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Protein

Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial

Gene

IDH3A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalytic subunit of the enzyme which catalyzes the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.1 Publication

Catalytic activityi

Isocitrate + NAD+ = 2-oxoglutarate + CO2 + NADH.2 Publications

Cofactori

Mg2+2 Publications, Mn2+1 PublicationNote: Divalent metal cations; Mn2+ or Mg2+. Activity higher in presence of Mn2+ than of Mg2+. Binds 1 Mg2+ or Mn2+ ion per subunit.1 Publication

Enzyme regulationi

The heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits can be allosterically activated by citrate (CIT) or/and ADP, and the two activators can act independently or synergistically. The heterodimer composed of IDH3A and IDH3B subunits cannot be allosterically regulated and the allosteric regulation of the heterotetramer is through the IDH3G subunit and not the IDH3B subunit. The IDH3G subunit contains the allosteric site which consists of a CIT-binding site and an ADP-binding site, and the binding of CIT and ADP causes conformational changes at the allosteric site which are transmitted to the active site in the catalytic subunit (IDH3A) through a cascade of conformational changes at the heterodimer interface, leading to stabilization of the isocitrate-binding at the active site and thus activation of the enzyme. ATP can activate the heterotetramer and the heterodimer composed of IDH3A and IDH3G subunits at low concentrations but inhibits their activities at high concentrations, whereas ATP exhibits only inhibitory effect on the heterodimer composed of IDH3A and IDH3B subunits.2 Publications

Kineticsi

kcat is 26.7 sec(-1) for the heterotetramer with isocitrate as substrate. kcat is 14.6 sec(-1) for the heterodimer composed of IDH3A and IDH3B subunits with isocitrate as substrate. kcat is 9.72 sec(-1) for the heterodimer composed of IDH3A and IDH3G subunits with isocitrate as substrate. kcat is 23.4 sec(-1) for the heterotetramer with isocitrate as substrate in the presence of citrate and ATP. kcat is 11.9 sec(-1) for the heterodimer composed of IDH3A and IDH3G subunits with isocitrate as substrate in the presence of citrate and ATP. kcat is 28.4 sec(-1) for the heterotetramer with isocitrate as substrate in the presence of citrate and ADP. kcat is 15.8 sec(-1) for the heterodimer composed of IDH3A and IDH3B subunits with isocitrate as substrate in the presence of citrate and ADP. kcat is 17.6 sec(-1) for the heterodimer composed of IDH3A and IDH3G subunits with isocitrate as substrate in the presence of citrate and ADP.1 Publication
    1. Vmax=20.0 µmol/min/mg enzyme with isocitrate as substrate (heterotetramer)1 Publication
    2. Vmax=10.9 µmol/min/mg enzyme with isocitrate as substrate (heterodimer composed of IDH3A and IDH3B subunits)1 Publication
    3. Vmax=7.29 µmol/min/mg enzyme with isocitrate as substrate (heterodimer composed of IDH3A and IDH3G subunits)1 Publication
    4. Vmax=20.7 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate (heterotetramer)1 Publication
    5. Vmax=11.2 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate (heterodimer composed of IDH3A and IDH3B subunits)1 Publication
    6. Vmax=10.0 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate (heterodimer composed of IDH3A and IDH3G subunits)1 Publication
    7. Vmax=22.1 µmol/min/mg enzyme with isocitrate as substrate in the presence of ADP (heterotetramer)1 Publication
    8. Vmax=11.2 µmol/min/mg enzyme with isocitrate as substrate in the presence of ADP (heterodimer composed of IDH3A and IDH3B subunits)1 Publication
    9. Vmax=9.42 µmol/min/mg enzyme with isocitrate as substrate in the presence of ADP (heterodimer composed of IDH3A and IDH3G subunits)1 Publication
    10. Vmax=21.3 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate and ADP (heterotetramer)1 Publication
    11. Vmax=11.9 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate and ADP (heterodimer composed of IDH3A and IDH3B subunits)1 Publication
    12. Vmax=13.1 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate and ADP (heterodimer composed of IDH3A and IDH3G subunits)1 Publication
    13. Vmax=17.7 µmol/min/mg enzyme with isocitrate as substrate in the presence of ATP (heterotetramer)1 Publication
    14. Vmax=6.62 µmol/min/mg enzyme with isocitrate as substrate in the presence ATP (heterodimer composed of IDH3A and IDH3G subunits)1 Publication
    15. Vmax=17.6 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate and ATP (heterotetramer)1 Publication
    16. Vmax=8.94 µmol/min/mg enzyme with isocitrate as substrate in the presence of citrate and ATP (heterodimer composed of IDH3A and IDH3G subunits)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei115Substrate1 Publication1
    Binding sitei125Substrate1 Publication1
    Binding sitei146Substrate1 Publication1
    Sitei153Critical for catalysis2 Publications1
    Sitei200Critical for catalysis1 Publication1
    Metal bindingi233Magnesium or manganese1 Publication1
    Metal bindingi257Magnesium or manganese1 Publication1
    Metal bindingi261Magnesium or manganese1 Publication1

    GO - Molecular functioni

    GO - Biological processi

    • carbohydrate metabolic process Source: ProtInc
    • tricarboxylic acid cycle Source: Reactome

    Keywordsi

    Molecular functionOxidoreductase
    Biological processTricarboxylic acid cycle
    LigandMagnesium, Manganese, Metal-binding, NAD

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000166411-MONOMER.
    ReactomeiR-HSA-71403. Citric acid cycle (TCA cycle).
    SABIO-RKiP50213.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (EC:1.1.1.412 Publications)
    Alternative name(s):
    Isocitric dehydrogenase subunit alpha
    NAD(+)-specific ICDH subunit alpha
    Gene namesi
    Name:IDH3A
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 15

    Organism-specific databases

    HGNCiHGNC:5384. IDH3A.

    Subcellular locationi

    GO - Cellular componenti

    • mitochondrial matrix Source: Reactome
    • mitochondrion Source: HPA
    • myelin sheath Source: Ensembl
    • nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi152E → A: No significant effect on the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate and ADP. 1 Publication1
    Mutagenesisi153Y → F: Complete loss of activity of the heterotetramer, heterodimer composed of IDH3A and IDH3B subunits and the heterodimer composed of IDH3A and IDH3G subunits with no effect on their oligomeric states. 1 Publication1
    Mutagenesisi169K → A: Significantly impairs the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate and ADP. 1 Publication1
    Mutagenesisi200K → A: Significantly impairs the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate. 1 Publication1
    Mutagenesisi202N → A: Significantly impairs the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate. 1 Publication1
    Mutagenesisi208D → A: Complete loss of the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate and ADP. 1 Publication1
    Mutagenesisi255Y → A: Significantly impairs the activation of the heterodimer composed of IDH3A and IDH3G subunits by citrate and ADP. 1 Publication1

    Organism-specific databases

    DisGeNETi3419.
    OpenTargetsiENSG00000166411.
    PharmGKBiPA29632.

    Chemistry databases

    DrugBankiDB00157. NADH.

    Polymorphism and mutation databases

    BioMutaiIDH3A.
    DMDMi1708399.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 27MitochondrionCombined sourcesAdd BLAST27
    ChainiPRO_000001443628 – 366Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrialAdd BLAST339

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei77N6-succinyllysineBy similarity1
    Modified residuei101PhosphothreonineBy similarity1
    Modified residuei223N6-acetyllysineBy similarity1
    Modified residuei343N6-acetyllysine; alternateCombined sources1
    Modified residuei343N6-succinyllysine; alternateBy similarity1
    Modified residuei350N6-succinyllysineBy similarity1

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiP50213.
    MaxQBiP50213.
    PaxDbiP50213.
    PeptideAtlasiP50213.
    PRIDEiP50213.

    2D gel databases

    OGPiP50213.
    REPRODUCTION-2DPAGEiIPI00030702.

    PTM databases

    iPTMnetiP50213.
    PhosphoSitePlusiP50213.
    SwissPalmiP50213.

    Expressioni

    Gene expression databases

    BgeeiENSG00000166411.
    CleanExiHS_IDH3A.
    ExpressionAtlasiP50213. baseline and differential.
    GenevisibleiP50213. HS.

    Organism-specific databases

    HPAiHPA041465.
    HPA062971.

    Interactioni

    Subunit structurei

    Heterooligomer of subunits alpha (IDH3A), beta (IDH3B), and gamma (IDH3G) in the apparent ratio of 2:1:1. The heterodimer containing one IDH3A and one IDH3B subunit and the heterodimer containing one IDH3A and one IDH3G subunit assemble into a heterotetramer (which contains two subunits of IDH3A, one of IDH3B and one of IDH3G) and further into the heterooctamer.2 Publications

    Protein-protein interaction databases

    BioGridi109645. 51 interactors.
    IntActiP50213. 11 interactors.
    MINTiMINT-1148360.
    STRINGi9606.ENSP00000299518.

    Structurei

    Secondary structure

    1366
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi32 – 37Combined sources6
    Helixi43 – 56Combined sources14
    Beta strandi60 – 65Combined sources6
    Helixi82 – 91Combined sources10
    Beta strandi93 – 96Combined sources4
    Helixi110 – 118Combined sources9
    Beta strandi122 – 128Combined sources7
    Beta strandi131 – 133Combined sources3
    Beta strandi141 – 147Combined sources7
    Beta strandi149 – 151Combined sources3
    Beta strandi157 – 161Combined sources5
    Beta strandi164 – 172Combined sources9
    Helixi173 – 189Combined sources17
    Beta strandi194 – 199Combined sources6
    Turni201 – 203Combined sources3
    Helixi205 – 220Combined sources16
    Beta strandi225 – 231Combined sources7
    Helixi232 – 239Combined sources8
    Helixi243 – 245Combined sources3
    Beta strandi248 – 251Combined sources4
    Helixi253 – 267Combined sources15
    Helixi270 – 272Combined sources3
    Beta strandi275 – 278Combined sources4
    Helixi280 – 282Combined sources3
    Beta strandi284 – 287Combined sources4
    Helixi294 – 296Combined sources3
    Turni297 – 300Combined sources4
    Helixi305 – 318Combined sources14
    Helixi321 – 337Combined sources17
    Beta strandi338 – 340Combined sources3
    Helixi343 – 345Combined sources3
    Helixi351 – 363Combined sources13

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5GREX-ray2.65A28-366[»]
    5GRFX-ray2.50A28-366[»]
    5GRHX-ray2.80A28-366[»]
    5GRIX-ray2.31A28-366[»]
    5GRLX-ray2.79A28-366[»]
    ProteinModelPortaliP50213.
    SMRiP50213.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG0785. Eukaryota.
    COG0473. LUCA.
    GeneTreeiENSGT00550000074918.
    HOGENOMiHOG000021113.
    HOVERGENiHBG052080.
    InParanoidiP50213.
    KOiK00030.
    OMAiFQQIQTR.
    OrthoDBiEOG091G094X.
    PhylomeDBiP50213.
    TreeFamiTF105692.

    Family and domain databases

    InterProiView protein in InterPro
    IPR019818. IsoCit/isopropylmalate_DH_CS.
    IPR004434. Isocitrate_DH_NAD.
    IPR024084. IsoPropMal-DH-like_dom.
    PfamiView protein in Pfam
    PF00180. Iso_dh. 1 hit.
    SMARTiView protein in SMART
    SM01329. Iso_dh. 1 hit.
    TIGRFAMsiTIGR00175. mito_nad_idh. 1 hit.
    PROSITEiView protein in PROSITE
    PS00470. IDH_IMDH. 1 hit.

    Sequences (2)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P50213-1) [UniParc]FASTAAdd to basket

    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.

    « Hide

            10         20         30         40         50
    MAGPAWISKV SRLLGAFHNP KQVTRGFTGG VQTVTLIPGD GIGPEISAAV
    60 70 80 90 100
    MKIFDAAKAP IQWEERNVTA IQGPGGKWMI PSEAKESMDK NKMGLKGPLK
    110 120 130 140 150
    TPIAAGHPSM NLLLRKTFDL YANVRPCVSI EGYKTPYTDV NIVTIRENTE
    160 170 180 190 200
    GEYSGIEHVI VDGVVQSIKL ITEGASKRIA EFAFEYARNN HRSNVTAVHK
    210 220 230 240 250
    ANIMRMSDGL FLQKCREVAE SCKDIKFNEM YLDTVCLNMV QDPSQFDVLV
    260 270 280 290 300
    MPNLYGDILS DLCAGLIGGL GVTPSGNIGA NGVAIFESVH GTAPDIAGKD
    310 320 330 340 350
    MANPTALLLS AVMMLRHMGL FDHAARIEAA CFATIKDGKS LTKDLGGNAK
    360
    CSDFTEEICR RVKDLD
    Length:366
    Mass (Da):39,592
    Last modified:October 1, 1996 - v1
    Checksum:i695F6A34F97430CF
    GO
    Isoform 2 (identifier: P50213-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-78: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:288
    Mass (Da):31,381
    Checksum:iBF8327BD4AA7D3EC
    GO

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0145161 – 78Missing in isoform 2. 1 PublicationAdd BLAST78

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U07681 mRNA. Translation: AAA85639.1.
    AL442090 mRNA. Translation: CAC09449.1.
    CH471136 Genomic DNA. Translation: EAW99181.1.
    CH471136 Genomic DNA. Translation: EAW99182.1.
    BC021967 mRNA. Translation: AAH21967.1.
    CCDSiCCDS10297.1. [P50213-1]
    PIRiS55282.
    RefSeqiNP_005521.1. NM_005530.2. [P50213-1]
    UniGeneiHs.591110.

    Genome annotation databases

    EnsembliENST00000299518; ENSP00000299518; ENSG00000166411. [P50213-1]
    GeneIDi3419.
    KEGGihsa:3419.
    UCSCiuc002bdd.4. human. [P50213-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiIDH3A_HUMAN
    AccessioniPrimary (citable) accession number: P50213
    Secondary accession number(s): D3DW83, Q9H3X0
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: August 30, 2017
    This is version 175 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 15
      Human chromosome 15: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families