FUMH_HUMAN
ID FUMH_HUMAN Reviewed; 510 AA.
AC P07954; B1ANK7;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 3.
DT 03-AUG-2022, entry version 239.
DE RecName: Full=Fumarate hydratase, mitochondrial {ECO:0000303|PubMed:21445611, ECO:0000303|PubMed:27037871};
DE Short=Fumarase {ECO:0000303|PubMed:27037871, ECO:0000303|PubMed:3828494, ECO:0000303|Ref.2};
DE Short=HsFH {ECO:0000303|PubMed:24419633};
DE EC=4.2.1.2 {ECO:0000269|PubMed:30761759};
DE Flags: Precursor;
GN Name=FH {ECO:0000303|PubMed:27037871, ECO:0000312|HGNC:HGNC:3700};
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 [MRNA].
RC TISSUE=Brain;
RA Gellera C., Baratta S., Cavadini P., Invernizzi F., Lamantea E.,
RA Didonato S., Taroni F.;
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bourgeron T., Parfait B., Chretien D., Rotig A., Munnich A., Rustin P.;
RT "Complete cDNA sequence of the human fumarase.";
RL Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Uterus;
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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 44-510.
RC TISSUE=Liver;
RX PubMed=3828494; DOI=10.1007/bf01116247;
RA Kinsella B.T., Doonan S.;
RT "Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human
RT liver.";
RL Biosci. Rep. 6:921-929(1986).
RN [8]
RP PROTEIN SEQUENCE OF 269-286 AND 422-444, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [9]
RP PARTIAL PROTEIN SEQUENCE (ISOFORM CYTOPLASMIC), CLEAVAGE OF INITIATOR
RP METHIONINE (ISOFORM CYTOPLASMIC), ALTERNATIVE INITIATION (ISOFORMS
RP MITOCHONDRIAL AND CYTOPLASMIC), AND SUBCELLULAR LOCATION (ISOFORMS
RP MITOCHONDRIAL AND CYTOPLASMIC).
RX PubMed=27037871; DOI=10.1111/tra.12397;
RA Dik E., Naamati A., Asraf H., Lehming N., Pines O.;
RT "Human fumarate hydratase is dual localized by an alternative transcription
RT initiation mechanism.";
RL Traffic 17:720-732(2016).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-80; LYS-94; LYS-256 AND
RP LYS-292, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [11]
RP FUNCTION (ISOFORM CYTOPLASMIC), AND SUBCELLULAR LOCATION (ISOFORM
RP CYTOPLASMIC).
RX PubMed=20231875; DOI=10.1371/journal.pbio.1000328;
RA Yogev O., Yogev O., Singer E., Shaulian E., Goldberg M., Fox T.D.,
RA Pines O.;
RT "Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear
RT component of the DNA damage response.";
RL PLoS Biol. 8:E1000328-E1000328(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=22509282; DOI=10.1371/journal.pone.0034237;
RA von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.;
RT "Assessment of the red cell proteome of young patients with unexplained
RT hemolytic anemia by two-dimensional differential in-gel electrophoresis
RT (DIGE).";
RL PLoS ONE 7:E34237-E34237(2012).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-90, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-366, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH H2AZ1,
RP PHOSPHORYLATION AT THR-236, MUTAGENESIS OF SER-46; THR-147; SER-187 AND
RP THR-236, AND CHARACTERIZATION OF VARIANT HLRCC HIS-233.
RX PubMed=26237645; DOI=10.1038/ncb3209;
RA Jiang Y., Qian X., Shen J., Wang Y., Li X., Liu R., Xia Y., Chen Q.,
RA Peng G., Lin S.Y., Lu Z.;
RT "Local generation of fumarate promotes DNA repair through inhibition of
RT histone H3 demethylation.";
RL Nat. Cell Biol. 17:1158-1168(2015).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [19]
RP CATALYTIC ACTIVITY, AND INVOLVEMENT IN HLRCC.
RX PubMed=30718813; DOI=10.1038/s41589-018-0217-y;
RA Kulkarni R.A., Bak D.W., Wei D., Bergholtz S.E., Briney C.A., Shrimp J.H.,
RA Alpsoy A., Thorpe A.L., Bavari A.E., Crooks D.R., Levy M., Florens L.,
RA Washburn M.P., Frizzell N., Dykhuizen E.C., Weerapana E., Linehan W.M.,
RA Meier J.L.;
RT "A chemoproteomic portrait of the oncometabolite fumarate.";
RL Nat. Chem. Biol. 15:391-400(2019).
RN [20] {ECO:0007744|PDB:3E04}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 44-510, AND SUBUNIT.
RX PubMed=21445611; DOI=10.1007/s10545-011-9294-8;
RA Picaud S., Kavanagh K.L., Yue W.W., Lee W.H., Muller-Knapp S., Gileadi O.,
RA Sacchettini J., Oppermann U.;
RT "Structural basis of fumarate hydratase deficiency.";
RL J. Inherit. Metab. Dis. 34:671-676(2011).
RN [21] {ECO:0007744|PDB:5D6B}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 49-510.
RX PubMed=24419633; DOI=10.1107/s2053230x13033955;
RA Pereira de Padua R.A., Nonato M.C.;
RT "Cloning, expression, purification, crystallization and preliminary X-ray
RT diffraction analysis of recombinant human fumarase.";
RL Acta Crystallogr. F 70:120-122(2014).
RN [22] {ECO:0007744|PDB:5UPP}
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 45-510, FUNCTION, CATALYTIC
RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=30761759; DOI=10.1111/febs.14782;
RA Ajalla Aleixo M.A., Rangel V.L., Rustiguel J.K., de Padua R.A.P.,
RA Nonato M.C.;
RT "Structural, biochemical and biophysical characterization of recombinant
RT human fumarate hydratase.";
RL FEBS J. 286:1925-1940(2019).
RN [23]
RP VARIANT FMRD THR-308.
RA Coughlin E.M., Chalmers R.A., Slaugenhaupt S.A., Gusella J.F., Shih V.E.,
RA Ramesh V.;
RT "Identification of a molecular defect in a fumarase deficient patient and
RT mapping of the fumarase gene.";
RL Am. J. Hum. Genet. 53:A896-A896(1993).
RN [24]
RP VARIANT HLRCC GLN-362.
RX PubMed=8200987; DOI=10.1172/jci117261;
RA Bourgeron T., Chretien D., Poggi-Bach J., Doonan S., Rabier D., Letouze P.,
RA Munnich A., Roetig A., Landrieu P., Rustin P.;
RT "Mutation of the fumarase gene in two siblings with progressive
RT encephalopathy and fumarase deficiency.";
RL J. Clin. Invest. 93:2514-2518(1994).
RN [25]
RP VARIANTS FMRD ARG-230; THR-308; CYS-312 AND VAL-425.
RX PubMed=9635293; DOI=10.1006/mgme.1998.2684;
RA Coughlin E.M., Christensen E., Kunz P.L., Krishnamoorthy K.S., Walker V.,
RA Dennis N.R., Chalmers R.A., Elpeleg O.N., Whelan D., Pollitt R.J.,
RA Ramesh V., Mandell R., Shih V.E.;
RT "Molecular analysis and prenatal diagnosis of human fumarase deficiency.";
RL Mol. Genet. Metab. 63:254-262(1998).
RN [26]
RP VARIANTS HLRCC THR-107; PRO-117; ARG-180; ARG-185; ARG-230; HIS-233;
RP VAL-282 AND ARG-328.
RX PubMed=11865300; DOI=10.1038/ng849;
RA Tomlinson I.P.M., Alam N.A., Rowan A.J., Barclay E., Jaeger E.E.M.,
RA Kelsell D., Leigh I., Gorman P., Lamlum H., Rahman S., Roylance R.R.,
RA Olpin S., Bevan S., Barker K., Hearle N., Houlston R.S., Kiuru M.,
RA Lehtonen R., Karhu A., Vilkki S., Laiho P., Eklund C., Vierimaa O.,
RA Aittomaeki K., Hietala M., Sistonen P., Paetau A., Salovaara R., Herva R.,
RA Launonen V., Aaltonen L.A.;
RT "Germline mutations in FH predispose to dominantly inherited uterine
RT fibroids, skin leiomyomata and papillary renal cell cancer.";
RL Nat. Genet. 30:406-410(2002).
CC -!- FUNCTION: Catalyzes the reversible stereospecific interconversion of
CC fumarate to L-malate (PubMed:30761759). Experiments in other species
CC have demonstrated that specific isoforms of this protein act in defined
CC pathways and favor one direction over the other (Probable).
CC {ECO:0000269|PubMed:30761759, ECO:0000305}.
CC -!- FUNCTION: [Isoform Mitochondrial]: Catalyzes the hydration of fumarate
CC to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a
CC transition step in the production of energy in the form of NADH.
CC {ECO:0000250|UniProtKB:P10173}.
CC -!- FUNCTION: [Isoform Cytoplasmic]: Catalyzes the dehydration of L-malate
CC to fumarate (By similarity). Fumarate metabolism in the cytosol plays a
CC role during urea cycle and arginine metabolism; fumarate being a by-
CC product of the urea cycle and amino-acid catabolism (By similarity).
CC Also plays a role in DNA repair by promoting non-homologous end-joining
CC (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage
CC and phosphorylation by PRKDC, translocates to the nucleus and
CC accumulates at DNA double-strand breaks (DSBs): acts by catalyzing
CC formation of fumarate, an inhibitor of KDM2B histone demethylase
CC activity, resulting in enhanced dimethylation of histone H3 'Lys-36'
CC (H3K36me2) (PubMed:26237645). {ECO:0000250|UniProtKB:P97807,
CC ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2;
CC Evidence={ECO:0000269|PubMed:30761759, ECO:0000305|PubMed:30718813};
CC -!- CATALYTIC ACTIVITY: [Isoform Mitochondrial]:
CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2;
CC Evidence={ECO:0000250|UniProtKB:P10173};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:12462;
CC Evidence={ECO:0000250|UniProtKB:P10173};
CC -!- CATALYTIC ACTIVITY: [Isoform Cytoplasmic]:
CC Reaction=(S)-malate = fumarate + H2O; Xref=Rhea:RHEA:12460,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15589, ChEBI:CHEBI:29806; EC=4.2.1.2;
CC Evidence={ECO:0000250|UniProtKB:P97807};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12461;
CC Evidence={ECO:0000250|UniProtKB:P97807};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.4 mM for L-malate (at pH 8.5) {ECO:0000269|PubMed:30761759};
CC KM=0.2 mM for fumarate (at pH 8.5) {ECO:0000269|PubMed:30761759};
CC Note=kcat is 280 sec(-1) with L-malate (at pH 8.5) (PubMed:30761759).
CC kcat is 170 sec(-1) with fumarate (at pH 8.5) (PubMed:30761759).
CC {ECO:0000269|PubMed:30761759};
CC pH dependence:
CC Optimum pH is 7.5-8.0. {ECO:0000269|PubMed:30761759};
CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate
CC from fumarate: step 1/1. {ECO:0000250|UniProtKB:P10173}.
CC -!- SUBUNIT: Homotetramer (PubMed:21445611, PubMed:30761759). Interacts
CC with H2AZ1 (PubMed:26237645). {ECO:0000269|PubMed:21445611,
CC ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:30761759}.
CC -!- INTERACTION:
CC P07954; Q9H6J7-2: C11orf49; NbExp=3; IntAct=EBI-1050358, EBI-13328871;
CC P07954; Q68D86: CCDC102B; NbExp=3; IntAct=EBI-1050358, EBI-10171570;
CC P07954; Q2TAC2-2: CCDC57; NbExp=3; IntAct=EBI-1050358, EBI-10961624;
CC P07954; Q14129: DGCR6; NbExp=3; IntAct=EBI-1050358, EBI-12206931;
CC P07954; Q9NQT4: EXOSC5; NbExp=3; IntAct=EBI-1050358, EBI-371876;
CC P07954; P0C0S5: H2AZ1; NbExp=5; IntAct=EBI-1050358, EBI-1199859;
CC P07954; Q8WZ60: KLHL6; NbExp=3; IntAct=EBI-1050358, EBI-6426464;
CC P07954; Q03252: LMNB2; NbExp=3; IntAct=EBI-1050358, EBI-2830427;
CC P07954; P11309: PIM1; NbExp=3; IntAct=EBI-1050358, EBI-696621;
CC P07954; O15160: POLR1C; NbExp=3; IntAct=EBI-1050358, EBI-1055079;
CC P07954; P21673: SAT1; NbExp=3; IntAct=EBI-1050358, EBI-711613;
CC P07954; O14787-2: TNPO2; NbExp=3; IntAct=EBI-1050358, EBI-12076664;
CC P07954; Q6DKK2: TTC19; NbExp=3; IntAct=EBI-1050358, EBI-948354;
CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion
CC {ECO:0000269|PubMed:27037871}.
CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm, cytosol
CC {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:22509282,
CC ECO:0000269|PubMed:26237645, ECO:0000269|PubMed:27037871}. Nucleus
CC {ECO:0000269|PubMed:20231875, ECO:0000269|PubMed:26237645}. Chromosome
CC {ECO:0000269|PubMed:26237645}. Note=Translocates to the nucleus in
CC response to DNA damage: localizes to DNA double-strand breaks (DSBs)
CC following phosphorylation by PRKDC. {ECO:0000269|PubMed:26237645}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Mitochondrial {ECO:0000303|PubMed:27037871};
CC IsoId=P07954-1; Sequence=Displayed;
CC Name=Cytoplasmic {ECO:0000303|PubMed:27037871};
CC IsoId=P07954-2; Sequence=VSP_018965;
CC -!- TISSUE SPECIFICITY: Expressed in red blood cells; underexpressed in red
CC blood cells (cytoplasm) of patients with hereditary non-spherocytic
CC hemolytic anemia of unknown etiology. {ECO:0000269|PubMed:22509282}.
CC -!- PTM: [Isoform Cytoplasmic]: Phosphorylation at Thr-236 by PRKDC in
CC response to DNA damage promotes translocation to the nucleus and
CC recruitment to DNA double-strand breaks (DSBs).
CC {ECO:0000269|PubMed:26237645}.
CC -!- DISEASE: Fumarase deficiency (FMRD) [MIM:606812]: A severe autosomal
CC recessive metabolic disorder characterized by early-onset hypotonia,
CC profound psychomotor retardation, and brain abnormalities, such as
CC agenesis of the corpus callosum, gyral defects, and ventriculomegaly.
CC Many patients show neonatal distress, metabolic acidosis, and/or
CC encephalopathy. {ECO:0000269|PubMed:9635293, ECO:0000269|Ref.23}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: [Isoform Cytoplasmic]: Hereditary leiomyomatosis and renal
CC cell cancer (HLRCC) [MIM:150800]: A disorder characterized by
CC predisposition to cutaneous and uterine leiomyomas, and papillary type
CC 2 renal cancer which occurs in about 20% of patients.
CC {ECO:0000269|PubMed:11865300, ECO:0000269|PubMed:26237645,
CC ECO:0000269|PubMed:8200987}. Note=The disease is caused by variants
CC affecting the gene represented in this entry. Isoform Cytoplasmic:
CC HLRCC is probably caused by an accumulation of fumarate
CC (PubMed:30718813). Accumulation of fumarate coupled with protonation
CC promotes the formation of non-enzymatic post-translational modification
CC cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as
CC SMARCC1 (PubMed:30718813). {ECO:0000269|PubMed:30718813}.
CC -!- MISCELLANEOUS: There are 2 substrate-binding sites: the catalytic A
CC site, and the non-catalytic B site that may play a role in the transfer
CC of substrate or product between the active site and the solvent.
CC Alternatively, the B site may bind allosteric effectors.
CC {ECO:0000250|UniProtKB:P05042, ECO:0000250|UniProtKB:P9WN93}.
CC -!- SIMILARITY: Belongs to the class-II fumarase/aspartase family. Fumarase
CC subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=TCA Cycle Gene Mutation Database;
CC URL="https://databases.lovd.nl/shared/genes/FH";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FHID40573ch1q42.html";
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DR EMBL; U59309; AAB66354.1; -; mRNA.
DR EMBL; U48857; AAD00071.1; -; mRNA.
DR EMBL; BT009839; AAP88841.1; -; mRNA.
DR EMBL; AK312415; BAG35325.1; -; mRNA.
DR EMBL; CH471098; EAW70092.1; -; Genomic_DNA.
DR EMBL; BC003108; AAH03108.1; -; mRNA.
DR EMBL; BC017444; AAH17444.1; -; mRNA.
DR EMBL; M15502; AAA52483.1; -; mRNA.
DR CCDS; CCDS1617.1; -. [P07954-1]
DR PIR; S06213; UFHUM.
DR RefSeq; NP_000134.2; NM_000143.3. [P07954-1]
DR PDB; 3E04; X-ray; 1.95 A; A/B/C/D=44-510.
DR PDB; 5D6B; X-ray; 2.10 A; A=49-510.
DR PDB; 5UPP; X-ray; 1.80 A; A/B=45-510.
DR PDB; 6EBT; X-ray; 2.30 A; A/B=45-510.
DR PDB; 6V8F; X-ray; 2.30 A; A/B=45-510.
DR PDB; 6VBE; X-ray; 1.90 A; A/B=45-510.
DR PDB; 7LUB; X-ray; 2.15 A; A/B=45-510.
DR PDBsum; 3E04; -.
DR PDBsum; 5D6B; -.
DR PDBsum; 5UPP; -.
DR PDBsum; 6EBT; -.
DR PDBsum; 6V8F; -.
DR PDBsum; 6VBE; -.
DR PDBsum; 7LUB; -.
DR AlphaFoldDB; P07954; -.
DR SMR; P07954; -.
DR BioGRID; 108562; 168.
DR DIP; DIP-46920N; -.
DR IntAct; P07954; 36.
DR MINT; P07954; -.
DR STRING; 9606.ENSP00000355518; -.
DR GlyGen; P07954; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P07954; -.
DR MetOSite; P07954; -.
DR PhosphoSitePlus; P07954; -.
DR SwissPalm; P07954; -.
DR BioMuta; FH; -.
DR DMDM; 1730117; -.
DR REPRODUCTION-2DPAGE; IPI00296053; -.
DR SWISS-2DPAGE; P07954; -.
DR UCD-2DPAGE; P07954; -.
DR EPD; P07954; -.
DR jPOST; P07954; -.
DR MassIVE; P07954; -.
DR MaxQB; P07954; -.
DR PaxDb; P07954; -.
DR PeptideAtlas; P07954; -.
DR PRIDE; P07954; -.
DR ProteomicsDB; 52052; -. [P07954-1]
DR ProteomicsDB; 52053; -. [P07954-2]
DR TopDownProteomics; P07954-2; -. [P07954-2]
DR Antibodypedia; 34701; 679 antibodies from 42 providers.
DR DNASU; 2271; -.
DR Ensembl; ENST00000366560.4; ENSP00000355518.4; ENSG00000091483.8. [P07954-1]
DR GeneID; 2271; -.
DR KEGG; hsa:2271; -.
DR MANE-Select; ENST00000366560.4; ENSP00000355518.4; NM_000143.4; NP_000134.2.
DR UCSC; uc001hyx.4; human. [P07954-1]
DR CTD; 2271; -.
DR DisGeNET; 2271; -.
DR GeneCards; FH; -.
DR GeneReviews; FH; -.
DR HGNC; HGNC:3700; FH.
DR HPA; ENSG00000091483; Tissue enhanced (liver).
DR MalaCards; FH; -.
DR MIM; 136850; gene.
DR MIM; 150800; phenotype.
DR MIM; 606812; phenotype.
DR neXtProt; NX_P07954; -.
DR OpenTargets; ENSG00000091483; -.
DR Orphanet; 24; Fumaric aciduria.
DR Orphanet; 523; Hereditary leiomyomatosis and renal cell cancer.
DR Orphanet; 29072; Hereditary pheochromocytoma-paraganglioma.
DR PharmGKB; PA28139; -.
DR VEuPathDB; HostDB:ENSG00000091483; -.
DR eggNOG; KOG1317; Eukaryota.
DR GeneTree; ENSGT00950000183122; -.
DR HOGENOM; CLU_021594_4_1_1; -.
DR InParanoid; P07954; -.
DR OMA; HDSMGEV; -.
DR OrthoDB; 507784at2759; -.
DR PhylomeDB; P07954; -.
DR TreeFam; TF300441; -.
DR BioCyc; MetaCyc:ENSG00000091483-MON; -.
DR BRENDA; 4.2.1.2; 2681.
DR PathwayCommons; P07954; -.
DR Reactome; R-HSA-71403; Citric acid cycle (TCA cycle).
DR SignaLink; P07954; -.
DR SIGNOR; P07954; -.
DR UniPathway; UPA00223; UER01007.
DR BioGRID-ORCS; 2271; 130 hits in 1082 CRISPR screens.
DR EvolutionaryTrace; P07954; -.
DR GenomeRNAi; 2271; -.
DR Pharos; P07954; Tbio.
DR PRO; PR:P07954; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P07954; protein.
DR Bgee; ENSG00000091483; Expressed in heart right ventricle and 210 other tissues.
DR ExpressionAtlas; P07954; baseline and differential.
DR Genevisible; P07954; HS.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0045239; C:tricarboxylic acid cycle enzyme complex; IEA:InterPro.
DR GO; GO:0004333; F:fumarate hydratase activity; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IPI:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0006106; P:fumarate metabolic process; IDA:UniProtKB.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR GO; GO:0006108; P:malate metabolic process; IDA:UniProtKB.
DR GO; GO:0000415; P:negative regulation of histone H3-K36 methylation; IDA:UniProtKB.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:2001034; P:positive regulation of double-strand break repair via nonhomologous end joining; IDA:UniProtKB.
DR GO; GO:0000821; P:regulation of arginine metabolic process; ISS:UniProtKB.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IBA:GO_Central.
DR GO; GO:0000050; P:urea cycle; ISS:UniProtKB.
DR CDD; cd01362; Fumarase_classII; 1.
DR Gene3D; 1.10.275.10; -; 1.
DR HAMAP; MF_00743; FumaraseC; 1.
DR InterPro; IPR005677; Fum_hydII.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR018951; Fumarase_C_C.
DR InterPro; IPR020557; Fumarate_lyase_CS.
DR InterPro; IPR000362; Fumarate_lyase_fam.
DR InterPro; IPR022761; Fumarate_lyase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR PANTHER; PTHR11444; PTHR11444; 1.
DR Pfam; PF10415; FumaraseC_C; 1.
DR Pfam; PF00206; Lyase_1; 1.
DR PRINTS; PR00149; FUMRATELYASE.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR00979; fumC_II; 1.
DR PROSITE; PS00163; FUMARATE_LYASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation; Chromosome; Cytoplasm;
KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; Lyase;
KW Mitochondrion; Nucleus; Phosphoprotein; Reference proteome;
KW Transit peptide; Tricarboxylic acid cycle; Tumor suppressor.
FT TRANSIT 1..44
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:P10173"
FT CHAIN 45..510
FT /note="Fumarate hydratase, mitochondrial"
FT /id="PRO_0000010319"
FT ACT_SITE 235
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT ACT_SITE 365
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 145..147
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 176..179
FT /ligand="substrate"
FT /note="in site B"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 186..188
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT BINDING 234
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 366
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT BINDING 371..373
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WN93"
FT SITE 378
FT /note="Important for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:P05042"
FT MOD_RES 61
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 61
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 66
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 66
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 80
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 80
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 85
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 90
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 94
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 115
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 115
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 122
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 122
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 213
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 223
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 223
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 236
FT /note="Phosphothreonine; by PRKDC"
FT /evidence="ECO:0000269|PubMed:26237645"
FT MOD_RES 256
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 292
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 292
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 366
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 467
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 473
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT MOD_RES 502
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P97807"
FT VAR_SEQ 1..43
FT /note="Missing (in isoform Cytoplasmic)"
FT /evidence="ECO:0000269|PubMed:27037871"
FT /id="VSP_018965"
FT VARIANT 107
FT /note="N -> T (in HLRCC; dbSNP:rs121913121)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013497"
FT VARIANT 117
FT /note="A -> P (in HLRCC; dbSNP:rs886039363)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013498"
FT VARIANT 180
FT /note="H -> R (in HLRCC; dbSNP:rs863224015)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013499"
FT VARIANT 185
FT /note="Q -> R (in HLRCC; dbSNP:rs779707997)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013500"
FT VARIANT 230
FT /note="K -> R (in FMRD and HLRCC; dbSNP:rs752232718)"
FT /evidence="ECO:0000269|PubMed:11865300,
FT ECO:0000269|PubMed:9635293"
FT /id="VAR_002445"
FT VARIANT 233
FT /note="R -> H (in HLRCC; catalytically inactive mutant;
FT abolished ability to promote DNA repair;
FT dbSNP:rs121913123)"
FT /evidence="ECO:0000269|PubMed:11865300,
FT ECO:0000269|PubMed:26237645"
FT /id="VAR_013501"
FT VARIANT 282
FT /note="G -> V (in HLRCC; dbSNP:rs935002190)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013502"
FT VARIANT 308
FT /note="A -> T (in FMRD; dbSNP:rs121913118)"
FT /evidence="ECO:0000269|PubMed:9635293, ECO:0000269|Ref.23"
FT /id="VAR_002446"
FT VARIANT 312
FT /note="F -> C (in FMRD; dbSNP:rs1553341046)"
FT /evidence="ECO:0000269|PubMed:9635293"
FT /id="VAR_002447"
FT VARIANT 328
FT /note="M -> R (in HLRCC)"
FT /evidence="ECO:0000269|PubMed:11865300"
FT /id="VAR_013503"
FT VARIANT 362
FT /note="E -> Q (in HLRCC; dbSNP:rs121913119)"
FT /evidence="ECO:0000269|PubMed:8200987"
FT /id="VAR_081606"
FT VARIANT 425
FT /note="D -> V (in FMRD)"
FT /evidence="ECO:0000269|PubMed:9635293"
FT /id="VAR_002448"
FT MUTAGEN 46
FT /note="S->A: Does not affect phosphorylation by PRKDC."
FT /evidence="ECO:0000269|PubMed:26237645"
FT MUTAGEN 147
FT /note="T->A: Does not affect phosphorylation by PRKDC."
FT /evidence="ECO:0000269|PubMed:26237645"
FT MUTAGEN 187
FT /note="S->A: Does not affect phosphorylation by PRKDC."
FT /evidence="ECO:0000269|PubMed:26237645"
FT MUTAGEN 236
FT /note="T->A: Abolished interaction with H2AZ1 and
FT localization to chromatin in response to DNA damage."
FT /evidence="ECO:0000269|PubMed:26237645"
FT MUTAGEN 236
FT /note="T->D: Phosphomimetic mutant; promotes interaction
FT with H2AZ1, leading to increased localization to chromatin
FT in response to DNA damage."
FT /evidence="ECO:0000269|PubMed:26237645"
FT STRAND 50..55
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 58..63
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 70..78
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 84..86
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 90..107
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 108..110
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 114..128
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 129..132
FT /evidence="ECO:0007829|PDB:6VBE"
FT HELIX 133..135
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 139..142
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 147..164
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 177..181
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 182..184
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 187..189
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 190..205
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 207..224
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 225..227
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 229..234
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 237..243
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 244..264
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 267..270
FT /evidence="ECO:0007829|PDB:5UPP"
FT TURN 277..279
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 289..301
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 311..316
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 319..345
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 349..352
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 366..368
FT /evidence="ECO:0007829|PDB:3E04"
FT HELIX 375..399
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 409..433
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 435..437
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 442..451
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 454..459
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 460..463
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 465..478
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 482..488
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 494..500
FT /evidence="ECO:0007829|PDB:5UPP"
FT HELIX 503..505
FT /evidence="ECO:0007829|PDB:5UPP"
FT STRAND 506..508
FT /evidence="ECO:0007829|PDB:5UPP"
FT INIT_MET P07954-2:1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:27037871"
SQ SEQUENCE 510 AA; 54637 MW; 86F91F95DC046F64 CRC64;
MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF RIEYDTFGEL
KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI
MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH
VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV
PLTLGQEFSG YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL
TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR SGLGELILPE
NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN GHFELNVFKP MMIKNVLHSA
RLLGDASVSF TENCVVGIQA NTERINKLMN ESLMLVTALN PHIGYDKAAK IAKTAHKNGS
TLKETAIELG YLTAEQFDEW VKPKDMLGPK
