ODPA_MOUSE
ID ODPA_MOUSE Reviewed; 390 AA.
AC P35486;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial;
DE EC=1.2.4.1;
DE AltName: Full=PDHE1-A type I;
DE Flags: Precursor;
GN Name=Pdha1; Synonyms=Pdha-1;
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 [MRNA].
RX PubMed=1581363; DOI=10.1016/0167-4781(92)90102-6;
RA Fitzgerald G.F., Hutchison W.M., Dahl H.-H.M.;
RT "Isolation and characterisation of the mouse pyruvate dehydrogenase E1
RT alpha genes.";
RL Biochim. Biophys. Acta 1131:83-90(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Mammary gland;
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 46-58; 120-127; 133-141; 159-182; 216-244; 246-263;
RP 268-274; 278-321; 324-343 AND 379-385, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC STRAIN=C57BL/6J; TISSUE=Brain, and Hippocampus;
RA Lubec G., Klug S., Kang S.U.;
RL Submitted (APR-2007) to UniProtKB.
RN [4]
RP DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=11708858; DOI=10.1006/mgme.2001.3249;
RA Johnson M.T., Mahmood S., Hyatt S.L., Yang H.S., Soloway P.D., Hanson R.W.,
RA Patel M.S.;
RT "Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its
RT effect on early embryonic development.";
RL Mol. Genet. Metab. 74:293-302(2001).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=17314311; DOI=10.1095/biolreprod.106.059899;
RA Johnson M.T., Freeman E.A., Gardner D.K., Hunt P.A.;
RT "Oxidative metabolism of pyruvate is required for meiotic maturation of
RT murine oocytes in vivo.";
RL Biol. Reprod. 77:2-8(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232 AND SER-293, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17208939; DOI=10.1074/mcp.m600218-mcp200;
RA Lee J., Xu Y., Chen Y., Sprung R., Kim S.C., Xie S., Zhao Y.;
RT "Mitochondrial phosphoproteome revealed by an improved IMAC method and
RT MS/MS/MS.";
RL Mol. Cell. Proteomics 6:669-676(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232; SER-293; SER-295 AND
RP SER-300, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=18586888; DOI=10.1152/ajpheart.00363.2008;
RA Sidhu S., Gangasani A., Korotchkina L.G., Suzuki G., Fallavollita J.A.,
RA Canty J.M. Jr., Patel M.S.;
RT "Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac
RT hypertrophy and sudden death of weaned male mice.";
RL Am. J. Physiol. 295:H946-H952(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-301, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=18034455; DOI=10.1021/pr0701254;
RA Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.;
RT "Large-scale identification and evolution indexing of tyrosine
RT phosphorylation sites from murine brain.";
RL J. Proteome Res. 7:311-318(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=18630941; DOI=10.1021/pr800223m;
RA Zhou H., Ye M., Dong J., Han G., Jiang X., Wu R., Zou H.;
RT "Specific phosphopeptide enrichment with immobilized titanium ion affinity
RT chromatography adsorbent for phosphoproteome analysis.";
RL J. Proteome Res. 7:3957-3967(2008).
RN [11]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-232; SER-293 AND SER-300.
RX PubMed=19341700; DOI=10.1016/j.ab.2009.03.040;
RA Rardin M.J., Wiley S.E., Naviaux R.K., Murphy A.N., Dixon J.E.;
RT "Monitoring phosphorylation of the pyruvate dehydrogenase complex.";
RL Anal. Biochem. 389:157-164(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [13]
RP DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=20841503; DOI=10.1152/ajpendo.00339.2010;
RA Srinivasan M., Choi C.S., Ghoshal P., Pliss L., Pandya J.D., Hill D.,
RA Cline G., Patel M.S.;
RT "Beta-cell-specific pyruvate dehydrogenase deficiency impairs glucose-
RT stimulated insulin secretion.";
RL Am. J. Physiol. 299:E910-E917(2010).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232; SER-293; SER-295 AND
RP SER-300, AND IDENTIFICATION BY 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 [15]
RP ACETYLATION AT LYS-336, AND MUTAGENESIS OF LYS-336.
RX PubMed=23835326; DOI=10.2337/db12-1650;
RA Jing E., O'Neill B.T., Rardin M.J., Kleinridders A., Ilkeyeva O.R.,
RA Ussar S., Bain J.R., Lee K.Y., Verdin E.M., Newgard C.B., Gibson B.W.,
RA Kahn C.R.;
RT "Sirt3 regulates metabolic flexibility of skeletal muscle through
RT reversible enzymatic deacetylation.";
RL Diabetes 62:3404-3417(2013).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-313, SUCCINYLATION [LARGE SCALE
RP ANALYSIS] AT LYS-63; LYS-244; LYS-277; LYS-313 AND LYS-385, 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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-63; LYS-244; LYS-267 AND LYS-321,
RP AND IDENTIFICATION BY MASS 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).
CC -!- FUNCTION: The pyruvate dehydrogenase complex catalyzes the overall
CC conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the
CC glycolytic pathway to the tricarboxylic cycle.
CC {ECO:0000269|PubMed:11708858, ECO:0000269|PubMed:20841503}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-N(6)-lipoyl-L-lysyl-[dihydrolipoyllysine-residue
CC acetyltransferase] + H(+) + pyruvate = (R)-N(6)-(S(8)-
CC acetyldihydrolipoyl)-L-lysyl-[dihydrolipoyllysine-residue
CC acetyltransferase] + CO2; Xref=Rhea:RHEA:19189, Rhea:RHEA-COMP:10480,
CC Rhea:RHEA-COMP:10481, ChEBI:CHEBI:15361, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:83099, ChEBI:CHEBI:83111; EC=1.2.4.1;
CC Evidence={ECO:0000269|PubMed:11708858, ECO:0000269|PubMed:20841503};
CC -!- COFACTOR:
CC Name=thiamine diphosphate; Xref=ChEBI:CHEBI:58937;
CC -!- ACTIVITY REGULATION: Pyruvate dehydrogenase activity is inhibited by
CC phosphorylation of PDHA1; it is reactivated by dephosphorylation.
CC -!- SUBUNIT: Heterotetramer of two PDHA1 and two PDHB subunits. The
CC heterotetramer interacts with DLAT, and is part of the multimeric
CC pyruvate dehydrogenase complex that contains multiple copies of
CC pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT,
CC E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to
CC an inner core composed of about 48 DLAT and 12 PDHX molecules (By
CC similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P35486; Q9QXS1: Plec; NbExp=2; IntAct=EBI-773613, EBI-774583;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:19341700}.
CC -!- TISSUE SPECIFICITY: In all tissues, but in very low amount in testis.
CC -!- PTM: Phosphorylation at Ser-232, Ser-293 and Ser-300 by PDK family
CC kinases inactivates the enzyme; for this phosphorylation at a single
CC site is sufficient. Phosphorylation at Ser-293 interferes with access
CC to active site, and thereby inactivates the enzyme. Dephosphorylation
CC at all three sites, i.e. at Ser-232, Ser-293 and Ser-300, is required
CC for reactivation (By similarity). {ECO:0000250}.
CC -!- PTM: Acetylation alters the phosphorylation pattern. Deacetylated by
CC SIRT3. {ECO:0000269|PubMed:19341700, ECO:0000269|PubMed:23835326}.
CC -!- DISRUPTION PHENOTYPE: Complete embryonic lethality. Normal embryonic
CC development ceases about 9.5 dpc. Conditional gene disruption in the
CC heart causes death shortly after weaning in male mice fed normal chow,
CC while mice on high fat diet survive, but develop left ventricular
CC hypertrophy, due to impaired glucose and energy metabolism in the
CC heart. Likewise, conditional gene disruption in pancreas islet beta
CC cells disrupts normal insulin secretion in response to glucose stimuli,
CC while conditional gene disruption in oocytes causes reduced ATP levels
CC and thereby prevents normal meiosis during oocyte maturation.
CC {ECO:0000269|PubMed:11708858, ECO:0000269|PubMed:17314311,
CC ECO:0000269|PubMed:18586888, ECO:0000269|PubMed:20841503}.
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DR EMBL; M76727; AAA53046.1; -; mRNA.
DR EMBL; BC007142; AAH07142.1; -; mRNA.
DR CCDS; CCDS41195.1; -.
DR PIR; S23506; S23506.
DR RefSeq; NP_032836.1; NM_008810.3.
DR AlphaFoldDB; P35486; -.
DR SMR; P35486; -.
DR BioGRID; 202090; 45.
DR ComplexPortal; CPX-377; Pyruvate dehydrogenase E1 heterotetramer.
DR IntAct; P35486; 49.
DR MINT; P35486; -.
DR STRING; 10090.ENSMUSP00000033662; -.
DR iPTMnet; P35486; -.
DR PhosphoSitePlus; P35486; -.
DR SwissPalm; P35486; -.
DR REPRODUCTION-2DPAGE; P35486; -.
DR EPD; P35486; -.
DR jPOST; P35486; -.
DR PaxDb; P35486; -.
DR PeptideAtlas; P35486; -.
DR PRIDE; P35486; -.
DR ProteomicsDB; 293926; -.
DR Antibodypedia; 24225; 674 antibodies from 37 providers.
DR DNASU; 18597; -.
DR Ensembl; ENSMUST00000033662; ENSMUSP00000033662; ENSMUSG00000031299.
DR GeneID; 18597; -.
DR KEGG; mmu:18597; -.
DR UCSC; uc009utc.1; mouse.
DR CTD; 5160; -.
DR MGI; MGI:97532; Pdha1.
DR VEuPathDB; HostDB:ENSMUSG00000031299; -.
DR eggNOG; KOG0225; Eukaryota.
DR GeneTree; ENSGT00530000063174; -.
DR HOGENOM; CLU_029393_5_2_1; -.
DR InParanoid; P35486; -.
DR OMA; LGYEMPC; -.
DR OrthoDB; 871160at2759; -.
DR PhylomeDB; P35486; -.
DR TreeFam; TF300742; -.
DR BRENDA; 1.2.1.104; 3474.
DR Reactome; R-MMU-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-MMU-389661; Glyoxylate metabolism and glycine degradation.
DR Reactome; R-MMU-5362517; Signaling by Retinoic Acid.
DR Reactome; R-MMU-70268; Pyruvate metabolism.
DR BioGRID-ORCS; 18597; 11 hits in 75 CRISPR screens.
DR ChiTaRS; Pdha1; mouse.
DR PRO; PR:P35486; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; P35486; protein.
DR Bgee; ENSMUSG00000031299; Expressed in heart right ventricle and 281 other tissues.
DR ExpressionAtlas; P35486; baseline and differential.
DR Genevisible; P35486; MM.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0043209; C:myelin sheath; HDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; ISO:MGI.
DR GO; GO:0045254; C:pyruvate dehydrogenase complex; ISS:UniProtKB.
DR GO; GO:0004739; F:pyruvate dehydrogenase (acetyl-transferring) activity; ISO:MGI.
DR GO; GO:0034604; F:pyruvate dehydrogenase (NAD+) activity; IMP:MGI.
DR GO; GO:0004738; F:pyruvate dehydrogenase activity; IMP:MGI.
DR GO; GO:0006086; P:acetyl-CoA biosynthetic process from pyruvate; ISS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0061732; P:mitochondrial acetyl-CoA biosynthetic process from pyruvate; IMP:MGI.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IEA:UniProtKB-KW.
DR InterPro; IPR001017; DH_E1.
DR InterPro; IPR017597; Pyrv_DH_E1_asu_subgrp-y.
DR InterPro; IPR029061; THDP-binding.
DR Pfam; PF00676; E1_dh; 1.
DR SUPFAM; SSF52518; SSF52518; 1.
DR TIGRFAMs; TIGR03182; PDH_E1_alph_y; 1.
PE 1: Evidence at protein level;
KW Acetylation; Carbohydrate metabolism; Direct protein sequencing;
KW Glucose metabolism; Mitochondrion; Oxidoreductase; Phosphoprotein;
KW Pyruvate; Reference proteome; Thiamine pyrophosphate; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1..29
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 30..390
FT /note="Pyruvate dehydrogenase E1 component subunit alpha,
FT somatic form, mitochondrial"
FT /id="PRO_0000020442"
FT MOD_RES 63
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 63
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 232
FT /note="Phosphoserine; by PDK1"
FT /evidence="ECO:0000269|PubMed:19341700,
FT ECO:0007744|PubMed:17208939, ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 244
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 244
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 267
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 277
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 293
FT /note="Phosphoserine; by PDK1, PDK2, PDK3 and PDK4"
FT /evidence="ECO:0000269|PubMed:19341700,
FT ECO:0007744|PubMed:17208939, ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:19144319, ECO:0007744|PubMed:21183079"
FT MOD_RES 295
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 300
FT /note="Phosphoserine; by PDK1, PDK2, PDK3 and PDK4"
FT /evidence="ECO:0000269|PubMed:19341700,
FT ECO:0007744|PubMed:17242355, ECO:0007744|PubMed:21183079"
FT MOD_RES 301
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:18034455"
FT MOD_RES 313
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 313
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 321
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 336
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:23835326"
FT MOD_RES 385
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MUTAGEN 336
FT /note="K->Q,R: Decreases phosphorylation at S-232 and S-300
FT but does not affect activity or substrate metabolism."
FT /evidence="ECO:0000269|PubMed:23835326"
SQ SEQUENCE 390 AA; 43232 MW; 40898944CE8E0A03 CRC64;
MRKMLAAVSR VLAGSAQKPA SRVLVASRNF ANDATFEIKK CDLHRLEEGP PVTTVLTRED
GLKYYRMMQT VRRMELKADQ LYKQKIIRGF CHLCDGQEAC CVGLEAGINP TDHLITAYRA
HGFTFTRGLP VRAILAELTG RRGGCAKGKG GSMHMYAKNF YGGNGIVGAQ VPLGAGIALA
CKYNGKDEVC LTLYGDGAAN QGQIFEAYNM AALWKLPCIF ICENNRYGMG TSVERAAAST
DYYKRGDFIP GLRVDGMDIL CVREATKFAA AYCRSGKGPI LMELQTYRYH GHSMSDPGVS
YRTREEIQEV RSKSDPIMLL KDRMVNSNLA SVEELKEIDV EVRKEIEDAA QFATADPEPP
LEELGYHIYS SDPPFEVRGA NQWIKFKSVS
