IDH3A_MOUSE
ID IDH3A_MOUSE Reviewed; 366 AA.
AC Q9D6R2; Q3UAM8; Q8C8A1; Q9D1L1;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial;
DE EC=1.1.1.41;
DE AltName: Full=Isocitric dehydrogenase subunit alpha;
DE AltName: Full=NAD(+)-specific ICDH subunit alpha;
DE Flags: Precursor;
GN Name=Idh3a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, and DBA/2J;
RC TISSUE=Bone marrow, Heart, Tongue, Visual cortex, and Wolffian duct;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=FVB/N; TISSUE=Liver;
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 [3]
RP PROTEIN SEQUENCE OF 59-85; 101-188; 206-214 AND 300-336, AND IDENTIFICATION
RP BY MASS SPECTROMETRY.
RC STRAIN=C57BL/6J, and OF1; TISSUE=Brain, and Hippocampus;
RA Lubec G., Kang S.U., Klug S., Yang J.W., Zigmond M., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-101, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-77; LYS-343 AND LYS-350, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast, and Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-223, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23576753; DOI=10.1073/pnas.1302961110;
RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B.,
RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.;
RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria
RT identifies substrates of SIRT3 in metabolic pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013).
RN [7]
RP DISRUPTION PHENOTYPE, AND MUTAGENESIS OF GLU-229.
RX PubMed=30478029; DOI=10.1242/dmm.036426;
RA Findlay A.S., Carter R.N., Starbuck B., McKie L., Novakova K., Budd P.S.,
RA Keighren M.A., Marsh J.A., Cross S.H., Simon M.M., Potter P.K.,
RA Morton N.M., Jackson I.J.;
RT "Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial
RT function.";
RL Dis. Model. Mech. 11:0-0(2018).
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:0000250|UniProtKB:P50213}.
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 -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P50213};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P50213};
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:0000250|UniProtKB:P50213};
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:0000250|UniProtKB:P50213}.
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:0000250|UniProtKB:P50213}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9D6R2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9D6R2-2; Sequence=VSP_014517;
CC -!- DISRUPTION PHENOTYPE: IDH3A-null homozygous mice do not survive early
CC embryogenesis (PubMed:30478029). Compound heterozygous mice for the
CC IDH3A-null allele and mutant p.E229K are viable and exhibit rapid
CC retinal degeneration (PubMed:30478029). {ECO:0000269|PubMed:30478029}.
CC -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC dehydrogenases family. {ECO:0000305}.
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DR EMBL; AK003393; BAB22760.1; -; mRNA.
DR EMBL; AK010065; BAB26679.1; -; mRNA.
DR EMBL; AK032787; BAC28021.1; -; mRNA.
DR EMBL; AK047951; BAC33199.1; -; mRNA.
DR EMBL; AK150618; BAE29708.1; -; mRNA.
DR EMBL; AK151304; BAE30286.1; -; mRNA.
DR EMBL; AK152353; BAE31145.1; -; mRNA.
DR EMBL; AK153459; BAE32011.1; -; mRNA.
DR EMBL; AK158646; BAE34596.1; -; mRNA.
DR EMBL; AK159051; BAE34785.1; -; mRNA.
DR EMBL; AK168049; BAE40031.1; -; mRNA.
DR EMBL; AK168149; BAE40114.1; -; mRNA.
DR EMBL; AK169152; BAE40931.1; -; mRNA.
DR EMBL; BC034273; AAH34273.1; -; mRNA.
DR EMBL; BC049956; AAH49956.1; -; mRNA.
DR CCDS; CCDS23191.1; -. [Q9D6R2-1]
DR RefSeq; NP_083849.1; NM_029573.2. [Q9D6R2-1]
DR AlphaFoldDB; Q9D6R2; -.
DR SMR; Q9D6R2; -.
DR BioGRID; 212466; 59.
DR ComplexPortal; CPX-556; Mitochondrial isocitrate dehydrogenase complex (NAD+).
DR IntAct; Q9D6R2; 12.
DR MINT; Q9D6R2; -.
DR STRING; 10090.ENSMUSP00000127526; -.
DR iPTMnet; Q9D6R2; -.
DR PhosphoSitePlus; Q9D6R2; -.
DR SwissPalm; Q9D6R2; -.
DR REPRODUCTION-2DPAGE; Q9D6R2; -.
DR UCD-2DPAGE; Q9D6R2; -.
DR CPTAC; non-CPTAC-3649; -.
DR EPD; Q9D6R2; -.
DR jPOST; Q9D6R2; -.
DR MaxQB; Q9D6R2; -.
DR PaxDb; Q9D6R2; -.
DR PeptideAtlas; Q9D6R2; -.
DR PRIDE; Q9D6R2; -.
DR ProteomicsDB; 269527; -. [Q9D6R2-1]
DR ProteomicsDB; 269528; -. [Q9D6R2-2]
DR TopDownProteomics; Q9D6R2-1; -. [Q9D6R2-1]
DR Antibodypedia; 14994; 299 antibodies from 34 providers.
DR DNASU; 67834; -.
DR Ensembl; ENSMUST00000167866; ENSMUSP00000127526; ENSMUSG00000032279. [Q9D6R2-1]
DR GeneID; 67834; -.
DR KEGG; mmu:67834; -.
DR UCSC; uc009prg.1; mouse. [Q9D6R2-1]
DR CTD; 3419; -.
DR MGI; MGI:1915084; Idh3a.
DR VEuPathDB; HostDB:ENSMUSG00000032279; -.
DR eggNOG; KOG0785; Eukaryota.
DR GeneTree; ENSGT00950000182989; -.
DR HOGENOM; CLU_031953_0_1_1; -.
DR InParanoid; Q9D6R2; -.
DR OrthoDB; 868374at2759; -.
DR PhylomeDB; Q9D6R2; -.
DR TreeFam; TF105692; -.
DR BRENDA; 1.1.1.41; 3474.
DR Reactome; R-MMU-71403; Citric acid cycle (TCA cycle).
DR BioGRID-ORCS; 67834; 21 hits in 73 CRISPR screens.
DR PRO; PR:Q9D6R2; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q9D6R2; protein.
DR Bgee; ENSMUSG00000032279; Expressed in sternocleidomastoid and 274 other tissues.
DR ExpressionAtlas; Q9D6R2; baseline and differential.
DR Genevisible; Q9D6R2; MM.
DR GO; GO:0005962; C:mitochondrial isocitrate dehydrogenase complex (NAD+); ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0043209; C:myelin sheath; HDA:UniProtKB.
DR GO; GO:0004449; F:isocitrate dehydrogenase (NAD+) activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; ISO:MGI.
DR GO; GO:0006102; P:isocitrate metabolic process; ISO:MGI.
DR GO; GO:0006734; P:NADH metabolic process; ISO:MGI.
DR GO; GO:0006099; P:tricarboxylic acid cycle; ISO:MGI.
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 Acetylation; Alternative splicing; Direct protein sequencing; Magnesium;
KW Manganese; Metal-binding; Mitochondrion; NAD; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 28..366
FT /note="Isocitrate dehydrogenase [NAD] subunit alpha,
FT mitochondrial"
FT /id="PRO_0000014438"
FT BINDING 115
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT BINDING 125
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT BINDING 146
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT BINDING 233
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT BINDING 257
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT BINDING 261
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT SITE 153
FT /note="Critical for catalysis"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT SITE 200
FT /note="Critical for catalysis"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT MOD_RES 77
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 101
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 223
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 343
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P50213"
FT MOD_RES 343
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 350
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT VAR_SEQ 1..78
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_014517"
FT MUTAGEN 229
FT /note="E->K: Homozygous mutant mice exhibit retinal
FT degeneration."
FT /evidence="ECO:0000269|PubMed:30478029"
FT CONFLICT 306
FT /note="A -> T (in Ref. 1; BAC33199)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 366 AA; 39639 MW; 9F1D68C269376955 CRC64;
MAGSAWVSKV SRLLGAFHNT KQVTRGFAGG VQTVTLIPGD GIGPEISASV MKIFDAAKAP
IQWEERNVTA IQGPGGKWMI PPEAKESMDK NKMGLKGPLK TPIAAGHPSM NLLLRKTFDL
YANVRPCVSI EGYKTPYTDV NIVTIRENTE GEYSGIEHVI VDGVVQSIKL ITEEASKRIA
EFAFEYARNN HRSNVTAVHK ANIMRMSDGL FLQKCREVAE NCKDIKFNEM YLDTVCLNMV
QDPSQFDVLV MPNLYGDILS DLCAGLIGGL GVTPSGNIGA NGVAIFESVH GTAPDIAGKD
MANPTALLLS AVMMLRHMGL FDHAAKIEAA CFATIKDGKS LTKDLGGNAK CSDFTEEICR
RVKDLD
