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 24-JAN-2024, entry version 168. 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-36513937; 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 ChEMBL; CHEMBL4879483; -. DR SwissLipids; SLP:000000328; -. DR SwissLipids; SLP:000000519; -. DR iPTMnet; Q7L5A8; -. DR PhosphoSitePlus; Q7L5A8; -. DR SwissPalm; Q7L5A8; -. DR BioMuta; FA2H; -. DR DMDM; 74749893; -. DR EPD; Q7L5A8; -. DR MassIVE; Q7L5A8; -. DR MaxQB; Q7L5A8; -. DR PaxDb; 9606-ENSP00000219368; -. DR PeptideAtlas; Q7L5A8; -. DR ProteomicsDB; 68806; -. [Q7L5A8-1] DR Antibodypedia; 30274; 248 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 AGR; HGNC:21197; -. 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; WTIIEYV; -. DR OrthoDB; 208810at2759; -. DR PhylomeDB; Q7L5A8; -. DR TreeFam; TF314955; -. DR BioCyc; MetaCyc:ENSG00000103089-MONOMER; -. 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; 10 hits in 1148 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 150 other cell types or tissues. DR ExpressionAtlas; Q7L5A8; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. 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; Cytochrome b5-like heme/steroid binding domain; 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:SF1; FATTY ACID 2-HYDROXYLASE; 1. DR PANTHER; PTHR12863; FATTY ACID HYDROXYLASE; 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; Cytochrome b5-like heme/steroid binding domain; 1. DR PROSITE; PS00191; CYTOCHROME_B5_1; 1. DR PROSITE; PS50255; CYTOCHROME_B5_2; 1. DR Genevisible; Q7L5A8; HS. 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 //