O75874 (IDHC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Isocitrate dehydrogenase [NADP] cytoplasmic
Short name=IDH
EC=1.1.1.42

Alternative name(s):
Cytosolic NADP-isocitrate dehydrogenase
IDP
NADP(+)-specific ICDH
Oxalosuccinate decarboxylase

Gene names

Name:	IDH1
Synonyms:	PICD

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	414 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH. Ref.11
Cofactor	Binds 1 magnesium or manganese ion per subunit. Ref.11
Subunit structure	Homodimer. Ref.10 Ref.11
Subcellular location	Cytoplasm. Peroxisome Ref.2.
Involvement in disease	Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. Note: The gene represented in this entry is involved in disease pathogenesis. Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R--2-hydroxyglutarate. Elevated levels of R--2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
Sequence similarities	Belongs to the isocitrate and isopropylmalate dehydrogenases family.
Biophysicochemical properties	Kinetic parameters: KM=49 µM for NADP Ref.11 KM=29 µM for magnesium chloride KM=65 µM for isocitrate

Ontologies

Keywords
Biological process	Glyoxylate bypass Tricarboxylic acid cycle
Cellular component	Cytoplasm Peroxisome
Coding sequence diversity	Polymorphism
Ligand	Magnesium Manganese Metal-binding NADP
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	2-oxoglutarate metabolic process Inferred from direct assay Ref.11. Source: UniProtKB NADPH regeneration Traceable author statement. Source: Reactome cellular lipid metabolic process Traceable author statement. Source: Reactome female gonad development Inferred from electronic annotation. Source: Compara glutathione metabolic process Inferred from electronic annotation. Source: Compara glyoxylate cycle Inferred from electronic annotation. Source: UniProtKB-KW isocitrate metabolic process Inferred from direct assay Ref.2Ref.11PubMed 20171178. Source: UniProtKB response to oxidative stress Inferred from electronic annotation. Source: Compara response to steroid hormone stimulus Inferred from electronic annotation. Source: Compara tricarboxylic acid cycle Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Inferred from direct assay Ref.2. Source: UniProtKB mitochondrion Inferred from electronic annotation. Source: Compara peroxisomal matrix Traceable author statement. Source: Reactome
Molecular_function	NAD binding Inferred from electronic annotation. Source: InterPro NADP binding Inferred from electronic annotation. Source: Compara isocitrate dehydrogenase (NADP+) activity Inferred from direct assay Ref.2Ref.11PubMed 20171178. Source: UniProtKB magnesium ion binding Inferred from direct assay Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 414

414

Isocitrate dehydrogenase [NADP] cytoplasmic

PRO_0000083575

Regions

Nucleotide binding

75 – 77

3

NADP

Nucleotide binding

310 – 315

6

NADP

Region

94 – 100

7

Substrate binding

Sites

Metal binding

252

1

Magnesium or manganese

Metal binding

275

1

Magnesium or manganese

Binding site

77

1

Substrate

Binding site

82

1

NADP

Binding site

109

1

Substrate

Binding site

132

1

Substrate

Binding site

260

1

NADP

Binding site

328

1

NADP; via amide nitrogen and carbonyl oxygen

Site

139

1

Critical for catalysis

Site

212

1

Critical for catalysis

Amino acid modifications

Modified residue

321

1

N6-acetyllysine Ref.8

Natural variations

Natural variant

132

1

R → C in colorectal cancer and glioma samples; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Ref.11 Ref.12 Ref.14

VAR_036013

Natural variant

132

1

R → G in a glioma sample; glioblastoma multiforme; somatic mutation. Ref.14

VAR_055454

Natural variant

132

1

R → H in a glioma sample; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Ref.11 Ref.13

VAR_055455

Natural variant

132

1

R → L in a glioma sample; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Ref.11 Ref.14

VAR_055456

Natural variant

132

1

R → S in a glioma sample; glioblastoma multiforme; somatic mutation; abolishes magnesium binding and alters enzyme activity so that isocitrate is no longer converted to alpha-ketoglutarate but instead alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Ref.11 Ref.13

VAR_055457

Natural variant

178

1

V → I.
Corresponds to variant rs34218846 [ dbSNP | Ensembl ].

VAR_049780

Experimental info

Sequence conflict

32

1

F → I in CAB66637. Ref.3

Sequence conflict

126

1

K → E in CAB66637. Ref.3

Sequence conflict

172

1

F → S in CAD97653. Ref.4

Sequence conflict

174

1

E → G in CAD97653. Ref.4

Sequence conflict

218

1

K → I in AAD02918. Ref.1

Sequence conflict

329

1

P → L in AAD02918. Ref.1

Sequence conflict

381

1

K → R in AAD02918. Ref.1

Secondary structure

1

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414

Helix Strand Turn

Details...

Beta strand

5 – 14

10

Helix

17 – 29

13

Turn

30 – 34

5

Beta strand

35 – 43

9

Helix

46 – 51

6

Turn

52 – 54

3

Helix

55 – 67

13

Beta strand

68 – 72

5

Helix

80 – 86

7

Helix

95 – 103

9

Beta strand

106 – 111

6

Beta strand

128 – 133

6

Helix

137 – 140

4

Beta strand

142 – 146

5

Beta strand

148 – 158

11

Beta strand

165 – 172

8

Beta strand

177 – 185

9

Helix

186 – 203

18

Beta strand

207 – 211

5

Turn

213 – 215

3

Helix

219 – 234

16

Helix

236 – 241

6

Beta strand

246 – 250

5

Helix

251 – 260

10

Beta strand

265 – 269

5

Helix

271 – 285

15

Beta strand

290 – 296

7

Beta strand

303 – 309

7

Helix

313 – 320

8

Helix

330 – 347

18

Helix

350 – 369

20

Helix

374 – 381

8

Helix

383 – 385

3

Helix

388 – 390

3

Helix

394 – 409

16

Sequences

	Sequence		Length	Mass (Da)
	O75874 [UniParc]. Last modified July 11, 2002. Version 2. Checksum: 60428B0B6E5851DC	FASTA	414	46,659
	10 20 30 40 50 60 MSKKISGGSV VEMQGDEMTR IIWELIKEKL IFPYVELDLH SYDLGIENRD ATNDQVTKDA 70 80 90 100 110 120 AEAIKKHNVG VKCATITPDE KRVEEFKLKQ MWKSPNGTIR NILGGTVFRE AIICKNIPRL 130 140 150 160 170 180 VSGWVKPIII GRHAYGDQYR ATDFVVPGPG KVEITYTPSD GTQKVTYLVH NFEEGGGVAM 190 200 210 220 230 240 GMYNQDKSIE DFAHSSFQMA LSKGWPLYLS TKNTILKKYD GRFKDIFQEI YDKQYKSQFE 250 260 270 280 290 300 AQKIWYEHRL IDDMVAQAMK SEGGFIWACK NYDGDVQSDS VAQGYGSLGM MTSVLVCPDG 310 320 330 340 350 360 KTVEAEAAHG TVTRHYRMYQ KGQETSTNPI ASIFAWTRGL AHRAKLDNNK ELAFFANALE 370 380 390 400 410 EVSIETIEAG FMTKDLAACI KGLPNVQRSD YLNTFEFMDK LGENLKIKLA QAKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family." Nekrutenko A., Hillis D.M., Patton J.C., Bradley R.D., Baker R.J. Mol. Biol. Evol. 15:1674-1684(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase." Geisbrecht B.V., Gould S.J. J. Biol. Chem. 274:30527-30533(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION.
[3]	"Towards a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs." Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., Ottenwaelder B., Obermaier B. , Tampe J., Heubner D., Wambutt R., Korn B., Klein M., Poustka A. Genome Res. 11:422-435(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[4]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Endometrium.
[5]	"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]. Tissue: Lung.
[6]	Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 5-20; 30-49; 101-109; 120-132; 141-212; 223-233; 250-270; 322-338 AND 389-400, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[7]	"Differential gene expression in epithelial cells induced by bile salts: identification by RNA arbitrarily primed PCR." Kullmann F., Vogt T., Welsh J., McClelland M. Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 100-253.
[8]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-321, MASS SPECTROMETRY.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity." Xu X., Zhao J., Xu Z., Peng B., Huang Q., Arnold E., Ding J. J. Biol. Chem. 279:33946-33957(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEXES WITH NADP; ISOCITRATE AND CALCIUM IONS, SUBUNIT.
[11]	"Cancer-associated IDH1 mutations produce 2-hydroxyglutarate." Dang L., White D.W., Gross S., Bennett B.D., Bittinger M.A., Driggers E.M., Fantin V.R., Jang H.G., Jin S., Keenan M.C., Marks K.M., Prins R.M., Ward P.S., Yen K.E., Liau L.M., Rabinowitz J.D., Cantley L.C., Thompson C.B., Vander Heiden M.G., Su S.M. Nature 462:739-744(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF VARIANT GBM HIS-132 IN COMPLEX WITH NADP AND ALPHA-KETOGLUTARATE, CATALYTIC ACTIVITY, SUBUNIT, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, CHARACTERIZATION OF VARIANTS CYS-132; HIS-132; LEU-132 AND SER-132.
[12]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] CYS-132.
[13]	"An integrated genomic analysis of human glioblastoma multiforme." Parsons D.W., Jones S., Zhang X., Lin J.C.-H., Leary R.J., Angenendt P., Mankoo P., Carter H., Siu I.-M., Gallia G.L., Olivi A., McLendon R., Rasheed B.A., Keir S., Nikolskaya T., Nikolsky Y., Busam D.A., Tekleab H. , Diaz L.A. Jr., Hartigan J., Smith D.R., Strausberg R.L., Marie S.K.N., Shinjo S.M.O., Yan H., Riggins G.J., Bigner D.D., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V.E., Kinzler K.W. Science 321:1807-1812(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HIS-132 AND SER-132.
[14]	"IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors." Bleeker F.E., Lamba S., Leenstra S., Troost D., Hulsebos T., Vandertop W.P., Frattini M., Molinari F., Knowles M., Cerrato A., Rodolfo M., Scarpa A., Felicioni L., Buttitta F., Malatesta S., Marchetti A., Bardelli A. Hum. Mutat. 30:7-11(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CYS-132; GLY-132 AND LEU-132, ROLE IN GLIOMAS.
+	Additional computationally mapped references.

Web resources

Wikipedia

Isocitrate dehydrogenase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF020038 mRNA. Translation: AAD02918.1.
AF113917 mRNA. Translation: AAD29284.1.
AL136702 mRNA. Translation: CAB66637.1.
BX537411 mRNA. Translation: CAD97653.1.
BC012846 mRNA. Translation: AAH12846.1.
U62389 mRNA. Translation: AAB17375.1.

IPI

IPI00027223.

PIR

T46280.

RefSeq

NP_005887.2. NM_005896.2.

UniGene

Hs.593422.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1T09	X-ray	2.70	A/B	1-414	[»]
1T0L	X-ray	2.41	A/B/C/D	1-414	[»]
3INM	X-ray	2.10	A/B/C	1-414	[»]
3MAP	X-ray	2.80	A/B	1-414	[»]
3MAR	X-ray	3.41	A/B	1-414	[»]
3MAS	X-ray	3.20	A/B	1-414	[»]

ProteinModelPortal

O75874.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-59311N.

IntAct

O75874. 3 interactions.

MINT

MINT-1424886.

STRING

9606.ENSP00000260985.

PTM databases

PhosphoSite

O75874.

2D gel databases

OGP

O75874.

REPRODUCTION-2DPAGE

IPI00027223.

UCD-2DPAGE

O75874.

Proteomic databases

PaxDb

O75874.

PeptideAtlas

O75874.

PRIDE

O75874.

Protocols and materials databases

DNASU

3417.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000345146; ENSP00000260985; ENSG00000138413.
ENST00000415913; ENSP00000390265; ENSG00000138413.
ENST00000446179; ENSP00000410513; ENSG00000138413.

GeneID

3417.

KEGG

hsa:3417.

UCSC

uc002vcs.3. human.

Organism-specific databases

CTD

3417.

GeneCards

GC02M209100.

H-InvDB

HIX0161877.

HGNC

HGNC:5382. IDH1.

HPA

HPA035248.

MIM

137800. phenotype.
147700. gene.

neXtProt

NX_O75874.

Orphanet

99646. Metaphyseal chondromatosis with d-2-hydroxyglutaric aciduria.

PharmGKB

PA29630.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0538.

HOGENOM

HOG000019858.

HOVERGEN

HBG006119.

InParanoid

O75874.

KO

K00031.

OMA

ALGMFNT.

OrthoDB

EOG47M1Z0.

PhylomeDB

O75874.

Enzyme and pathway databases

BioCyc

MetaCyc:HS06502-MONOMER.

Reactome

REACT_111217. Metabolism.

SABIO-RK

O75874.

Gene expression databases

ArrayExpress

O75874.

Bgee

O75874.

CleanEx

HS_IDH1.

Genevestigator

O75874.

GermOnline

ENSG00000138413. Homo sapiens.

Family and domain databases

Gene3D

3.40.718.10. 1 hit.

InterPro

IPR019818. IsoCit/isopropylmalate_DH_CS.
IPR004790. Isocitrate_DH_NADP.
IPR024084. IsoPropMal-DH-like_dom.
[Graphical view]

PANTHER

PTHR11822. PTHR11822. 1 hit.

Pfam

PF00180. Iso_dh. 1 hit.
[Graphical view]

PIRSF

PIRSF000108. IDH_NADP. 1 hit.

TIGRFAMs

TIGR00127. nadp_idh_euk. 1 hit.

PROSITE

PS00470. IDH_IMDH. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL2007625.

ChiTaRS

IDH1. human.

EvolutionaryTrace

O75874.

GenomeRNAi

3417.

NextBio

13470.

SOURCE

Search...

Entry information

Entry name

IDHC_HUMAN

Accession

Primary (citable) accession number: O75874
Secondary accession number(s): Q7Z3V0 , Q93090, Q9NTJ9, Q9UKW8

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	July 11, 2002
Last modified:	May 1, 2013
This is version 141 of the entry and version 2 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.