IDH3A_HUMAN
ID IDH3A_HUMAN Reviewed; 366 AA.
AC P50213; D3DW83; Q9H3X0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial;
DE EC=1.1.1.41 {ECO:0000269|PubMed:28098230, ECO:0000269|PubMed:28139779};
DE AltName: Full=Isocitric dehydrogenase subunit alpha;
DE AltName: Full=NAD(+)-specific ICDH subunit alpha;
DE Flags: Precursor;
GN Name=IDH3A;
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 [MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RX PubMed=7755589; DOI=10.1042/bj3080063;
RA Kim Y.O., Oh I.U., Park H.S., Jeng J., Song B.J., Huh T.L.;
RT "Characterization of a cDNA clone for human NAD(+)-specific isocitrate
RT dehydrogenase alpha-subunit and structural comparison with its isoenzymes
RT from different species.";
RL Biochem. J. 308:63-68(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain cortex;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 [5]
RP PROTEIN SEQUENCE OF 135-146; 179-188 AND 300-316, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-343, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [8]
RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER PHE-27, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [9]
RP FUNCTION, SUBUNIT, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
RP COFACTOR, CATALYTIC ACTIVITY, AND MUTAGENESIS OF TYR-153.
RX PubMed=28139779; DOI=10.1038/srep41882;
RA Ma T., Peng Y., Huang W., Liu Y., Ding J.;
RT "The beta and gamma subunits play distinct functional roles in the
RT alpha2betagamma heterotetramer of human NAD-dependent isocitrate
RT dehydrogenase.";
RL Sci. Rep. 7:41882-41882(2017).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 28-366 IN COMPLEX WITH MAGNESIUM
RP AND CITRATE, SUBUNIT, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION,
RP AND MUTAGENESIS OF GLU-152; TYR-153; LYS-169; LYS-200; ASN-202; ASP-208 AND
RP TYR-255.
RX PubMed=28098230; DOI=10.1038/srep40921;
RA Ma T., Peng Y., Huang W., Ding J.;
RT "Molecular mechanism of the allosteric regulation of the alphagamma
RT heterodimer of human NAD-dependent isocitrate dehydrogenase.";
RL Sci. Rep. 7:40921-40921(2017).
RN [11]
RP VARIANTS RP90 155-GLY--ASP-366 DEL; VAL-175; THR-239; HIS-304; THR-313 AND
RP CYS-316, AND INVOLVEMENT IN RP90.
RX PubMed=28412069; DOI=10.1016/j.ophtha.2017.03.010;
RA Pierrache L.H.M., Kimchi A., Ratnapriya R., Roberts L., Astuti G.D.N.,
RA Obolensky A., Beryozkin A., Tjon-Fo-Sang M.J.H., Schuil J., Klaver C.C.W.,
RA Bongers E.M.H.F., Haer-Wigman L., Schalij N., Breuning M.H., Fischer G.M.,
RA Banin E., Ramesar R.S., Swaroop A., van den Born L.I., Sharon D.,
RA Cremers F.P.M.;
RT "Whole-exome sequencing identifies biallelic IDH3A variants as a cause of
RT retinitis pigmentosa accompanied by pseudocoloboma.";
RL Ophthalmology 124:992-1003(2017).
RN [12]
RP VARIANT RP90 ILE-204, AND INVOLVEMENT IN RP90.
RX PubMed=30058936; DOI=10.1080/13816810.2018.1502788;
RA Sun W., Zhang Q.;
RT "A novel variant in IDH3A identified in a case with Leber congenital
RT amaurosis accompanied by macular pseudocoloboma.";
RL Ophthalmic Genet. 39:662-663(2018).
RN [13]
RP VARIANT RP90 THR-122, AND INVOLVEMENT IN RP90.
RX PubMed=31012789; DOI=10.1080/13816810.2019.1605391;
RA Peter V.G., Nikopoulos K., Quinodoz M., Granse L., Farinelli P.,
RA Superti-Furga A., Andreasson S., Rivolta C.;
RT "A novel missense variant in IDH3A causes autosomal recessive retinitis
RT pigmentosa.";
RL Ophthalmic Genet. 40:177-181(2019).
CC -!- FUNCTION: Catalytic subunit of the enzyme which catalyzes the
CC decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The
CC heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and
CC the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G)
CC subunits, have considerable basal activity but the full activity of the
CC heterotetramer (containing two subunits of IDH3A, one of IDH3B and one
CC of IDH3G) requires the assembly and cooperative function of both
CC heterodimers. {ECO:0000269|PubMed:28139779}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH;
CC Xref=Rhea:RHEA:23632, ChEBI:CHEBI:15562, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.41;
CC Evidence={ECO:0000269|PubMed:28098230, ECO:0000269|PubMed:28139779};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:28098230, ECO:0000269|PubMed:28139779};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:28139779};
CC Note=Divalent metal cations; Mn(2+) or Mg(2+). Activity higher in
CC presence of Mn(2+) than of Mg(2+). Binds 1 Mg(2+) or Mn(2+) ion per
CC subunit. {ECO:0000269|PubMed:28139779};
CC -!- ACTIVITY REGULATION: The heterotetramer and the heterodimer composed of
CC IDH3A and IDH3G subunits can be allosterically activated by citrate
CC (CIT) or/and ADP, and the two activators can act independently or
CC synergistically. The heterodimer composed of IDH3A and IDH3B subunits
CC cannot be allosterically regulated and the allosteric regulation of the
CC heterotetramer is through the IDH3G subunit and not the IDH3B subunit.
CC The IDH3G subunit contains the allosteric site which consists of a CIT-
CC binding site and an ADP-binding site, and the binding of CIT and ADP
CC causes conformational changes at the allosteric site which are
CC transmitted to the active site in the catalytic subunit (IDH3A) through
CC a cascade of conformational changes at the heterodimer interface,
CC leading to stabilization of the isocitrate-binding at the active site
CC and thus activation of the enzyme. ATP can activate the heterotetramer
CC and the heterodimer composed of IDH3A and IDH3G subunits at low
CC concentrations but inhibits their activities at high concentrations,
CC whereas ATP exhibits only inhibitory effect on the heterodimer composed
CC of IDH3A and IDH3B subunits. {ECO:0000269|PubMed:28098230,
CC ECO:0000269|PubMed:28139779}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=20.0 umol/min/mg enzyme with isocitrate as substrate
CC (heterotetramer) {ECO:0000269|PubMed:28139779};
CC Vmax=10.9 umol/min/mg enzyme with isocitrate as substrate
CC (heterodimer composed of IDH3A and IDH3B subunits)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=7.29 umol/min/mg enzyme with isocitrate as substrate
CC (heterodimer composed of IDH3A and IDH3G subunits)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=20.7 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate (heterotetramer) {ECO:0000269|PubMed:28139779};
CC Vmax=11.2 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate (heterodimer composed of IDH3A and IDH3B
CC subunits) {ECO:0000269|PubMed:28139779};
CC Vmax=10.0 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate (heterodimer composed of IDH3A and IDH3G
CC subunits) {ECO:0000269|PubMed:28139779};
CC Vmax=22.1 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of ADP (heterotetramer) {ECO:0000269|PubMed:28139779};
CC Vmax=11.2 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of ADP (heterodimer composed of IDH3A and IDH3B subunits)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=9.42 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of ADP (heterodimer composed of IDH3A and IDH3G subunits)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=21.3 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate and ADP (heterotetramer)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=11.9 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate and ADP (heterodimer composed of IDH3A and IDH3B
CC subunits) {ECO:0000269|PubMed:28139779};
CC Vmax=13.1 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate and ADP (heterodimer composed of IDH3A and IDH3G
CC subunits) {ECO:0000269|PubMed:28139779};
CC Vmax=17.7 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of ATP (heterotetramer) {ECO:0000269|PubMed:28139779};
CC Vmax=6.62 umol/min/mg enzyme with isocitrate as substrate in the
CC presence ATP (heterodimer composed of IDH3A and IDH3G subunits)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=17.6 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate and ATP (heterotetramer)
CC {ECO:0000269|PubMed:28139779};
CC Vmax=8.94 umol/min/mg enzyme with isocitrate as substrate in the
CC presence of citrate and ATP (heterodimer composed of IDH3A and IDH3G
CC subunits) {ECO:0000269|PubMed:28139779};
CC Note=kcat is 26.7 sec(-1) for the heterotetramer with isocitrate as
CC substrate. kcat is 14.6 sec(-1) for the heterodimer composed of IDH3A
CC and IDH3B subunits with isocitrate as substrate. kcat is 9.72 sec(-1)
CC for the heterodimer composed of IDH3A and IDH3G subunits with
CC isocitrate as substrate. kcat is 23.4 sec(-1) for the heterotetramer
CC with isocitrate as substrate in the presence of citrate and ATP. kcat
CC is 11.9 sec(-1) for the heterodimer composed of IDH3A and IDH3G
CC subunits with isocitrate as substrate in the presence of citrate and
CC ATP. kcat is 28.4 sec(-1) for the heterotetramer with isocitrate as
CC substrate in the presence of citrate and ADP. kcat is 15.8 sec(-1)
CC for the heterodimer composed of IDH3A and IDH3B subunits with
CC isocitrate as substrate in the presence of citrate and ADP. kcat is
CC 17.6 sec(-1) for the heterodimer composed of IDH3A and IDH3G subunits
CC with isocitrate as substrate in the presence of citrate and ADP.
CC {ECO:0000269|PubMed:28139779};
CC -!- SUBUNIT: Heterooligomer of subunits alpha (IDH3A), beta (IDH3B), and
CC gamma (IDH3G) in the apparent ratio of 2:1:1. The heterodimer
CC containing one IDH3A and one IDH3B subunit and the heterodimer
CC containing one IDH3A and one IDH3G subunit assemble into a
CC heterotetramer (which contains two subunits of IDH3A, one of IDH3B and
CC one of IDH3G) and further into the heterooctamer.
CC {ECO:0000269|PubMed:28098230, ECO:0000269|PubMed:28139779}.
CC -!- INTERACTION:
CC P50213; P51553: IDH3G; NbExp=5; IntAct=EBI-355999, EBI-1210876;
CC P50213; P34896: SHMT1; NbExp=6; IntAct=EBI-355999, EBI-715117;
CC PRO_0000014436; O43837-2: IDH3B; NbExp=2; IntAct=EBI-25820746, EBI-725399;
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P50213-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50213-2; Sequence=VSP_014516;
CC -!- DISEASE: Retinitis pigmentosa 90 (RP90) [MIM:619007]: A form of
CC retinitis pigmentosa, a retinal dystrophy belonging to the group of
CC pigmentary retinopathies. Retinitis pigmentosa is characterized by
CC retinal pigment deposits visible on fundus examination and primary loss
CC of rod photoreceptor cells followed by secondary loss of cone
CC photoreceptors. Patients typically have night vision blindness and loss
CC of midperipheral visual field. RP90 is an autosomal recessive form.
CC {ECO:0000269|PubMed:28412069, ECO:0000269|PubMed:30058936,
CC ECO:0000269|PubMed:31012789}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC dehydrogenases family. {ECO:0000305}.
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DR EMBL; U07681; AAA85639.1; -; mRNA.
DR EMBL; AL442090; CAC09449.1; -; mRNA.
DR EMBL; CH471136; EAW99181.1; -; Genomic_DNA.
DR EMBL; CH471136; EAW99182.1; -; Genomic_DNA.
DR EMBL; BC021967; AAH21967.1; -; mRNA.
DR CCDS; CCDS10297.1; -. [P50213-1]
DR PIR; S55282; S55282.
DR RefSeq; NP_005521.1; NM_005530.2. [P50213-1]
DR PDB; 5GRE; X-ray; 2.65 A; A=28-366.
DR PDB; 5GRF; X-ray; 2.50 A; A=28-366.
DR PDB; 5GRH; X-ray; 2.80 A; A=28-366.
DR PDB; 5GRI; X-ray; 2.31 A; A=28-366.
DR PDB; 5GRL; X-ray; 2.79 A; A=28-366.
DR PDB; 5YVT; X-ray; 2.40 A; A=28-366.
DR PDB; 6KDE; X-ray; 3.00 A; A/C=28-366.
DR PDB; 6KDF; X-ray; 3.05 A; A/B/E/G/I/K/M/O=28-366.
DR PDB; 6KDY; X-ray; 3.02 A; A/C/E/G=28-366.
DR PDB; 6KE3; X-ray; 3.31 A; A/C/E/G=28-366.
DR PDB; 6L57; X-ray; 2.30 A; A=28-366.
DR PDB; 6L59; X-ray; 2.25 A; A=28-366.
DR PDB; 7CE3; X-ray; 3.47 A; A/C=1-366.
DR PDBsum; 5GRE; -.
DR PDBsum; 5GRF; -.
DR PDBsum; 5GRH; -.
DR PDBsum; 5GRI; -.
DR PDBsum; 5GRL; -.
DR PDBsum; 5YVT; -.
DR PDBsum; 6KDE; -.
DR PDBsum; 6KDF; -.
DR PDBsum; 6KDY; -.
DR PDBsum; 6KE3; -.
DR PDBsum; 6L57; -.
DR PDBsum; 6L59; -.
DR PDBsum; 7CE3; -.
DR AlphaFoldDB; P50213; -.
DR SMR; P50213; -.
DR BioGRID; 109645; 93.
DR ComplexPortal; CPX-553; Mitochondrial isocitrate dehydrogenase complex (NAD+).
DR CORUM; P50213; -.
DR IntAct; P50213; 24.
DR MINT; P50213; -.
DR STRING; 9606.ENSP00000299518; -.
DR ChEMBL; CHEMBL4296004; -.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB06757; Manganese.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB09092; Xanthinol.
DR CarbonylDB; P50213; -.
DR GlyGen; P50213; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P50213; -.
DR MetOSite; P50213; -.
DR PhosphoSitePlus; P50213; -.
DR SwissPalm; P50213; -.
DR BioMuta; IDH3A; -.
DR DMDM; 1708399; -.
DR OGP; P50213; -.
DR REPRODUCTION-2DPAGE; IPI00030702; -.
DR EPD; P50213; -.
DR jPOST; P50213; -.
DR MassIVE; P50213; -.
DR MaxQB; P50213; -.
DR PaxDb; P50213; -.
DR PeptideAtlas; P50213; -.
DR PRIDE; P50213; -.
DR ProteomicsDB; 56201; -. [P50213-1]
DR ProteomicsDB; 56202; -. [P50213-2]
DR Antibodypedia; 14994; 299 antibodies from 34 providers.
DR DNASU; 3419; -.
DR Ensembl; ENST00000299518.7; ENSP00000299518.2; ENSG00000166411.14. [P50213-1]
DR GeneID; 3419; -.
DR KEGG; hsa:3419; -.
DR MANE-Select; ENST00000299518.7; ENSP00000299518.2; NM_005530.3; NP_005521.1.
DR UCSC; uc002bdd.4; human. [P50213-1]
DR CTD; 3419; -.
DR DisGeNET; 3419; -.
DR GeneCards; IDH3A; -.
DR HGNC; HGNC:5384; IDH3A.
DR HPA; ENSG00000166411; Tissue enhanced (tongue).
DR MalaCards; IDH3A; -.
DR MIM; 601149; gene.
DR MIM; 619007; phenotype.
DR neXtProt; NX_P50213; -.
DR OpenTargets; ENSG00000166411; -.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA29632; -.
DR VEuPathDB; HostDB:ENSG00000166411; -.
DR eggNOG; KOG0785; Eukaryota.
DR GeneTree; ENSGT00950000182989; -.
DR HOGENOM; CLU_031953_0_1_1; -.
DR InParanoid; P50213; -.
DR OMA; KKGDPWP; -.
DR OrthoDB; 868374at2759; -.
DR PhylomeDB; P50213; -.
DR TreeFam; TF105692; -.
DR BioCyc; MetaCyc:ENSG00000166411-MON; -.
DR BRENDA; 1.1.1.41; 2681.
DR PathwayCommons; P50213; -.
DR Reactome; R-HSA-71403; Citric acid cycle (TCA cycle).
DR SABIO-RK; P50213; -.
DR SignaLink; P50213; -.
DR SIGNOR; P50213; -.
DR BioGRID-ORCS; 3419; 279 hits in 1085 CRISPR screens.
DR ChiTaRS; IDH3A; human.
DR GeneWiki; IDH3A; -.
DR GenomeRNAi; 3419; -.
DR Pharos; P50213; Tbio.
DR PRO; PR:P50213; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P50213; protein.
DR Bgee; ENSG00000166411; Expressed in right atrium auricular region and 206 other tissues.
DR ExpressionAtlas; P50213; baseline and differential.
DR Genevisible; P50213; HS.
DR GO; GO:0005962; C:mitochondrial isocitrate dehydrogenase complex (NAD+); IPI:ComplexPortal.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0004449; F:isocitrate dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0005975; P:carbohydrate metabolic process; NAS:ProtInc.
DR GO; GO:0006102; P:isocitrate metabolic process; IBA:GO_Central.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IDA:ComplexPortal.
DR InterPro; IPR019818; IsoCit/isopropylmalate_DH_CS.
DR InterPro; IPR004434; Isocitrate_DH_NAD.
DR InterPro; IPR024084; IsoPropMal-DH-like_dom.
DR Pfam; PF00180; Iso_dh; 1.
DR SMART; SM01329; Iso_dh; 1.
DR TIGRFAMs; TIGR00175; mito_nad_idh; 1.
DR PROSITE; PS00470; IDH_IMDH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Direct protein sequencing;
KW Disease variant; Magnesium; Manganese; Metal-binding; Mitochondrion; NAD;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Retinitis pigmentosa;
KW Transit peptide; Tricarboxylic acid cycle.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0007744|PubMed:25944712"
FT CHAIN 28..366
FT /note="Isocitrate dehydrogenase [NAD] subunit alpha,
FT mitochondrial"
FT /id="PRO_0000014436"
FT BINDING 115
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28098230"
FT BINDING 125
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28098230"
FT BINDING 146
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28098230"
FT BINDING 233
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:28098230"
FT BINDING 257
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:28098230"
FT BINDING 261
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:28098230"
FT SITE 153
FT /note="Critical for catalysis"
FT /evidence="ECO:0000269|PubMed:28098230,
FT ECO:0000269|PubMed:28139779"
FT SITE 200
FT /note="Critical for catalysis"
FT /evidence="ECO:0000269|PubMed:28098230"
FT MOD_RES 77
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D6R2"
FT MOD_RES 101
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9D6R2"
FT MOD_RES 223
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D6R2"
FT MOD_RES 343
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 343
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9D6R2"
FT MOD_RES 350
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D6R2"
FT VAR_SEQ 1..78
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_014516"
FT VARIANT 122
FT /note="A -> T (in RP90; unknown pathological significance;
FT dbSNP:rs756333430)"
FT /evidence="ECO:0000269|PubMed:31012789"
FT /id="VAR_084723"
FT VARIANT 155..366
FT /note="Missing (in RP90)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084724"
FT VARIANT 175
FT /note="A -> V (in RP90; unknown pathological significance;
FT dbSNP:rs765473830)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084725"
FT VARIANT 204
FT /note="M -> I (in RP90; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:30058936"
FT /id="VAR_084726"
FT VARIANT 239
FT /note="M -> T (in RP90; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084727"
FT VARIANT 304
FT /note="P -> H (in RP90; unknown pathological significance;
FT dbSNP:rs756712426)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084728"
FT VARIANT 313
FT /note="M -> T (in RP90; unknown pathological significance;
FT dbSNP:rs149862950)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084729"
FT VARIANT 316
FT /note="R -> C (in RP90; unknown pathological significance;
FT dbSNP:rs770798851)"
FT /evidence="ECO:0000269|PubMed:28412069"
FT /id="VAR_084730"
FT MUTAGEN 152
FT /note="E->A: No significant effect on the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by citrate
FT and ADP."
FT /evidence="ECO:0000269|PubMed:28098230"
FT MUTAGEN 153
FT /note="Y->F: Complete loss of activity of the
FT heterotetramer, heterodimer composed of IDH3A and IDH3B
FT subunits and the heterodimer composed of IDH3A and IDH3G
FT subunits with no effect on their oligomeric states."
FT /evidence="ECO:0000269|PubMed:28139779"
FT MUTAGEN 169
FT /note="K->A: Significantly impairs the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by citrate
FT and ADP."
FT /evidence="ECO:0000269|PubMed:28098230"
FT MUTAGEN 200
FT /note="K->A: Significantly impairs the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by
FT citrate."
FT /evidence="ECO:0000269|PubMed:28098230"
FT MUTAGEN 202
FT /note="N->A: Significantly impairs the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by
FT citrate."
FT /evidence="ECO:0000269|PubMed:28098230"
FT MUTAGEN 208
FT /note="D->A: Complete loss of the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by citrate
FT and ADP."
FT /evidence="ECO:0000269|PubMed:28098230"
FT MUTAGEN 255
FT /note="Y->A: Significantly impairs the activation of the
FT heterodimer composed of IDH3A and IDH3G subunits by citrate
FT and ADP."
FT /evidence="ECO:0000269|PubMed:28098230"
FT STRAND 33..37
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 40..42
FT /evidence="ECO:0007829|PDB:6KE3"
FT HELIX 43..56
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 62..65
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 82..91
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 93..96
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 104..106
FT /evidence="ECO:0007829|PDB:6KDE"
FT HELIX 110..118
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 122..128
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:5GRI"
FT STRAND 141..147
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 149..151
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 157..161
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 164..172
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 173..189
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 194..199
FT /evidence="ECO:0007829|PDB:6L59"
FT TURN 201..203
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 205..220
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 232..239
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 243..245
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 248..251
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 253..267
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 270..272
FT /evidence="ECO:0007829|PDB:6L57"
FT STRAND 275..278
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 280..282
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 284..287
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 294..296
FT /evidence="ECO:0007829|PDB:6L59"
FT TURN 297..300
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 305..318
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 321..337
FT /evidence="ECO:0007829|PDB:6L59"
FT STRAND 338..340
FT /evidence="ECO:0007829|PDB:5GRF"
FT STRAND 345..347
FT /evidence="ECO:0007829|PDB:6L59"
FT HELIX 351..363
FT /evidence="ECO:0007829|PDB:6L59"
SQ SEQUENCE 366 AA; 39592 MW; 695F6A34F97430CF CRC64;
MAGPAWISKV SRLLGAFHNP KQVTRGFTGG VQTVTLIPGD GIGPEISAAV MKIFDAAKAP
IQWEERNVTA IQGPGGKWMI PSEAKESMDK NKMGLKGPLK TPIAAGHPSM NLLLRKTFDL
YANVRPCVSI EGYKTPYTDV NIVTIRENTE GEYSGIEHVI VDGVVQSIKL ITEGASKRIA
EFAFEYARNN HRSNVTAVHK ANIMRMSDGL FLQKCREVAE SCKDIKFNEM YLDTVCLNMV
QDPSQFDVLV MPNLYGDILS DLCAGLIGGL GVTPSGNIGA NGVAIFESVH GTAPDIAGKD
MANPTALLLS AVMMLRHMGL FDHAARIEAA CFATIKDGKS LTKDLGGNAK CSDFTEEICR
RVKDLD
