D2HDH_HUMAN
ID D2HDH_HUMAN Reviewed; 521 AA.
AC Q8N465; B4E3L6; E7ENP2; Q6IQ24; Q8N5Q8;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 04-APR-2006, sequence version 3.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=D-2-hydroxyglutarate dehydrogenase, mitochondrial;
DE EC=1.1.99.39 {ECO:0000269|PubMed:15070399, ECO:0000269|PubMed:15609246, ECO:0000269|PubMed:16037974, ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826, ECO:0000305|PubMed:16442322};
DE Flags: Precursor;
GN Name=D2HGDH; Synonyms=D2HGD;
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] (ISOFORM 3).
RC TISSUE=Uterus;
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Hippocampus, and 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 [4]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=15070399; DOI=10.1042/bj20031933;
RA Achouri Y., Noel G., Vertommen D., Rider M.H., Veiga-Da-Cunha M.,
RA van Schaftingen E.;
RT "Identification of a dehydrogenase acting on D-2-hydroxyglutarate.";
RL Biochem. J. 381:35-42(2004).
RN [5]
RP VARIANTS D2HGA1 SER-147 AND ALA-444, CHARACTERIZATION OF VARIANTS D2HGA1
RP SER-147 AND ALA-444, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=15609246; DOI=10.1086/427890;
RA Struys E.A., Salomons G.S., Achouri Y., van Schaftingen E., Grosso S.,
RA Craigen W.J., Verhoeven N.M., Jakobs C.;
RT "Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-
RT hydroxyglutaric aciduria.";
RL Am. J. Hum. Genet. 76:358-360(2005).
RN [6]
RP VARIANT D2HGA1 ASP-439, CHARACTERIZATION OF VARIANT D2HGA1 ASP-439,
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16037974; DOI=10.1002/ana.20559;
RA Struys E.A., Korman S.H., Salomons G.S., Darmin P.S., Achouri Y.,
RA van Schaftingen E., Verhoeven N.M., Jakobs C.;
RT "Mutations in phenotypically mild D-2-hydroxyglutaric aciduria.";
RL Ann. Neurol. 58:626-630(2005).
RN [7]
RP VARIANT D2HGA1 TYR-375.
RX PubMed=16081310; DOI=10.1016/j.ymgme.2005.06.005;
RA Misra V.K., Struys E.A., O'brien W., Salomons G.S., Glover T., Jakobs C.,
RA Innis J.W.;
RT "Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric
RT aciduria in monozygotic twins.";
RL Mol. Genet. Metab. 86:200-205(2005).
RN [8]
RP VARIANTS GLY-15 AND VAL-436, AND CATALYTIC ACTIVITY.
RX PubMed=16442322; DOI=10.1016/j.ymgme.2005.12.002;
RA Struys E.A., Verhoeven N.M., Salomons G.S., Berthelot J., Vianay-Saban C.,
RA Chabrier S., Thomas J.A., Tsai A.C.-H., Gibson K.M., Jakobs C.;
RT "D-2-Hydroxyglutaric aciduria in three patients with proven SSADH
RT deficiency: genetic coincidence or a related biochemical epiphenomenon?";
RL Mol. Genet. Metab. 88:53-57(2006).
RN [9]
RP VARIANT D2HGA1 THR-153.
RX PubMed=19169842; DOI=10.1007/s10545-009-0933-2;
RA Haliloglu G., Temucin C.M., Oguz K.K., Celiker A., Coskun T., Sass J.O.,
RA Fischer J., Topcu M.;
RT "Peripheral neuropathy in a patient with D-2-hydroxyglutaric aciduria.";
RL J. Inherit. Metab. Dis. 32:S21-S25(2009).
RN [10]
RP VARIANTS D2HGA1 TRP-109; LYS-127; VAL-131; SER-147; THR-153; VAL-153;
RP 169-GLN--ALA-521 DEL; TYR-172; LEU-189; VAL-205; VAL-231; SER-233; TYR-375;
RP MET-399; 400-TYR--ALA-521 DEL; HIS-419; THR-426; ASP-439; ALA-444; VAL-446
RP AND ARG-477, CHARACTERIZATION OF VARIANTS D2HGA1 TRP-109; VAL-153; TYR-172;
RP 400-TYR--ALA-521 DEL; HIS-419 AND THR-426, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=20020533; DOI=10.1002/humu.21186;
RA Kranendijk M., Struys E.A., Gibson K.M., Wickenhagen W.V., Abdenur J.E.,
RA Buechner J., Christensen E., de Kremer R.D., Errami A., Gissen P.,
RA Gradowska W., Hobson E., Islam L., Korman S.H., Kurczynski T., Maranda B.,
RA Meli C., Rizzo C., Sansaricq C., Trefz F.K., Webster R., Jakobs C.,
RA Salomons G.S.;
RT "Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.";
RL Hum. Mutat. 31:279-283(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.21 ANGSTROMS) OF 51-521 IN COMPLEX WITH
RP D-2-HYDROXYGLUTARATE; D-MALATE; D-LACTATE; L-2-HYDROXYGLUTARATE AND
RP 2-OXOGLUTARATE, FUNCTION, CATALYTIC ACTIVITY, ZINC-BINDING SITES,
RP BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF ARG-386; THR-390; LYS-401;
RP HIS-434; HIS-441; ASN-443; GLU-475 AND HIS-476, CHARACTERIZATION OF
RP VARIANTS D2HGA1 TRP-109; LYS-127; VAL-131; SER-147; THR-153; VAL-153;
RP TYR-172; LEU-189; VAL-205; VAL-231; SER-233; TYR-375; MET-399; HIS-419;
RP THR-426; ASP-439; ALA-444; VAL-446 AND ARG-477, AND CHARACTERIZATION OF
RP VARIANT VAL-436.
RX PubMed=33431826; DOI=10.1038/s41421-020-00227-0;
RA Yang J., Zhu H., Zhang T., Ding J.;
RT "Structure, substrate specificity, and catalytic mechanism of human D-2-
RT HGDH and insights into pathogenicity of disease-associated mutations.";
RL Cell Discov. 7:3-3(2021).
CC -!- FUNCTION: Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to
CC alpha-ketoglutarate (PubMed:15070399, PubMed:15609246, PubMed:16037974,
CC PubMed:20020533, PubMed:33431826). Also catalyzes the oxidation of
CC other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC)
CC (PubMed:33431826). Exhibits high activities towards D-2-HG and D-MAL
CC but a very weak activity towards D-LAC (PubMed:33431826).
CC {ECO:0000269|PubMed:15070399, ECO:0000269|PubMed:15609246,
CC ECO:0000269|PubMed:16037974, ECO:0000269|PubMed:20020533,
CC ECO:0000269|PubMed:33431826}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-2-hydroxyglutarate + A = 2-oxoglutarate + AH2;
CC Xref=Rhea:RHEA:38295, ChEBI:CHEBI:13193, ChEBI:CHEBI:15801,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:17499; EC=1.1.99.39;
CC Evidence={ECO:0000269|PubMed:15070399, ECO:0000269|PubMed:15609246,
CC ECO:0000269|PubMed:16037974, ECO:0000269|PubMed:20020533,
CC ECO:0000269|PubMed:33431826, ECO:0000305|PubMed:16442322};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38296;
CC Evidence={ECO:0000305|PubMed:33431826};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-malate + A = AH2 + oxaloacetate; Xref=Rhea:RHEA:67460,
CC ChEBI:CHEBI:13193, ChEBI:CHEBI:15588, ChEBI:CHEBI:16452,
CC ChEBI:CHEBI:17499; Evidence={ECO:0000269|PubMed:33431826};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67461;
CC Evidence={ECO:0000305|PubMed:33431826};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- ACTIVITY REGULATION: Activated by zinc and cobalt ions.
CC {ECO:0000269|PubMed:15070399}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.12 mM for D-2-hydroxyglutarate {ECO:0000269|PubMed:33431826};
CC KM=0.17 mM for D-malate {ECO:0000269|PubMed:33431826};
CC KM=0.15 mM for D-lactate {ECO:0000269|PubMed:33431826};
CC Vmax=2.29 umol/min/mg enzyme towards D-2-hydroxyglutarate
CC {ECO:0000269|PubMed:33431826};
CC Vmax=2.96 umol/min/mg enzyme towards D-malate
CC {ECO:0000269|PubMed:33431826};
CC Vmax=0.17 umol/min/mg enzyme towards D-lactate
CC {ECO:0000269|PubMed:33431826};
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000305|PubMed:15070399}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8N465-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N465-2; Sequence=VSP_017876, VSP_017877, VSP_017878;
CC Name=3;
CC IsoId=Q8N465-3; Sequence=VSP_054389, VSP_054390;
CC -!- DISEASE: D-2-hydroxyglutaric aciduria 1 (D2HGA1) [MIM:600721]: A rare
CC recessive neurometabolic disorder causing developmental delay,
CC epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe
CC phenotype exist. The severe phenotype is homogeneous and is
CC characterized by early infantile-onset epileptic encephalopathy and
CC cardiomyopathy. The mild phenotype has a more variable clinical
CC presentation. Diagnosis is based on the presence of an excess of D-2-
CC hydroxyglutaric acid in the urine. {ECO:0000269|PubMed:15609246,
CC ECO:0000269|PubMed:16037974, ECO:0000269|PubMed:16081310,
CC ECO:0000269|PubMed:19169842, ECO:0000269|PubMed:20020533,
CC ECO:0000269|PubMed:33431826}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the FAD-binding oxidoreductase/transferase type
CC 4 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAX82020.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AK304773; BAG65528.1; -; mRNA.
DR EMBL; AC114730; AAX82020.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC036604; AAH36604.2; -; mRNA.
DR EMBL; BC071598; AAH71598.1; -; mRNA.
DR CCDS; CCDS33426.1; -. [Q8N465-1]
DR RefSeq; NP_001274178.1; NM_001287249.1.
DR RefSeq; NP_689996.4; NM_152783.4. [Q8N465-1]
DR RefSeq; XP_011510062.1; XM_011511760.2. [Q8N465-3]
DR PDB; 6LPN; X-ray; 2.21 A; A/B=51-521.
DR PDB; 6LPP; X-ray; 2.65 A; A/B=51-521.
DR PDB; 6LPQ; X-ray; 2.80 A; A/B=51-521.
DR PDB; 6LPT; X-ray; 2.62 A; A/B=51-521.
DR PDB; 6LPU; X-ray; 2.92 A; A/B=51-521.
DR PDB; 6LPX; X-ray; 2.80 A; A/B=51-521.
DR PDBsum; 6LPN; -.
DR PDBsum; 6LPP; -.
DR PDBsum; 6LPQ; -.
DR PDBsum; 6LPT; -.
DR PDBsum; 6LPU; -.
DR PDBsum; 6LPX; -.
DR AlphaFoldDB; Q8N465; -.
DR SMR; Q8N465; -.
DR BioGRID; 608722; 176.
DR IntAct; Q8N465; 11.
DR MINT; Q8N465; -.
DR STRING; 9606.ENSP00000315351; -.
DR iPTMnet; Q8N465; -.
DR PhosphoSitePlus; Q8N465; -.
DR BioMuta; D2HGDH; -.
DR DMDM; 91208273; -.
DR EPD; Q8N465; -.
DR jPOST; Q8N465; -.
DR MassIVE; Q8N465; -.
DR MaxQB; Q8N465; -.
DR PaxDb; Q8N465; -.
DR PeptideAtlas; Q8N465; -.
DR PRIDE; Q8N465; -.
DR ProteomicsDB; 5910; -.
DR ProteomicsDB; 71889; -. [Q8N465-1]
DR ProteomicsDB; 71890; -. [Q8N465-2]
DR Antibodypedia; 34576; 117 antibodies from 18 providers.
DR DNASU; 728294; -.
DR Ensembl; ENST00000321264.9; ENSP00000315351.4; ENSG00000180902.18. [Q8N465-1]
DR GeneID; 728294; -.
DR KEGG; hsa:728294; -.
DR MANE-Select; ENST00000321264.9; ENSP00000315351.4; NM_152783.5; NP_689996.4.
DR UCSC; uc002wce.3; human. [Q8N465-1]
DR CTD; 728294; -.
DR DisGeNET; 728294; -.
DR GeneCards; D2HGDH; -.
DR HGNC; HGNC:28358; D2HGDH.
DR HPA; ENSG00000180902; Low tissue specificity.
DR MalaCards; D2HGDH; -.
DR MIM; 600721; phenotype.
DR MIM; 609186; gene.
DR neXtProt; NX_Q8N465; -.
DR OpenTargets; ENSG00000180902; -.
DR Orphanet; 79315; D-2-hydroxyglutaric aciduria.
DR PharmGKB; PA143485446; -.
DR VEuPathDB; HostDB:ENSG00000180902; -.
DR eggNOG; KOG1232; Eukaryota.
DR GeneTree; ENSGT00550000075086; -.
DR InParanoid; Q8N465; -.
DR OMA; CNDNMLA; -.
DR OrthoDB; 515900at2759; -.
DR PhylomeDB; Q8N465; -.
DR TreeFam; TF323342; -.
DR BioCyc; MetaCyc:ENSG00000180902-MON; -.
DR BRENDA; 1.1.99.39; 2681.
DR PathwayCommons; Q8N465; -.
DR Reactome; R-HSA-880009; Interconversion of 2-oxoglutarate and 2-hydroxyglutarate.
DR SignaLink; Q8N465; -.
DR SIGNOR; Q8N465; -.
DR BioGRID-ORCS; 728294; 10 hits in 1079 CRISPR screens.
DR ChiTaRS; D2HGDH; human.
DR GeneWiki; D2HGDH; -.
DR GenomeRNAi; 728294; -.
DR Pharos; Q8N465; Tbio.
DR PRO; PR:Q8N465; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q8N465; protein.
DR Bgee; ENSG00000180902; Expressed in right uterine tube and 154 other tissues.
DR ExpressionAtlas; Q8N465; baseline and differential.
DR Genevisible; Q8N465; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0051990; F:(R)-2-hydroxyglutarate dehydrogenase activity; IMP:UniProtKB.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; TAS:Reactome.
DR GO; GO:0006108; P:malate metabolic process; IDA:UniProtKB.
DR GO; GO:0019538; P:protein metabolic process; ISS:HGNC-UCL.
DR GO; GO:0032025; P:response to cobalt ion; ISS:HGNC-UCL.
DR GO; GO:0010042; P:response to manganese ion; ISS:HGNC-UCL.
DR GO; GO:0010043; P:response to zinc ion; ISS:HGNC-UCL.
DR Gene3D; 1.10.45.10; -; 1.
DR Gene3D; 3.30.43.10; -; 1.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016167; FAD-bd_PCMH_sub1.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR016164; FAD-linked_Oxase-like_C.
DR InterPro; IPR004113; FAD-linked_oxidase_C.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR InterPro; IPR016171; Vanillyl_alc_oxidase_C-sub2.
DR Pfam; PF02913; FAD-oxidase_C; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF55103; SSF55103; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Disease variant; FAD; Flavoprotein;
KW Metal-binding; Mitochondrion; Oxidoreductase; Reference proteome;
KW Transit peptide; Zinc.
FT TRANSIT 1..13
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 14..521
FT /note="D-2-hydroxyglutarate dehydrogenase, mitochondrial"
FT /id="PRO_0000231674"
FT DOMAIN 96..275
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT BINDING 386
FT /ligand="(R)-2-hydroxyglutarate"
FT /ligand_id="ChEBI:CHEBI:15801"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPP"
FT BINDING 386
FT /ligand="(R)-lactate"
FT /ligand_id="ChEBI:CHEBI:16004"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPT"
FT BINDING 386
FT /ligand="(R)-malate"
FT /ligand_id="ChEBI:CHEBI:15588"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPQ"
FT BINDING 390
FT /ligand="(R)-2-hydroxyglutarate"
FT /ligand_id="ChEBI:CHEBI:15801"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPP"
FT BINDING 390
FT /ligand="(R)-malate"
FT /ligand_id="ChEBI:CHEBI:15588"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPQ"
FT BINDING 401
FT /ligand="(R)-2-hydroxyglutarate"
FT /ligand_id="ChEBI:CHEBI:15801"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPP"
FT BINDING 401
FT /ligand="(R)-malate"
FT /ligand_id="ChEBI:CHEBI:15588"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPQ"
FT BINDING 434
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:33431826"
FT BINDING 441
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:33431826"
FT BINDING 443
FT /ligand="(R)-2-hydroxyglutarate"
FT /ligand_id="ChEBI:CHEBI:15801"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPP"
FT BINDING 475
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:33431826"
FT BINDING 476
FT /ligand="(R)-2-hydroxyglutarate"
FT /ligand_id="ChEBI:CHEBI:15801"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPP"
FT BINDING 476
FT /ligand="(R)-lactate"
FT /ligand_id="ChEBI:CHEBI:16004"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPT"
FT BINDING 476
FT /ligand="(R)-malate"
FT /ligand_id="ChEBI:CHEBI:15588"
FT /evidence="ECO:0000269|PubMed:33431826,
FT ECO:0007744|PDB:6LPQ"
FT MOD_RES 101
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8CIM3"
FT VAR_SEQ 165..172
FT /note="ILVCQAGC -> GL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017876"
FT VAR_SEQ 285..319
FT /note="GCPGFAEVLQTFSTCKGMLGEILSAFEFMDAVCMQ -> VTCVPPACGPGSP
FT RPARLPHPALRTPGVCPQPLRL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054389"
FT VAR_SEQ 285..313
FT /note="GCPGFAEVLQTFSTCKGMLGEILSAFEFM -> VTCVLPACGPGSPRPARLP
FT HPALRTPGLR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017877"
FT VAR_SEQ 314..521
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017878"
FT VAR_SEQ 320..521
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054390"
FT VARIANT 15
FT /note="R -> G (in dbSNP:rs4675887)"
FT /evidence="ECO:0000269|PubMed:16442322"
FT /id="VAR_025889"
FT VARIANT 109
FT /note="S -> W (in D2HGA1; unknown pathological
FT significance; significant loss of catalytic activity;
FT dbSNP:rs142050154)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084974"
FT VARIANT 127
FT /note="N -> K (in D2HGA1; unknown pathological
FT significance; complete loss of catalytic activity;
FT dbSNP:rs762857195)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084975"
FT VARIANT 131
FT /note="G -> V (in D2HGA1; unknown pathological
FT significance; complete loss of catalytic activity)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084976"
FT VARIANT 147
FT /note="I -> S (in D2HGA1; severe phenotype; unknown
FT pathological significance; almost complete loss of
FT catalytic activity; dbSNP:rs121434361)"
FT /evidence="ECO:0000269|PubMed:15609246,
FT ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826"
FT /id="VAR_025890"
FT VARIANT 153
FT /note="M -> T (in D2HGA1; unknown pathological
FT significance; significant loss of catalytic activity)"
FT /evidence="ECO:0000269|PubMed:19169842,
FT ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826"
FT /id="VAR_084977"
FT VARIANT 153
FT /note="M -> V (in D2HGA1; unknown pathological
FT significance; significant loss of catalytic activity;
FT dbSNP:rs1432270139)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084978"
FT VARIANT 169..521
FT /note="Missing (in D2HGA1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:20020533"
FT /id="VAR_084979"
FT VARIANT 172
FT /note="C -> Y (in D2HGA1; unknown pathological
FT significance; moderate reduction in catalytic activity;
FT dbSNP:rs773735172)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084980"
FT VARIANT 189
FT /note="P -> L (in D2HGA1; unknown pathological
FT significance; almost complete loss of catalytic activity;
FT dbSNP:rs587783517)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084981"
FT VARIANT 205
FT /note="A -> V (in D2HGA1; unknown pathological
FT significance; almost complete loss of catalytic activity;
FT dbSNP:rs750889931)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084982"
FT VARIANT 231
FT /note="A -> V (in D2HGA1; unknown pathological
FT significance; significant loss of catalytic activity)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084983"
FT VARIANT 233
FT /note="G -> S (in D2HGA1; unknown pathological
FT significance; no effect on catalytic activity;
FT dbSNP:rs374535734)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084984"
FT VARIANT 338
FT /note="V -> I (in dbSNP:rs1106639)"
FT /id="VAR_050433"
FT VARIANT 361
FT /note="A -> V (in dbSNP:rs1105273)"
FT /id="VAR_050434"
FT VARIANT 375
FT /note="D -> Y (in D2HGA1; unknown pathological
FT significance; moderate reduction in catalytic activity;
FT dbSNP:rs267606759)"
FT /evidence="ECO:0000269|PubMed:16081310,
FT ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826"
FT /id="VAR_025891"
FT VARIANT 399
FT /note="V -> M (in D2HGA1; unknown pathological
FT significance; moderate reduction in catalytic activity;
FT dbSNP:rs746519212)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084985"
FT VARIANT 400..521
FT /note="Missing (in D2HGA1; unknown pathological
FT significance; complete loss of catalytic activity)"
FT /evidence="ECO:0000269|PubMed:20020533"
FT /id="VAR_084986"
FT VARIANT 419
FT /note="R -> H (in D2HGA1; unknown pathological
FT significance; moderate reduction in catalytic activity;
FT dbSNP:rs199908032)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084987"
FT VARIANT 426
FT /note="A -> T (in D2HGA1; unknown pathological
FT significance; no effect on catalytic activity;
FT dbSNP:rs146578303)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084988"
FT VARIANT 436
FT /note="G -> V (slight reduction in catalytic activity)"
FT /evidence="ECO:0000269|PubMed:16442322,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_025892"
FT VARIANT 439
FT /note="N -> D (in D2HGA1; mild phenotype; unknown
FT pathological significance; moderate reduction in catalytic
FT activity; dbSNP:rs121434362)"
FT /evidence="ECO:0000269|PubMed:16037974,
FT ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826"
FT /id="VAR_025893"
FT VARIANT 444
FT /note="V -> A (in D2HGA1; severe phenotype; unknown
FT pathological significance; significant reduction in
FT catalytic activity; dbSNP:rs121434360)"
FT /evidence="ECO:0000269|PubMed:15609246,
FT ECO:0000269|PubMed:20020533, ECO:0000269|PubMed:33431826"
FT /id="VAR_025894"
FT VARIANT 446
FT /note="A -> V (in D2HGA1; unknown pathological
FT significance; moderate reduction in catalytic activity;
FT dbSNP:rs746956176)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084989"
FT VARIANT 477
FT /note="G -> R (in D2HGA1; unknown pathological
FT significance; almost complete loss of catalytic activity;
FT dbSNP:rs1453924640)"
FT /evidence="ECO:0000269|PubMed:20020533,
FT ECO:0000269|PubMed:33431826"
FT /id="VAR_084990"
FT MUTAGEN 386
FT /note="R->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 390
FT /note="T->A: Significantly reduced catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 401
FT /note="K->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 434
FT /note="H->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 441
FT /note="H->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 443
FT /note="N->A: Significantly reduced catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 475
FT /note="E->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT MUTAGEN 476
FT /note="H->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:33431826"
FT CONFLICT 55
FT /note="R -> Q (in Ref. 3; AAH36604)"
FT /evidence="ECO:0000305"
FT HELIX 64..73
FT /evidence="ECO:0007829|PDB:6LPN"
FT TURN 82..85
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 86..89
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 109..122
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 126..132
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 146..149
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 156..159
FT /evidence="ECO:0007829|PDB:6LPN"
FT TURN 161..163
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 165..169
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 174..182
FT /evidence="ECO:0007829|PDB:6LPN"
FT TURN 183..185
FT /evidence="ECO:0007829|PDB:6LPN"
FT TURN 193..197
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 200..206
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 213..216
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 219..222
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 223..229
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 235..238
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 252..255
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 264..271
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 277..288
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 289..302
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 304..306
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 307..314
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 315..325
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 335..345
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 347..363
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 368..373
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 376..387
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 389..394
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 396..405
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 408..410
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 413..422
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 423..425
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 426..434
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 435..437
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 439..448
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 451..457
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 460..467
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 471..476
FT /evidence="ECO:0007829|PDB:6LPN"
FT TURN 479..484
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 486..488
FT /evidence="ECO:0007829|PDB:6LPN"
FT HELIX 492..505
FT /evidence="ECO:0007829|PDB:6LPN"
FT STRAND 515..517
FT /evidence="ECO:0007829|PDB:6LPN"
SQ SEQUENCE 521 AA; 56416 MW; 65D88C4315FA45CE CRC64;
MLPRRPLAWP AWLLRGAPGA AGSWGRPVGP LARRGCCSAP GTPEVPLTRE RYPVRRLPFS
TVSKQDLAAF ERIVPGGVVT DPEALQAPNV DWLRTLRGCS KVLLRPRTSE EVSHILRHCH
ERNLAVNPQG GNTGMVGGSV PVFDEIILST ARMNRVLSFH SVSGILVCQA GCVLEELSRY
VEERDFIMPL DLGAKGSCHI GGNVATNAGG LRFLRYGSLH GTVLGLEVVL ADGTVLDCLT
SLRKDNTGYD LKQLFIGSEG TLGIITTVSI LCPPKPRAVN VAFLGCPGFA EVLQTFSTCK
GMLGEILSAF EFMDAVCMQL VGRHLHLASP VQESPFYVLI ETSGSNAGHD AEKLGHFLEH
ALGSGLVTDG TMATDQRKVK MLWALRERIT EALSRDGYVY KYDLSLPVER LYDIVTDLRA
RLGPHAKHVV GYGHLGDGNL HLNVTAEAFS PSLLAALEPH VYEWTAGQQG SVSAEHGVGF
RKRDVLGYSK PPGALQLMQQ LKALLDPKGI LNPYKTLPSQ A
