L2HDH_HUMAN
ID L2HDH_HUMAN Reviewed; 463 AA.
AC Q9H9P8; Q9BRR1;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 3.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=L-2-hydroxyglutarate dehydrogenase, mitochondrial;
DE EC=1.1.99.2;
DE AltName: Full=Duranin;
DE Flags: Precursor;
GN Name=L2HGDH; Synonyms=C14orf160;
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] (ISOFORM 1), VARIANTS L2HGA GLU-81 AND ASP-176,
RP AND CHARACTERIZATION OF VARIANTS L2HGA GLU-81 AND ASP-176.
RX PubMed=15548604; DOI=10.1073/pnas.0404840101;
RA Rzem R., Veiga-da-Cunha M., Noel G., Goffette S., Nassogne M.-C.,
RA Tabarki B., Schoeller C., Marquardt T., Vikkula M., van Schaftingen E.;
RT "A gene encoding a putative FAD-dependent L-2-hydroxyglutarate
RT dehydrogenase is mutated in L-2-hydroxyglutaric aciduria.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:16849-16854(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ARG-18.
RC TISSUE=Placenta;
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 CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION,
RP AND COFACTOR.
RX PubMed=16005139; DOI=10.1016/j.biochi.2005.06.005;
RA Rzem R., Van Schaftingen E., Veiga-da-Cunha M.;
RT "The gene mutated in L-2-hydroxyglutaric aciduria encodes L-2-
RT hydroxyglutarate dehydrogenase.";
RL Biochimie 88:113-116(2006).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-155, AND IDENTIFICATION BY MASS
RP 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 [7]
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 [8]
RP IDENTIFICATION BY 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 [9]
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 [10]
RP VARIANTS L2HGA ASP-55; TYR-98 AND LEU-302, AND TISSUE SPECIFICITY.
RX PubMed=15385440; DOI=10.1093/hmg/ddh300;
RA Topcu M., Jobard F., Halliez S., Coskun T., Yalcinkayal C., Gerceker F.O.,
RA Wanders R.J.A., Prud'homme J.-F., Lathrop M., Ozguc M., Fischer J.;
RT "L-2-hydroxyglutaric aciduria: identification of a mutant gene C14orf160,
RT localized on chromosome 14q22.1.";
RL Hum. Mol. Genet. 13:2803-2811(2004).
RN [11]
RP VARIANTS L2HGA ARG-57; ARG-98; LEU-302 AND PRO-434, AND VARIANTS ARG-18 AND
RP PHE-178.
RX PubMed=16134148; DOI=10.1002/humu.9373;
RA Vilarinho L., Cardoso M.L., Gaspar P., Barbot C., Azevedo L., Diogo L.,
RA Santos M., Carrilho I., Fineza I., Kok F., Chorao R., Alegria P.,
RA Martins E., Teixeira J., Cabral-Fernandes H., Verhoeven N.M.,
RA Salomons G.S., Santorelli F.M., Cabral P., Amorim A., Jakobs C.;
RT "Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of
RT Portuguese origin.";
RL Hum. Mutat. 26:395-396(2005).
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-2-hydroxyglutarate + A = 2-oxoglutarate + AH2;
CC Xref=Rhea:RHEA:21252, ChEBI:CHEBI:13193, ChEBI:CHEBI:16782,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:17499; EC=1.1.99.2;
CC Evidence={ECO:0000269|PubMed:16005139};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:16005139};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=800 uM for L-2-hydroxyglutarate {ECO:0000269|PubMed:16005139};
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16005139}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H9P8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H9P8-2; Sequence=VSP_017662, VSP_017663;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in brain, testis
CC and muscle. Expressed to a lower extent in lymphocytes, fibroblasts,
CC keratinocytes, placenta, bladder, small intestine, liver and bone
CC marrow. {ECO:0000269|PubMed:15385440}.
CC -!- DISEASE: L-2-hydroxyglutaric aciduria (L2HGA) [MIM:236792]: A rare
CC autosomal recessive disorder clinically characterized by mild
CC psychomotor delay in the first years of life, followed by progressive
CC cerebellar ataxia, dysarthria and moderate to severe intellectual
CC disability. Diagnosis is based on the presence of an excess of L-2-
CC hydroxyglutaric acid in urine, blood and cerebrospinal fluid.
CC {ECO:0000269|PubMed:15385440, ECO:0000269|PubMed:15548604,
CC ECO:0000269|PubMed:16134148}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Was named 'duranin' in honor of Marinus Duran, who first
CC described L-2-hydroxyglutaric aciduria.
CC -!- SIMILARITY: Belongs to the L2HGDH family. {ECO:0000305}.
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DR EMBL; AY757363; AAV52330.1; -; mRNA.
DR EMBL; AK022680; BAB14174.1; -; mRNA.
DR EMBL; AL109758; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL359397; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006117; AAH06117.1; -; mRNA.
DR CCDS; CCDS9698.1; -. [Q9H9P8-1]
DR RefSeq; NP_079160.1; NM_024884.2. [Q9H9P8-1]
DR RefSeq; XP_005268132.1; XM_005268075.4. [Q9H9P8-1]
DR AlphaFoldDB; Q9H9P8; -.
DR SMR; Q9H9P8; -.
DR BioGRID; 123016; 70.
DR IntAct; Q9H9P8; 18.
DR STRING; 9606.ENSP00000267436; -.
DR GlyGen; Q9H9P8; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9H9P8; -.
DR PhosphoSitePlus; Q9H9P8; -.
DR SwissPalm; Q9H9P8; -.
DR BioMuta; L2HGDH; -.
DR DMDM; 317373422; -.
DR EPD; Q9H9P8; -.
DR jPOST; Q9H9P8; -.
DR MassIVE; Q9H9P8; -.
DR MaxQB; Q9H9P8; -.
DR PaxDb; Q9H9P8; -.
DR PeptideAtlas; Q9H9P8; -.
DR PRIDE; Q9H9P8; -.
DR ProteomicsDB; 81345; -. [Q9H9P8-1]
DR ProteomicsDB; 81346; -. [Q9H9P8-2]
DR Antibodypedia; 47264; 190 antibodies from 26 providers.
DR DNASU; 79944; -.
DR Ensembl; ENST00000267436.9; ENSP00000267436.4; ENSG00000087299.12. [Q9H9P8-1]
DR Ensembl; ENST00000421284.7; ENSP00000405559.3; ENSG00000087299.12. [Q9H9P8-1]
DR GeneID; 79944; -.
DR KEGG; hsa:79944; -.
DR MANE-Select; ENST00000267436.9; ENSP00000267436.4; NM_024884.3; NP_079160.1.
DR UCSC; uc001wxu.4; human. [Q9H9P8-1]
DR CTD; 79944; -.
DR DisGeNET; 79944; -.
DR GeneCards; L2HGDH; -.
DR HGNC; HGNC:20499; L2HGDH.
DR HPA; ENSG00000087299; Low tissue specificity.
DR MalaCards; L2HGDH; -.
DR MIM; 236792; phenotype.
DR MIM; 609584; gene.
DR neXtProt; NX_Q9H9P8; -.
DR OpenTargets; ENSG00000087299; -.
DR Orphanet; 79314; L-2-hydroxyglutaric aciduria.
DR PharmGKB; PA134971279; -.
DR VEuPathDB; HostDB:ENSG00000087299; -.
DR eggNOG; KOG2665; Eukaryota.
DR GeneTree; ENSGT00490000043421; -.
DR HOGENOM; CLU_024775_0_0_1; -.
DR InParanoid; Q9H9P8; -.
DR OMA; GVHFTRM; -.
DR OrthoDB; 1310154at2759; -.
DR PhylomeDB; Q9H9P8; -.
DR TreeFam; TF105922; -.
DR BRENDA; 1.1.99.2; 2681.
DR PathwayCommons; Q9H9P8; -.
DR Reactome; R-HSA-880009; Interconversion of 2-oxoglutarate and 2-hydroxyglutarate.
DR SABIO-RK; Q9H9P8; -.
DR SignaLink; Q9H9P8; -.
DR BioGRID-ORCS; 79944; 11 hits in 1081 CRISPR screens.
DR ChiTaRS; L2HGDH; human.
DR GeneWiki; L2HGDH; -.
DR GenomeRNAi; 79944; -.
DR Pharos; Q9H9P8; Tbio.
DR PRO; PR:Q9H9P8; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9H9P8; protein.
DR Bgee; ENSG00000087299; Expressed in muscle of leg and 137 other tissues.
DR ExpressionAtlas; Q9H9P8; baseline and differential.
DR Genevisible; Q9H9P8; HS.
DR GO; GO:0016021; C:integral component of membrane; IDA:HGNC-UCL.
DR GO; GO:0031305; C:integral component of mitochondrial inner membrane; NAS:HGNC-UCL.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HGNC-UCL.
DR GO; GO:0003973; F:(S)-2-hydroxy-acid oxidase activity; IBA:GO_Central.
DR GO; GO:0047545; F:2-hydroxyglutarate dehydrogenase activity; IDA:HGNC-UCL.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; IDA:HGNC-UCL.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR006076; FAD-dep_OxRdtase.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01266; DAO; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Disease variant; FAD; Flavoprotein;
KW Mitochondrion; Oxidoreductase; Reference proteome; Transit peptide.
FT TRANSIT 1..51
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 52..463
FT /note="L-2-hydroxyglutarate dehydrogenase, mitochondrial"
FT /id="PRO_0000228129"
FT MOD_RES 104
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q91YP0"
FT MOD_RES 155
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 173
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q91YP0"
FT VAR_SEQ 400
FT /note="G -> QVAVRGPSWLWQQPMKVSDNNIYCFLWRCFALLLTGSTCSFK (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017662"
FT VAR_SEQ 401..463
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017663"
FT VARIANT 18
FT /note="L -> R (in dbSNP:rs2275591)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:16134148"
FT /id="VAR_025681"
FT VARIANT 33
FT /note="R -> S (in dbSNP:rs35710558)"
FT /id="VAR_057808"
FT VARIANT 55
FT /note="G -> D (in L2HGA; dbSNP:rs118204021)"
FT /evidence="ECO:0000269|PubMed:15385440"
FT /id="VAR_025682"
FT VARIANT 57
FT /note="G -> R (in L2HGA; dbSNP:rs199690954)"
FT /evidence="ECO:0000269|PubMed:16134148"
FT /id="VAR_025683"
FT VARIANT 81
FT /note="K -> E (in L2HGA; alters protein processing and
FT abolishes catalytic activity; dbSNP:rs970541687)"
FT /evidence="ECO:0000269|PubMed:15548604"
FT /id="VAR_025684"
FT VARIANT 98
FT /note="H -> R (in L2HGA; dbSNP:rs267607206)"
FT /evidence="ECO:0000269|PubMed:16134148"
FT /id="VAR_025685"
FT VARIANT 98
FT /note="H -> Y (in L2HGA)"
FT /evidence="ECO:0000269|PubMed:15385440"
FT /id="VAR_025686"
FT VARIANT 176
FT /note="E -> D (in L2HGA; alters protein processing and
FT abolishes catalytic activity)"
FT /evidence="ECO:0000269|PubMed:15548604"
FT /id="VAR_025687"
FT VARIANT 178
FT /note="Y -> F (in dbSNP:rs770542189)"
FT /evidence="ECO:0000269|PubMed:16134148"
FT /id="VAR_025688"
FT VARIANT 302
FT /note="P -> L (in L2HGA; dbSNP:rs118204020)"
FT /evidence="ECO:0000269|PubMed:15385440,
FT ECO:0000269|PubMed:16134148"
FT /id="VAR_025689"
FT VARIANT 434
FT /note="H -> P (in L2HGA; dbSNP:rs750044734)"
FT /evidence="ECO:0000269|PubMed:16134148"
FT /id="VAR_025690"
SQ SEQUENCE 463 AA; 50316 MW; 1B6BC0C88543B7FF CRC64;
MVPALRYLVG ACGRARGLFA GGSPGACGFA SGRPRPLCGG SRSASTSSFD IVIVGGGIVG
LASARALILR HPSLSIGVLE KEKDLAVHQT GHNSGVIHSG IYYKPESLKA KLCVQGAALL
YEYCQQKGIS YKQCGKLIVA VEQEEIPRLQ ALYEKGLQNG VPGLRLIQQE DIKKKEPYCR
GLMAIDCPHT GIVDYRQVAL SFAQDFQEAG GSVLTNFEVK GIEMAKESPS RSIDGMQYPI
VIKNTKGEEI RCQYVVTCAG LYSDRISELS GCTPDPRIVP FRGDYLLLKP EKCYLVKGNI
YPVPDSRFPF LGVHFTPRMD GSIWLGPNAV LAFKREGYRP FDFSATDVMD IIINSGLIKL
ASQNFSYGVT EMYKACFLGA TVKYLQKFIP EITISDILRG PAGVRAQALD RDGNLVEDFV
FDAGVGDIGN RILHVRNAPS PAATSSIAIS GMIADEVQQR FEL
