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Q8N465 (D2HDH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 109. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
D-2-hydroxyglutarate dehydrogenase, mitochondrial

EC=1.1.99.-
Gene names
Name:D2HGDH
Synonyms:D2HGD
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length521 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Catalyzes the oxidation of D-2-hydroxyglutarate to alpha-ketoglutarate. Ref.4

Catalytic activity

(R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.

Cofactor

FAD Potential.

Enzyme regulation

Activated by zinc and cobalt. Ref.4

Subcellular location

Mitochondrion Probable Ref.4.

Involvement in disease

D-2-hydroxyglutaric aciduria 1 (D2HGA1) [MIM:600721]: A rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.6 Ref.7

Sequence similarities

Belongs to the FAD-binding oxidoreductase/transferase type 4 family.

Contains 1 FAD-binding PCMH-type domain.

Sequence caution

The sequence AAX82020.1 differs from that shown. Reason: Erroneous gene model prediction.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

RAB25P577351EBI-1053783,EBI-1050500

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q8N465-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q8N465-2)

The sequence of this isoform differs from the canonical sequence as follows:
     165-172: ILVCQAGC → GL
     285-313: GCPGFAEVLQTFSTCKGMLGEILSAFEFM → VTCVLPACGPGSPRPARLPHPALRTPGLR
     314-521: Missing.
Note: No experimental confirmation available.
Isoform 3 (identifier: Q8N465-3)

The sequence of this isoform differs from the canonical sequence as follows:
     285-319: GCPGFAEVLQTFSTCKGMLGEILSAFEFMDAVCMQ → VTCVPPACGPGSPRPARLPHPALRTPGVCPQPLRL
     320-521: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 1313Mitochondrion Potential
Chain14 – 521508D-2-hydroxyglutarate dehydrogenase, mitochondrial
PRO_0000231674

Regions

Domain96 – 275180FAD-binding PCMH-type

Amino acid modifications

Modified residue1011N6-succinyllysine By similarity

Natural variations

Alternative sequence165 – 1728ILVCQAGC → GL in isoform 2.
VSP_017876
Alternative sequence285 – 31935GCPGF…AVCMQ → VTCVPPACGPGSPRPARLPH PALRTPGVCPQPLRL in isoform 3.
VSP_054389
Alternative sequence285 – 31329GCPGF…AFEFM → VTCVLPACGPGSPRPARLPH PALRTPGLR in isoform 2.
VSP_017877
Alternative sequence314 – 521208Missing in isoform 2.
VSP_017878
Alternative sequence320 – 521202Missing in isoform 3.
VSP_054390
Natural variant151R → G. Ref.8
Corresponds to variant rs4675887 [ dbSNP | Ensembl ].
VAR_025889
Natural variant1471I → S in D2HGA1; severe phenotype; loss of catalytic activity. Ref.5
VAR_025890
Natural variant3381V → I.
Corresponds to variant rs1106639 [ dbSNP | Ensembl ].
VAR_050433
Natural variant3611A → V.
Corresponds to variant rs1105273 [ dbSNP | Ensembl ].
VAR_050434
Natural variant3751D → Y in D2HGA1. Ref.7
VAR_025891
Natural variant4361G → V. Ref.8
VAR_025892
Natural variant4391N → D in D2HGA1; mild phenotype; altered catalytic activity. Ref.6
VAR_025893
Natural variant4441V → A in D2HGA1; severe phenotype; altered catalytic activity. Ref.5
VAR_025894

Experimental info

Sequence conflict551R → Q in AAH36604. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified April 4, 2006. Version 3.
Checksum: 65D88C4315FA45CE

FASTA52156,416
        10         20         30         40         50         60 
MLPRRPLAWP AWLLRGAPGA AGSWGRPVGP LARRGCCSAP GTPEVPLTRE RYPVRRLPFS 

        70         80         90        100        110        120 
TVSKQDLAAF ERIVPGGVVT DPEALQAPNV DWLRTLRGCS KVLLRPRTSE EVSHILRHCH 

       130        140        150        160        170        180 
ERNLAVNPQG GNTGMVGGSV PVFDEIILST ARMNRVLSFH SVSGILVCQA GCVLEELSRY 

       190        200        210        220        230        240 
VEERDFIMPL DLGAKGSCHI GGNVATNAGG LRFLRYGSLH GTVLGLEVVL ADGTVLDCLT 

       250        260        270        280        290        300 
SLRKDNTGYD LKQLFIGSEG TLGIITTVSI LCPPKPRAVN VAFLGCPGFA EVLQTFSTCK 

       310        320        330        340        350        360 
GMLGEILSAF EFMDAVCMQL VGRHLHLASP VQESPFYVLI ETSGSNAGHD AEKLGHFLEH 

       370        380        390        400        410        420 
ALGSGLVTDG TMATDQRKVK MLWALRERIT EALSRDGYVY KYDLSLPVER LYDIVTDLRA 

       430        440        450        460        470        480 
RLGPHAKHVV GYGHLGDGNL HLNVTAEAFS PSLLAALEPH VYEWTAGQQG SVSAEHGVGF 

       490        500        510        520 
RKRDVLGYSK PPGALQLMQQ LKALLDPKGI LNPYKTLPSQ A 

« Hide

Isoform 2 [UniParc].

Checksum: 2EA2EA997C5E4968
Show »

FASTA30732,933
Isoform 3 [UniParc].

Checksum: 6C7BDA672635D743
Show »

FASTA31934,173

References

« Hide 'large scale' references
[1]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Uterus.
[2]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Tissue: Hippocampus and Placenta.
[4]"Identification of a dehydrogenase acting on D-2-hydroxyglutarate."
Achouri Y., Noel G., Vertommen D., Rider M.H., Veiga-Da-Cunha M., van Schaftingen E.
Biochem. J. 381:35-42(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION.
[5]"Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria."
Struys E.A., Salomons G.S., Achouri Y., van Schaftingen E., Grosso S., Craigen W.J., Verhoeven N.M., Jakobs C.
Am. J. Hum. Genet. 76:358-360(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS D2HGA1 SER-147 AND ALA-444, CHARACTERIZATION OF VARIANTS D2HGA1 SER-147 AND ALA-444.
[6]"Mutations in phenotypically mild D-2-hydroxyglutaric aciduria."
Struys E.A., Korman S.H., Salomons G.S., Darmin P.S., Achouri Y., van Schaftingen E., Verhoeven N.M., Jakobs C.
Ann. Neurol. 58:626-630(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT D2HGA1 ASP-439, CHARACTERIZATION OF VARIANT D2HGA1 ASP-439.
[7]"Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins."
Misra V.K., Struys E.A., O'brien W., Salomons G.S., Glover T., Jakobs C., Innis J.W.
Mol. Genet. Metab. 86:200-205(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT D2HGA1 TYR-375.
[8]"D-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?"
Struys E.A., Verhoeven N.M., Salomons G.S., Berthelot J., Vianay-Saban C., Chabrier S., Thomas J.A., Tsai A.C.-H., Gibson K.M., Jakobs C.
Mol. Genet. Metab. 88:53-57(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS GLY-15 AND VAL-436.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK304773 mRNA. Translation: BAG65528.1.
AC114730 Genomic DNA. Translation: AAX82020.1. Sequence problems.
BC036604 mRNA. Translation: AAH36604.2.
BC071598 mRNA. Translation: AAH71598.1.
CCDSCCDS33426.1. [Q8N465-1]
RefSeqNP_001274178.1. NM_001287249.1.
NP_689996.4. NM_152783.4. [Q8N465-1]
UniGeneHs.516813.

3D structure databases

ProteinModelPortalQ8N465.
SMRQ8N465. Positions 61-517.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid608722. 2 interactions.
STRING9606.ENSP00000315351.

PTM databases

PhosphoSiteQ8N465.

Polymorphism databases

DMDM91208273.

Proteomic databases

MaxQBQ8N465.
PaxDbQ8N465.
PeptideAtlasQ8N465.
PRIDEQ8N465.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000321264; ENSP00000315351; ENSG00000180902. [Q8N465-1]
ENST00000342518; ENSP00000339536; ENSG00000180902.
GeneID728294.
KEGGhsa:728294.
UCSCuc002wce.1. human. [Q8N465-1]

Organism-specific databases

CTD728294.
GeneCardsGC02P242673.
H-InvDBHIX0023187.
HGNCHGNC:28358. D2HGDH.
HPAHPA056216.
MIM600721. phenotype.
609186. gene.
neXtProtNX_Q8N465.
Orphanet79315. D-2-hydroxyglutaric aciduria.
PharmGKBPA143485446.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0277.
HOGENOMHOG000230997.
HOVERGENHBG079809.
InParanoidQ8N465.
OMAVYEWTAR.
OrthoDBEOG7BS49D.
PhylomeDBQ8N465.
TreeFamTF323342.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.

Gene expression databases

ArrayExpressQ8N465.
BgeeQ8N465.
CleanExHS_D2HGDH.
GenevestigatorQ8N465.

Family and domain databases

Gene3D1.10.45.10. 1 hit.
3.30.43.10. 1 hit.
3.30.465.10. 1 hit.
InterProIPR016169. CO_DH_flavot_FAD-bd_sub2.
IPR016166. FAD-bd_2.
IPR016167. FAD-bd_2_sub1.
IPR016164. FAD-linked_Oxase-like_C.
IPR004113. FAD-linked_oxidase_C.
IPR006094. Oxid_FAD_bind_N.
IPR016171. Vanillyl_alc_oxidase_C-sub2.
[Graphical view]
PfamPF02913. FAD-oxidase_C. 1 hit.
PF01565. FAD_binding_4. 1 hit.
[Graphical view]
SUPFAMSSF55103. SSF55103. 1 hit.
SSF56176. SSF56176. 1 hit.
PROSITEPS51387. FAD_PCMH. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiD2HGDH.
GenomeRNAi728294.
NextBio126719.
PROQ8N465.
SOURCESearch...

Entry information

Entry nameD2HDH_HUMAN
AccessionPrimary (citable) accession number: Q8N465
Secondary accession number(s): B4E3L6 expand/collapse secondary AC list , E7ENP2, Q6IQ24, Q8N5Q8
Entry history
Integrated into UniProtKB/Swiss-Prot: April 4, 2006
Last sequence update: April 4, 2006
Last modified: July 9, 2014
This is version 109 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM