Optimum pH is 7.6-7.8. {ECO:0000269|PubMed:15863841};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000269|PubMed:15863841, ECO:0000269|PubMed:22517924}.
CC -!- PATHWAY: Sphingolipid metabolism; galactosylceramide biosynthesis.
CC {ECO:0000269|PubMed:22517924}.
CC -!- INTERACTION:
CC Q7L5A8; Q13520: AQP6; NbExp=3; IntAct=EBI-11337888, EBI-13059134;
CC Q7L5A8; Q5T9G4-2: ARMC12; NbExp=3; IntAct=EBI-11337888, EBI-23667468;
CC Q7L5A8; P07307-3: ASGR2; NbExp=3; IntAct=EBI-11337888, EBI-12808270;
CC Q7L5A8; P11912: CD79A; NbExp=3; IntAct=EBI-11337888, EBI-7797864;
CC Q7L5A8; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-11337888, EBI-6942903;
CC Q7L5A8; Q15700: DLG2; NbExp=3; IntAct=EBI-11337888, EBI-80426;
CC Q7L5A8; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-11337888, EBI-356015;
CC Q7L5A8; Q15125: EBP; NbExp=3; IntAct=EBI-11337888, EBI-3915253;
CC Q7L5A8; Q9GZR5: ELOVL4; NbExp=3; IntAct=EBI-11337888, EBI-18535450;
CC Q7L5A8; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-11337888, EBI-781551;
CC Q7L5A8; O75477: ERLIN1; NbExp=3; IntAct=EBI-11337888, EBI-359299;
CC Q7L5A8; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-11337888, EBI-18304435;
CC Q7L5A8; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-11337888, EBI-13345167;
CC Q7L5A8; Q8TED1: GPX8; NbExp=3; IntAct=EBI-11337888, EBI-11721746;
CC Q7L5A8; Q92876: KLK6; NbExp=3; IntAct=EBI-11337888, EBI-2432309;
CC Q7L5A8; Q5T0T0: MARCHF8; NbExp=3; IntAct=EBI-11337888, EBI-14061946;
CC Q7L5A8; P21757: MSR1; NbExp=3; IntAct=EBI-11337888, EBI-1776976;
CC Q7L5A8; O00623: PEX12; NbExp=3; IntAct=EBI-11337888, EBI-594836;
CC Q7L5A8; O15173: PGRMC2; NbExp=3; IntAct=EBI-11337888, EBI-1050125;
CC Q7L5A8; Q7Z5B4-5: RIC3; NbExp=3; IntAct=EBI-11337888, EBI-12375429;
CC Q7L5A8; O95470: SGPL1; NbExp=3; IntAct=EBI-11337888, EBI-1046170;
CC Q7L5A8; Q14973: SLC10A1; NbExp=3; IntAct=EBI-11337888, EBI-3923031;
CC Q7L5A8; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11337888, EBI-18159983;
CC Q7L5A8; Q8N9I0: SYT2; NbExp=3; IntAct=EBI-11337888, EBI-8032987;
CC Q7L5A8; Q96MV1: TLCD4; NbExp=3; IntAct=EBI-11337888, EBI-12947623;
CC Q7L5A8; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-11337888, EBI-8638294;
CC Q7L5A8; Q96HV5: TMEM41A; NbExp=3; IntAct=EBI-11337888, EBI-10288884;
CC Q7L5A8; Q9Y320: TMX2; NbExp=3; IntAct=EBI-11337888, EBI-6447886;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q5MPP0}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:15337768}. Microsome membrane
CC {ECO:0000269|PubMed:15337768}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:15337768}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q7L5A8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7L5A8-2; Sequence=VSP_056135;
CC -!- TISSUE SPECIFICITY: Detected in differentiating cultured keratinocytes
CC (at protein level). Detected in epidermis and cultured keratinocytes
CC (PubMed:17355976). Highly expressed in brain and colon. Detected at
CC lower levels in testis, prostate, pancreas and kidney
CC (PubMed:15337768). {ECO:0000269|PubMed:15337768,
CC ECO:0000269|PubMed:17355976}.
CC -!- INDUCTION: Up-regulated during keratinocyte differentiation.
CC {ECO:0000269|PubMed:17355976}.
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:0000269|PubMed:15337768}.
CC -!- DISEASE: Spastic paraplegia 35, autosomal recessive, with or without
CC neurodegeneration (SPG35) [MIM:612319]: A form of spastic paraplegia, a
CC neurodegenerative disorder characterized by a slow, gradual,
CC progressive weakness and spasticity of the lower limbs. Rate of
CC progression and the severity of symptoms are quite variable. Initial
CC symptoms may include difficulty with balance, weakness and stiffness in
CC the legs, muscle spasms, and dragging the toes when walking. In some
CC forms of the disorder, bladder symptoms (such as incontinence) may
CC appear, or the weakness and stiffness may spread to other parts of the
CC body. SPG35 is a complicated form characterized by childhood onset of
CC gait difficulties. It has a rapid progression and many patients become
CC wheelchair-bound as young adults. Patients manifest cognitive decline
CC associated with leukodystrophy. Other variable neurologic features,
CC such as dystonia, optic atrophy, and seizures may also occur.
CC {ECO:0000269|PubMed:19068277, ECO:0000269|PubMed:20104589,
CC ECO:0000269|PubMed:20853438}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the sterol desaturase family. SCS7 subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC23496.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AK058016; BAB71632.1; -; mRNA.
DR EMBL; AK303878; BAH14072.1; -; mRNA.
DR EMBL; AC004685; AAC23496.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC009132; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471114; EAW95678.1; -; Genomic_DNA.
DR EMBL; BC002679; AAH02679.2; -; mRNA.
DR EMBL; BC004263; AAH04263.2; -; mRNA.
DR EMBL; BC017049; AAH17049.2; -; mRNA.
DR EMBL; AJ278219; CAC20436.1; -; mRNA.
DR CCDS; CCDS10911.1; -. [Q7L5A8-1]
DR RefSeq; NP_077282.3; NM_024306.4. [Q7L5A8-1]
DR AlphaFoldDB; Q7L5A8; -.
DR SMR; Q7L5A8; -.
DR BioGRID; 122570; 47.
DR IntAct; Q7L5A8; 31.
DR MINT; Q7L5A8; -.
DR STRING; 9606.ENSP00000219368; -.
DR BindingDB; Q7L5A8; -.
DR SwissLipids; SLP:000000328; -.
DR SwissLipids; SLP:000000519; -.
DR iPTMnet; Q7L5A8; -.
DR PhosphoSitePlus; Q7L5A8; -.
DR BioMuta; FA2H; -.
DR DMDM; 74749893; -.
DR EPD; Q7L5A8; -.
DR MassIVE; Q7L5A8; -.
DR MaxQB; Q7L5A8; -.
DR PaxDb; Q7L5A8; -.
DR PeptideAtlas; Q7L5A8; -.
DR PRIDE; Q7L5A8; -.
DR ProteomicsDB; 68806; -. [Q7L5A8-1]
DR ProteomicsDB; 6981; -.
DR Antibodypedia; 30274; 224 antibodies from 30 providers.
DR DNASU; 79152; -.
DR Ensembl; ENST00000219368.8; ENSP00000219368.3; ENSG00000103089.9. [Q7L5A8-1]
DR GeneID; 79152; -.
DR KEGG; hsa:79152; -.
DR MANE-Select; ENST00000219368.8; ENSP00000219368.3; NM_024306.5; NP_077282.3.
DR UCSC; uc002fde.3; human. [Q7L5A8-1]
DR CTD; 79152; -.
DR DisGeNET; 79152; -.
DR GeneCards; FA2H; -.
DR GeneReviews; FA2H; -.
DR HGNC; HGNC:21197; FA2H.
DR HPA; ENSG00000103089; Group enriched (brain, stomach).
DR MalaCards; FA2H; -.
DR MIM; 611026; gene.
DR MIM; 612319; phenotype.
DR neXtProt; NX_Q7L5A8; -.
DR OpenTargets; ENSG00000103089; -.
DR Orphanet; 171629; Autosomal recessive spastic paraplegia type 35.
DR Orphanet; 329308; Fatty acid hydroxylase-associated neurodegeneration.
DR PharmGKB; PA145148065; -.
DR VEuPathDB; HostDB:ENSG00000103089; -.
DR eggNOG; KOG0537; Eukaryota.
DR eggNOG; KOG0539; Eukaryota.
DR GeneTree; ENSGT00390000002142; -.
DR HOGENOM; CLU_034756_2_0_1; -.
DR InParanoid; Q7L5A8; -.
DR OMA; HFADYEN; -.
DR OrthoDB; 1049908at2759; -.
DR PhylomeDB; Q7L5A8; -.
DR TreeFam; TF314955; -.
DR BioCyc; MetaCyc:ENSG00000103089-MON; -.
DR BRENDA; 1.14.18.6; 2681.
DR PathwayCommons; Q7L5A8; -.
DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR SignaLink; Q7L5A8; -.
DR UniPathway; UPA00199; -.
DR UniPathway; UPA00787; -.
DR BioGRID-ORCS; 79152; 9 hits in 1069 CRISPR screens.
DR ChiTaRS; FA2H; human.
DR GeneWiki; FA2H; -.
DR GenomeRNAi; 79152; -.
DR Pharos; Q7L5A8; Tbio.
DR PRO; PR:Q7L5A8; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q7L5A8; protein.
DR Bgee; ENSG00000103089; Expressed in C1 segment of cervical spinal cord and 148 other tissues.
DR ExpressionAtlas; Q7L5A8; baseline and differential.
DR Genevisible; Q7L5A8; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; 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:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0080132; F:fatty acid alpha-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0032286; P:central nervous system myelin maintenance; IEA:Ensembl.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0061436; P:establishment of skin barrier; IMP:UniProtKB.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006631; P:fatty acid metabolic process; IBA:GO_Central.
DR GO; GO:0006682; P:galactosylceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006679; P:glucosylceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0030258; P:lipid modification; IEA:Ensembl.
DR GO; GO:0032287; P:peripheral nervous system myelin maintenance; IEA:Ensembl.
DR GO; GO:0044857; P:plasma membrane raft organization; ISS:UniProtKB.
DR GO; GO:1904697; P:regulation of acinar cell proliferation; IEA:Ensembl.
DR GO; GO:0042634; P:regulation of hair cycle; IEA:Ensembl.
DR GO; GO:1904002; P:regulation of sebum secreting cell proliferation; IEA:Ensembl.
DR GO; GO:0001949; P:sebaceous gland cell differentiation; IEA:Ensembl.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
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 1: Evidence at protein level;
KW Alternative splicing; Disease variant; Endoplasmic reticulum;
KW Fatty acid biosynthesis; Fatty acid metabolism; Heme;
KW Hereditary spastic paraplegia; Iron; Leukodystrophy; Lipid biosynthesis;
KW Lipid metabolism; Membrane; Metal-binding; Microsome; Neurodegeneration;
KW Oxidoreductase; Reference proteome; Sphingolipid metabolism; Transmembrane;
KW Transmembrane helix; Zinc.
FT CHAIN 1..372
FT /note="Fatty acid 2-hydroxylase"
FT /id="PRO_0000312349"
FT TRANSMEM 168..188
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 213..233
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 268..288
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 290..310
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"
FT VAR_SEQ 1..213
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056135"
FT VARIANT 35
FT /note="D -> Y (in SPG35; patients present spastic
FT paraparesis associated with leukodystrophy and dystonia;
FT dbSNP:rs121918217)"
FT /evidence="ECO:0000269|PubMed:19068277"
FT /id="VAR_054893"
FT VARIANT 53..58
FT /note="Missing (in SPG35; significantly reduced enzymatic
FT function)"
FT /evidence="ECO:0000269|PubMed:20104589"
FT /id="VAR_064620"
FT VARIANT 97
FT /note="P -> A (in dbSNP:rs35874850)"
FT /id="VAR_037503"
FT VARIANT 154
FT /note="R -> C (in SPG35; dbSNP:rs387907040)"
FT /evidence="ECO:0000269|PubMed:20853438"
FT /id="VAR_065245"
FT VARIANT 235
FT /note="R -> C (in SPG35; significantly reduced enzymatic
FT function; dbSNP:rs387907039)"
FT /evidence="ECO:0000269|PubMed:20104589"
FT /id="VAR_064621"
FT CONFLICT 184
FT /note="S -> G (in Ref. 1; BAB71632)"
FT /evidence="ECO:0000305"
FT CONFLICT 356
FT /note="D -> G (in Ref. 1; BAB71632)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 372 AA; 42791 MW; 3F56B4C689B317BE CRC64;
MAPAPPPAAS FSPSEVQRRL AAGACWVRRG ARLYDLSSFV RHHPGGEQLL RARAGQDISA
DLDGPPHRHS ANARRWLEQY YVGELRGEQQ GSMENEPVAL EETQKTDPAM EPRFKVVDWD
KDLVDWRKPL LWQVGHLGEK YDEWVHQPVT RPIRLFHSDL IEGLSKTVWY SVPIIWVPLV
LYLSWSYYRT FAQGNVRLFT SFTTEYTVAV PKSMFPGLFM LGTFLWSLIE YLIHRFLFHM
KPPSDSYYLI MLHFVMHGQH HKAPFDGSRL VFPPVPASLV IGVFYLCMQL ILPEAVGGTV
FAGGLLGYVL YDMTHYYLHF GSPHKGSYLY SLKAHHVKHH FAHQKSGFGI STKLWDYCFH
TLTPEKPHLK TQ
