ODPAT_HUMAN
ID ODPAT_HUMAN Reviewed; 388 AA.
AC P29803; B2R9Q3; Q0VDI5; Q4VC02; Q6NXQ1;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1993, sequence version 1.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial;
DE EC=1.2.4.1;
DE AltName: Full=PDHE1-A type II;
DE Flags: Precursor;
GN Name=PDHA2; Synonyms=PDHAL;
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 [GENOMIC DNA].
RC TISSUE=Testis;
RX PubMed=2249846; DOI=10.1016/0888-7543(90)90275-y;
RA Dahl H.-H.M., Brown R.M., Hutchison W.M., Maragos C., Brown G.K.;
RT "A testis-specific form of the human pyruvate dehydrogenase E1 alpha
RT subunit is coded for by an intronless gene on chromosome 4.";
RL Genomics 8:225-232(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [4]
RP SUBUNIT.
RX PubMed=14638692; DOI=10.1074/jbc.m308172200;
RA Hiromasa Y., Fujisawa T., Aso Y., Roche T.E.;
RT "Organization of the cores of the mammalian pyruvate dehydrogenase complex
RT formed by E2 and E2 plus the E3-binding protein and their capacities to
RT bind the E1 and E3 components.";
RL J. Biol. Chem. 279:6921-6933(2004).
RN [5]
RP CATALYTIC ACTIVITY, FUNCTION, PHOSPHORYLATION AT SER-291 AND SER-298, AND
RP MUTAGENESIS OF SER-230; SER-291 AND SER-298.
RX PubMed=16436377; DOI=10.1074/jbc.m511481200;
RA Korotchkina L.G., Sidhu S., Patel M.S.;
RT "Characterization of testis-specific isoenzyme of human pyruvate
RT dehydrogenase.";
RL J. Biol. Chem. 281:9688-9696(2006).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=22750801; DOI=10.1016/j.gene.2012.06.068;
RA Pinheiro A., Silva M.J., Graca I., Silva J., Sa R., Sousa M., Barros A.,
RA Tavares de Almeida I., Rivera I.;
RT "Pyruvate dehydrogenase complex: mRNA and protein expression patterns of
RT E1alpha subunit genes in human spermatogenesis.";
RL Gene 506:173-178(2012).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT SER-291 AND
RP SER-293, AND MUTAGENESIS OF SER-291 AND SER-293.
RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057;
RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A.,
RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J.,
RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G.,
RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y.,
RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.;
RT "Rewiring of the Human Mitochondrial Interactome during Neuronal
RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis.";
RL IScience 19:1114-1132(2019).
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:16436377}.
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:16436377};
CC -!- COFACTOR:
CC Name=thiamine diphosphate; Xref=ChEBI:CHEBI:58937;
CC -!- ACTIVITY REGULATION: Pyruvate dehydrogenase activity is inhibited by
CC phosphorylation of PDHA2; it is reactivated by dephosphorylation.
CC -!- SUBUNIT: Heterotetramer of two PDHA2 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.
CC {ECO:0000269|PubMed:14638692}.
CC -!- INTERACTION:
CC P29803; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-2957428, EBI-16439278;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- TISSUE SPECIFICITY: Testis. Expressed in postmeiotic spermatogenic
CC cells. {ECO:0000269|PubMed:22750801}.
CC -!- PTM: Phosphorylation at Ser-291, Ser-293 and Ser-298 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-291, Ser-293 and Ser-298, is required
CC for reactivation. {ECO:0000269|PubMed:16436377}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH94760.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; M86808; AAA60232.1; -; Genomic_DNA.
DR EMBL; AK313872; BAG36600.1; -; mRNA.
DR EMBL; BC030697; AAH30697.3; -; mRNA.
DR EMBL; BC066953; AAH66953.2; -; mRNA.
DR EMBL; BC094760; AAH94760.1; ALT_INIT; mRNA.
DR EMBL; BC119656; AAI19657.1; -; mRNA.
DR EMBL; BC119657; AAI19658.1; -; mRNA.
DR EMBL; BC127637; AAI27638.1; -; mRNA.
DR EMBL; BC127638; AAI27639.1; -; mRNA.
DR CCDS; CCDS3644.1; -.
DR PIR; A37104; DEHUPT.
DR RefSeq; NP_005381.1; NM_005390.4.
DR AlphaFoldDB; P29803; -.
DR SMR; P29803; -.
DR BioGRID; 111187; 19.
DR ComplexPortal; CPX-6242; Mitochondrial pyruvate dehydrogenase complex, testis-specific variant.
DR IntAct; P29803; 9.
DR MINT; P29803; -.
DR STRING; 9606.ENSP00000295266; -.
DR DrugBank; DB00157; NADH.
DR iPTMnet; P29803; -.
DR PhosphoSitePlus; P29803; -.
DR BioMuta; PDHA2; -.
DR EPD; P29803; -.
DR jPOST; P29803; -.
DR MassIVE; P29803; -.
DR MaxQB; P29803; -.
DR PaxDb; P29803; -.
DR PeptideAtlas; P29803; -.
DR PRIDE; P29803; -.
DR ProteomicsDB; 54610; -.
DR Antibodypedia; 25781; 156 antibodies from 26 providers.
DR DNASU; 5161; -.
DR Ensembl; ENST00000295266.6; ENSP00000295266.4; ENSG00000163114.6.
DR GeneID; 5161; -.
DR KEGG; hsa:5161; -.
DR MANE-Select; ENST00000295266.6; ENSP00000295266.4; NM_005390.5; NP_005381.1.
DR UCSC; uc003htr.5; human.
DR CTD; 5161; -.
DR DisGeNET; 5161; -.
DR GeneCards; PDHA2; -.
DR HGNC; HGNC:8807; PDHA2.
DR HPA; ENSG00000163114; Tissue enriched (testis).
DR MalaCards; PDHA2; -.
DR MIM; 179061; gene.
DR neXtProt; NX_P29803; -.
DR OpenTargets; ENSG00000163114; -.
DR PharmGKB; PA33151; -.
DR VEuPathDB; HostDB:ENSG00000163114; -.
DR eggNOG; KOG0225; Eukaryota.
DR GeneTree; ENSGT00530000063174; -.
DR HOGENOM; CLU_029393_5_2_1; -.
DR InParanoid; P29803; -.
DR OMA; FGMPGVT; -.
DR OrthoDB; 871160at2759; -.
DR PhylomeDB; P29803; -.
DR TreeFam; TF300742; -.
DR PathwayCommons; P29803; -.
DR Reactome; R-HSA-204174; Regulation of pyruvate dehydrogenase (PDH) complex.
DR Reactome; R-HSA-389661; Glyoxylate metabolism and glycine degradation.
DR Reactome; R-HSA-5362517; Signaling by Retinoic Acid.
DR Reactome; R-HSA-70268; Pyruvate metabolism.
DR SignaLink; P29803; -.
DR SIGNOR; P29803; -.
DR BioGRID-ORCS; 5161; 13 hits in 1074 CRISPR screens.
DR ChiTaRS; PDHA2; human.
DR GeneWiki; Pyruvate_dehydrogenase_(lipoamide)_alpha_2; -.
DR GenomeRNAi; 5161; -.
DR Pharos; P29803; Tbio.
DR PRO; PR:P29803; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P29803; protein.
DR Bgee; ENSG00000163114; Expressed in sperm and 27 other tissues.
DR Genevisible; P29803; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0004739; F:pyruvate dehydrogenase (acetyl-transferring) activity; IDA:UniProtKB.
DR GO; GO:0034604; F:pyruvate dehydrogenase (NAD+) activity; IEA:Ensembl.
DR GO; GO:0006086; P:acetyl-CoA biosynthetic process from pyruvate; IBA:GO_Central.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006090; P:pyruvate metabolic process; IDA:UniProtKB.
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 Carbohydrate metabolism; Glucose metabolism; Mitochondrion; Oxidoreductase;
KW Phosphoprotein; Pyruvate; Reference proteome; Thiamine pyrophosphate;
KW Transit peptide; Tricarboxylic acid cycle.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 28..388
FT /note="Pyruvate dehydrogenase E1 component subunit alpha,
FT testis-specific form, mitochondrial"
FT /id="PRO_0000020447"
FT MOD_RES 291
FT /note="Phosphoserine; by PDK1, PDK2, PDK3 and PDK4"
FT /evidence="ECO:0000269|PubMed:16436377,
FT ECO:0000269|PubMed:31536960"
FT MOD_RES 293
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:31536960"
FT MOD_RES 298
FT /note="Phosphoserine; by PDK3"
FT /evidence="ECO:0000269|PubMed:16436377"
FT VARIANT 376
FT /note="R -> G (in dbSNP:rs17024795)"
FT /id="VAR_034359"
FT MUTAGEN 230
FT /note="S->A: Slightly reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:16436377"
FT MUTAGEN 291
FT /note="S->A: Strongly reduces enzyme activity. Increases
FT enzyme activity in stem cells."
FT /evidence="ECO:0000269|PubMed:16436377,
FT ECO:0000269|PubMed:31536960"
FT MUTAGEN 291
FT /note="S->E,D: Abolishes enzyme activity. Increases
FT neuronal cell death in response to glutamate
FT excitotoxicity."
FT /evidence="ECO:0000269|PubMed:16436377,
FT ECO:0000269|PubMed:31536960"
FT MUTAGEN 293
FT /note="S->A: Increases enzyme activity in stem cells."
FT /evidence="ECO:0000269|PubMed:31536960"
FT MUTAGEN 293
FT /note="S->D: Abolishes enzyme activity. Increases neuronal
FT cell death in response to glutamate excitotoxicity."
FT /evidence="ECO:0000269|PubMed:31536960"
FT MUTAGEN 298
FT /note="S->A: Slightly reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:16436377"
FT CONFLICT 127
FT /note="L -> P (in Ref. 3; AAH66953)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 388 AA; 42933 MW; 075B6CFF6DC73CC5 CRC64;
MLAAFISRVL RRVAQKSARR VLVASRNSSN DATFEIKKCD LYLLEEGPPV TTVLTRAEGL
KYYRMMLTVR RMELKADQLY KQKFIRGFCH LCDGQEACCV GLEAGINPSD HVITSYRAHG
VCYTRGLSVR SILAELTGRR GGCAKGKGGS MHMYTKNFYG GNGIVGAQGP LGAGIALACK
YKGNDEICLT LYGDGAANQG QIAEAFNMAA LWKLPCVFIC ENNLYGMGTS TERAAASPDY
YKRGNFIPGL KVDGMDVLCV REATKFAANY CRSGKGPILM ELQTYRYHGH SMSDPGVSYR
TREEIQEVRS KRDPIIILQD RMVNSKLATV EELKEIGAEV RKEIDDAAQF ATTDPEPHLE
ELGHHIYSSD SSFEVRGANP WIKFKSVS
