Q8N465 (D2HDH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
D-2-hydroxyglutarate dehydrogenase, mitochondrial
EC=1.1.99.-

Gene names

Name:	D2HGDH
Synonyms:	D2HGD

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	521 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the oxidation of D-2-hydroxyglutarate to alpha-ketoglutarate. Ref.3
Catalytic activity	(R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.
Cofactor	FAD Potential.
Enzyme regulation	Activated by zinc and cobalt. Ref.3
Subcellular location	Mitochondrion Probable Ref.3.
Involvement in disease	Defects in D2HGDH are the cause of D-2-hydroxyglutaric aciduria type 1 (D2HGA1) [MIM:600721]. D2HGA1 is 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. Ref.4 Ref.5 Ref.6
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.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	FAD Flavoprotein
Molecular function	Oxidoreductase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	2-oxoglutarate metabolic process Traceable author statement. Source: Reactome cellular protein metabolic process Inferred from sequence or structural similarity Ref.3. Source: HGNC response to cobalt ion Inferred from sequence or structural similarity Ref.3. Source: HGNC response to manganese ion Inferred from sequence or structural similarity Ref.3. Source: HGNC response to zinc ion Inferred from sequence or structural similarity Ref.3. Source: HGNC
Cellular component	mitochondrial matrix Traceable author statement. Source: Reactome
Molecular function	(R)-2-hydroxyglutarate dehydrogenase activity Inferred from sequence or structural similarity Ref.3. Source: HGNC UDP-N-acetylmuramate dehydrogenase activity Inferred from electronic annotation. Source: InterPro flavin adenine dinucleotide binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RAB25	P57735	1	EBI-1053783,EBI-1050500

Alternative products

This entry describes 2 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.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 13	13	Mitochondrion Potential
	Chain	14 – 521	508	D-2-hydroxyglutarate dehydrogenase, mitochondrial		PRO_0000231674
Regions
	Domain	96 – 275	180	FAD-binding PCMH-type
Natural variations
	Alternative sequence	165 – 172	8	ILVCQAGC → GL in isoform 2.		VSP_017876
	Alternative sequence	285 – 313	29	GCPGF…AFEFM → VTCVLPACGPGSPRPARLPH PALRTPGLR in isoform 2.		VSP_017877
	Alternative sequence	314 – 521	208	Missing in isoform 2.		VSP_017878
	Natural variant	15	1	R → G. Ref.7 Corresponds to variant rs4675887 [ dbSNP | Ensembl ].		VAR_025889
	Natural variant	147	1	I → S in D2HGA1; severe phenotype; loss of catalytic activity. Ref.4		VAR_025890
	Natural variant	338	1	V → I. Corresponds to variant rs1106639 [ dbSNP | Ensembl ].		VAR_050433
	Natural variant	361	1	A → V. Corresponds to variant rs1105273 [ dbSNP | Ensembl ].		VAR_050434
	Natural variant	375	1	D → Y in D2HGA1. Ref.6		VAR_025891
	Natural variant	436	1	G → V. Ref.7		VAR_025892
	Natural variant	439	1	N → D in D2HGA1; mild phenotype; altered catalytic activity. Ref.5		VAR_025893
	Natural variant	444	1	V → A in D2HGA1; severe phenotype; altered catalytic activity. Ref.4		VAR_025894
Experimental info
	Sequence conflict	55	1	R → Q in AAH36604. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 4, 2006. Version 3. Checksum: 65D88C4315FA45CE	FASTA	521	56,416
	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
	Isoform 2 [UniParc]. Checksum: 2EA2EA997C5E4968	FASTA	307	32,933
	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 SVSGGLVLEE LSRYVEERDF 190 200 210 220 230 240 IMPLDLGAKG SCHIGGNVAT NAGGLRFLRY GSLHGTVLGL EVVLADGTVL DCLTSLRKDN 250 260 270 280 290 300 TGYDLKQLFI GSEGTLGIIT TVSILCPPKP RAVNVAFLVT CVLPACGPGS PRPARLPHPA LRTPGLR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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. , 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: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Hippocampus and Placenta.
[3]	"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: 15070399] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION.
[4]	"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: 15609246] [Abstract] Cited for: VARIANTS D2HGA1 SER-147 AND ALA-444, CHARACTERIZATION OF VARIANTS D2HGA1 SER-147 AND ALA-444.
[5]	"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: 16037974] [Abstract] Cited for: VARIANT D2HGA1 ASP-439, CHARACTERIZATION OF VARIANT D2HGA1 ASP-439.
[6]	"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: 16081310] [Abstract] Cited for: VARIANT D2HGA1 TYR-375.
[7]	"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: 16442322] [Abstract] Cited for: VARIANTS GLY-15 AND VAL-436.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AC114730 Genomic DNA. Translation: AAX82020.1. Sequence problems. BC036604 mRNA. Translation: AAH36604.2. BC071598 mRNA. Translation: AAH71598.1.
IPI	IPI00166642. IPI00883619.
RefSeq	NP_689996.4. NM_152783.3.
UniGene	Hs.516813.
3D structure databases
ProteinModelPortal	Q8N465.
SMR	Q8N465. Positions 61-517.
ModBase	Search...
Protein-protein interaction databases
STRING	Q8N465.
PTM databases
PhosphoSite	Q8N465.
Polymorphism databases
DMDM	91208273.
Proteomic databases
PeptideAtlas	Q8N465.
PRIDE	Q8N465.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000321264; ENSP00000315351; ENSG00000180902.
GeneID	728294.
KEGG	hsa:728294.
UCSC	uc002wce.1. human.
Organism-specific databases
CTD	728294.
GeneCards	GC02P242673.
H-InvDB	HIX0023187.
HGNC	HGNC:28358. D2HGDH.
MIM	600721. phenotype. 609186. gene.
neXtProt	NX_Q8N465.
Orphanet	19. 2-hydroxyglutaricaciduria.
PharmGKB	PA143485446.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG05858.
GeneTree	ENSGT00550000075086.
HOGENOM	HBG553036.
HOVERGEN	HBG079809.
InParanoid	Q8N465.
OMA	EPFVYEW.
OrthoDB	EOG46WZ8B.
PhylomeDB	Q8N465.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism.
Gene expression databases
ArrayExpress	Q8N465.
Bgee	Q8N465.
CleanEx	HS_D2HGDH.
Genevestigator	Q8N465.
GermOnline	ENSG00000180902. Homo sapiens.
Family and domain databases
InterPro	IPR016166. FAD-bd_2. IPR016167. FAD-bd_2_sub1. IPR016164. FAD-linked_Oxase-like_C. IPR016168. FAD-linked_Oxase_FAD-bd_sub2. IPR004113. FAD-linked_oxidase_C. IPR006094. Oxid_FAD_bind_N. IPR016171. Vanillyl_alc_oxidase_C-sub2. [Graphical view]
Gene3D	G3DSA:3.30.43.10. FAD-binding_2_sub1. 1 hit. G3DSA:3.30.465.20. FAD-linked_oxidase_FAD-bd_sub2. 1 hit. G3DSA:1.10.45.10. Vanillyl_alc_oxidase_C-sub2. 1 hit.
Pfam	PF02913. FAD-oxidase_C. 1 hit. PF01565. FAD_binding_4. 1 hit. [Graphical view]
SUPFAM	SSF55103. FAD-binding_2. 1 hit. SSF56176. FAD-binding_2. 1 hit.
PROSITE	PS51387. FAD_PCMH. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	126719.
SOURCE	Search...

Entry information

Entry name

D2HDH_HUMAN

Accession

Primary (citable) accession number: Q8N465
Secondary accession number(s): Q6IQ24, Q8N5Q8

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 4, 2006
Last sequence update:	April 4, 2006
Last modified:	January 25, 2012
This is version 88 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.