ID ODBA_HUMAN Reviewed; 445 AA. AC P12694; B4DP47; E7EW46; Q16034; Q16472; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 2. DT 27-MAR-2024, entry version 247. DE RecName: Full=2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial {ECO:0000305|PubMed:10745006}; DE EC=1.2.4.4 {ECO:0000269|PubMed:10745006, ECO:0000269|PubMed:7883996, ECO:0000269|PubMed:9582350}; DE AltName: Full=Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; DE Short=BCKDE1A; DE Short=BCKDH E1-alpha; DE Flags: Precursor; GN Name=BCKDHA {ECO:0000312|HGNC:HGNC:986}; 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). RX PubMed=1420356; DOI=10.1016/0167-4781(92)90149-t; RA McKean M.C., Winkeler K.A., Danner D.J.; RT "Nucleotide sequence of the 5' end including the initiation codon of cDNA RT for the E1 alpha subunit of the human branched chain alpha-ketoacid RT dehydrogenase complex."; RL Biochim. Biophys. Acta 1171:109-112(1992). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Bone marrow, and Lung; 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 NUCLEOTIDE SEQUENCE [MRNA] OF 3-445 (ISOFORM 1). RX PubMed=2914958; DOI=10.1016/s0021-9258(18)94087-1; RA Fisher C.W., Chuang J.L., Griffin T.A., Lau K.S., Cox R.P., Chuang D.T.; RT "Molecular phenotypes in cultured maple syrup urine disease cells. Complete RT E1 alpha cDNA sequence and mRNA and subunit contents of the human branched RT chain alpha-keto acid dehydrogenase complex."; RL J. Biol. Chem. 264:3448-3453(1989). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 3-445, AND VARIANT MSUD1A ASN-438. RX PubMed=2060625; DOI=10.1016/0014-5793(91)80755-r; RA Dariush N., Fisher C.W., Cox R.P., Chuang D.T.; RT "Structure of the gene encoding the entire mature E1 alpha subunit of human RT branched-chain alpha-keto acid dehydrogenase complex."; RL FEBS Lett. 284:34-38(1991). RN [7] RP ERRATUM OF PUBMED:2060625. RX PubMed=1682165; DOI=10.1016/0014-5793(91)81324-2; RA Dariush N., Fisher C.W., Cox R.P., Chuang D.T.; RL FEBS Lett. 291:376-377(1991). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 68-445 (ISOFORM 1). RC TISSUE=Liver; RX PubMed=3224821; DOI=10.1016/0378-1119(88)90390-3; RA Zhang B., Crabb D.W., Harris R.A.; RT "Nucleotide and deduced amino acid sequence of the E1 alpha subunit of RT human liver branched-chain alpha-ketoacid dehydrogenase."; RL Gene 69:159-164(1988). RN [9] RP PROTEIN SEQUENCE OF 46-57, AND TRANSIT PEPTIDE. RX PubMed=7918575; DOI=10.1016/0304-4165(94)90161-9; RA Wynn R.M., Kochi H., Cox R.P., Chuang D.T.; RT "Differential processing of human and rat E1 alpha precursors of the RT branched-chain alpha-keto acid dehydrogenase complex caused by an N- RT terminal proline in the rat sequence."; RL Biochim. Biophys. Acta 1201:125-128(1994). RN [10] RP PHOSPHORYLATION AT SER-337, AND MUTAGENESIS OF SER-337 AND SER-347. RX PubMed=19411760; DOI=10.1172/jci38151; RA Lu G., Sun H., She P., Youn J.Y., Warburton S., Ping P., Vondriska T.M., RA Cai H., Lynch C.J., Wang Y.; RT "Protein phosphatase 2Cm is a critical regulator of branched-chain amino RT acid catabolism in mice and cultured cells."; RL J. Clin. Invest. 119:1678-1687(2009). RN [11] RP PHOSPHORYLATION AT SER-337, AND INTERACTION WITH PPM1K. RX PubMed=22589535; DOI=10.1074/jbc.m112.351031; RA Zhou M., Lu G., Gao C., Wang Y., Sun H.; RT "Tissue-specific and nutrient regulation of the branched-chain alpha-keto RT acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm)."; RL J. Biol. Chem. 287:23397-23406(2012). RN [12] {ECO:0007744|PDB:1DTW} RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 46-445 IN COMPLEX WITH BCKDHB; RP THIAMINE PYROPHOSPHATE; POTASSIUM AND MAGNESIUM, FUNCTION, CATALYTIC RP ACTIVITY, COFACTOR, SUBUNIT, SUBCELLULAR LOCATION, VARIANTS MSUD1A ASP-254 RP AND HIS-297, AND CHARACTERIZATION OF VARIANTS MSUD1A SER-159; LYS-190; RP MET-211; SER-249; THR-253; ASP-254; TRP-265; SER-267; PRO-285; ARG-290; RP HIS-297; ARG-310; CYS-409; CYS-413 AND ASN-438. RX PubMed=10745006; DOI=10.1016/s0969-2126(00)00105-2; RA Aevarsson A., Chuang J.L., Wynn R.M., Turley S., Chuang D.T., Hol W.G.J.; RT "Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and RT the molecular basis of multienzyme complex deficiency in maple syrup urine RT disease."; RL Structure 8:277-291(2000). RN [13] RP VARIANT MSUD1A CYS-413. RX PubMed=8037208; RA Chuang J.L., Fisher C.R., Cox R.P., Chuang D.T.; RT "Molecular basis of maple syrup urine disease: novel mutations at the E1 RT alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady- RT state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase RT complex."; RL Am. J. Hum. Genet. 55:297-304(1994). RN [14] RP VARIANT MSUD1A ASN-438. RX PubMed=2703538; DOI=10.1172/jci114033; RA Zhang B., Edenberg H.J., Crabb D.W., Harris R.A.; RT "Evidence for both a regulatory mutation and a structural mutation in a RT family with maple syrup urine disease."; RL J. Clin. Invest. 83:1425-1429(1989). RN [15] RP VARIANT MSUD1A ASN-438. RX PubMed=2241958; DOI=10.1016/0006-291x(90)90723-z; RA Matsuda I., Nobukuni Y., Mitsubuchi H., Indo Y., Endo F., Asaka J., RA Harada A.; RT "A T-to-A substitution in the E1 alpha subunit gene of the branched-chain RT alpha-ketoacid dehydrogenase complex in two cell lines derived from RT Menonite maple syrup urine disease patients."; RL Biochem. Biophys. Res. Commun. 172:646-651(1990). RN [16] RP VARIANT MSUD1A ASN-438. RX PubMed=1867199; RA Fisher C.R., Fisher C.W., Chuang D.T., Cox R.P.; RT "Occurrence of a Tyr393-->Asn (Y393N) mutation in the E1 alpha gene of the RT branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine RT disease patients from a Mennonite population."; RL Am. J. Hum. Genet. 49:429-434(1991). RN [17] RP VARIANT MSUD1A ASN-438. RX PubMed=1885764; DOI=10.1172/jci115363; RA Fisher C.R., Chuang J.L., Cox R.P., Fisher C.W., Star R.A., Chuang D.T.; RT "Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation RT in E1 alpha impedes assembly of the E1 component of branched-chain alpha- RT keto acid dehydrogenase complex."; RL J. Clin. Invest. 88:1034-1037(1991). RN [18] RP VARIANTS MSUD1A TRP-159; LYS-190; THR-253 AND THR-326. RX PubMed=8161368; DOI=10.1016/0925-4439(93)90123-i; RA Nobukuni Y., Mitsubuchi H., Hayashida Y., Ohta K., Indo Y., Ichiba Y., RA Endo F., Matsuda I.; RT "Heterogeneity of mutations in maple syrup urine disease (MSUD): screening RT and identification of affected E1 alpha and E1 beta subunits of the RT branched-chain alpha-keto-acid dehydrogenase multienzyme complex."; RL Biochim. Biophys. Acta 1225:64-70(1993). RN [19] RP VARIANTS MSUD1A ARG-290 AND CYS-409, CATALYTIC ACTIVITY, FUNCTION, AND RP CHARACTERIZATION OF VARIANTS MSUD1A ARG-290 AND CYS-409. RX PubMed=7883996; DOI=10.1172/jci117804; RA Chuang J.L., Davie J.R., Chinsky J.M., Wynn R.M., Cox R.P., Chuang D.T.; RT "Molecular and biochemical basis of intermediate maple syrup urine disease: RT occurrence of homozygous G245R and F364C mutations at the E1-alpha locus of RT Hispanic-Mexican patients."; RL J. Clin. Invest. 95:954-963(1995). RN [20] RP VARIANTS MSUD1A SER-249; TRP-265; SER-267; PRO-285; ARG-290; ARG-310; RP CYS-409; CYS-413 AND ASN-438, CHARACTERIZATION OF VARIANTS MSUD1A SER-249; RP TRP-265; SER-267; PRO-285; ARG-290; ARG-310; CYS-409; CYS-413 AND ASN-438, RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=9582350; DOI=10.1074/jbc.273.21.13110; RA Wynn R.M., Davie J.R., Chuang J.L., Cote C.D., Chuang D.T.; RT "Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid RT dehydrogenase complex in type IA maple syrup urine disease."; RL J. Biol. Chem. 273:13110-13118(1998). RN [21] RP VARIANTS MSUD1A MET-211; VAL-220; CYS-346; LYS-PRO-403 INS AND RP 427-LEU-ALA-428 DELINS PRO. RX PubMed=21844576; RA Park H.D., Lee D.H., Hong Y.H., Kang D.H., Lee Y.K., Song J., Lee S.Y., RA Kim J.W., Ki C.S., Lee Y.W.; RT "Three Korean patients with maple syrup urine disease: four novel mutations RT in the BCKDHA gene."; RL Ann. Clin. Lab. Sci. 41:167-173(2011). CC -!- FUNCTION: Together with BCKDHB forms the heterotetrameric E1 subunit of CC the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) CC complex. The BCKD complex catalyzes the multi-step oxidative CC decarboxylation of alpha-ketoacids derived from the branched-chain CC amino-acids valine, leucine and isoleucine producing CO2 and acyl-CoA CC which is subsequently utilized to produce energy. The E1 subunit CC catalyzes the first step with the decarboxylation of the alpha-ketoacid CC forming an enzyme-product intermediate. A reductive acylation mediated CC by the lipoylamide cofactor of E2 extracts the acyl group from the E1 CC active site for the next step of the reaction. CC {ECO:0000269|PubMed:10745006, ECO:0000269|PubMed:7883996, CC ECO:0000269|PubMed:9582350}. CC -!- CATALYTIC ACTIVITY: CC Reaction=3-methyl-2-oxobutanoate + H(+) + N(6)-[(R)-lipoyl]-L-lysyl- CC [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] = CO2 + CC N(6)-[(R)-S(8)-2-methylpropanoyldihydrolipoyl]-L-lysyl- CC [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase]; CC Xref=Rhea:RHEA:13457, Rhea:RHEA-COMP:10488, Rhea:RHEA-COMP:10489, CC ChEBI:CHEBI:11851, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, CC ChEBI:CHEBI:83099, ChEBI:CHEBI:83142; EC=1.2.4.4; CC Evidence={ECO:0000269|PubMed:10745006, ECO:0000269|PubMed:7883996, CC ECO:0000269|PubMed:9582350}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13458; CC Evidence={ECO:0000305|PubMed:7883996}; CC -!- COFACTOR: CC Name=thiamine diphosphate; Xref=ChEBI:CHEBI:58937; CC Evidence={ECO:0000269|PubMed:10745006}; CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10745006}; CC -!- SUBUNIT: Heterotetramer of 2 alpha/BCKDHA and 2 beta chains/BCKDHB that CC forms the branched-chain alpha-keto acid decarboxylase (E1) component CC of the BCKD complex (PubMed:10745006, PubMed:9582350). The branched- CC chain alpha-ketoacid dehydrogenase is a large complex composed of three CC major building blocks E1, E2 and E3. It is organized around E2, a 24- CC meric cubic core composed of DBT, to which are associated 6 to 12 CC copies of E1, and approximately 6 copies of the dehydrogenase E3, a DLD CC dimer (PubMed:10745006). Interacts with PPM1K. CC {ECO:0000269|PubMed:10745006, ECO:0000269|PubMed:22589535, CC ECO:0000269|PubMed:9582350, ECO:0000303|PubMed:10745006}. CC -!- INTERACTION: CC P12694; P21953: BCKDHB; NbExp=14; IntAct=EBI-1029053, EBI-1029067; CC P12694-1; P21953-1: BCKDHB; NbExp=3; IntAct=EBI-15489562, EBI-15489569; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix CC {ECO:0000305|PubMed:10745006}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P12694-1; Sequence=Displayed; CC Name=2; CC IsoId=P12694-2; Sequence=VSP_056156, VSP_056157; CC -!- PTM: Phosphorylated at Ser-337 by BCKDK and dephosphorylated by protein CC phosphatase PPM1K. {ECO:0000269|PubMed:19411760, CC ECO:0000269|PubMed:22589535}. CC -!- DISEASE: Maple syrup urine disease 1A (MSUD1A) [MIM:248600]: A CC metabolic disorder due to an enzyme defect in the catabolic pathway of CC the branched-chain amino acids leucine, isoleucine, and valine. CC Accumulation of these 3 amino acids and their corresponding keto acids CC leads to encephalopathy and progressive neurodegeneration. Clinical CC features include mental and physical retardation, feeding problems, and CC a maple syrup odor to the urine. The keto acids of the branched-chain CC amino acids are present in the urine. If untreated, maple syrup urine CC disease can lead to seizures, coma, and death. The disease is often CC classified by its pattern of signs and symptoms. The most common and CC severe form of the disease is the classic type, which becomes apparent CC soon after birth. Variant forms of the disorder become apparent later CC in infancy or childhood and are typically milder, but they still CC involve developmental delay and other medical problems if not treated. CC {ECO:0000269|PubMed:10745006, ECO:0000269|PubMed:1867199, CC ECO:0000269|PubMed:1885764, ECO:0000269|PubMed:2060625, CC ECO:0000269|PubMed:21844576, ECO:0000269|PubMed:2241958, CC ECO:0000269|PubMed:2703538, ECO:0000269|PubMed:7883996, CC ECO:0000269|PubMed:8037208, ECO:0000269|PubMed:8161368, CC ECO:0000269|PubMed:9582350}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the BCKDHA family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB59549.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z14093; CAA78475.1; -; mRNA. DR EMBL; AK298188; BAG60459.1; -; mRNA. DR EMBL; AC011462; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC007878; AAH07878.1; -; mRNA. DR EMBL; BC008933; AAH08933.1; -; mRNA. DR EMBL; BC023983; AAH23983.1; -; mRNA. DR EMBL; J04474; AAB59549.1; ALT_INIT; mRNA. DR EMBL; AH003771; AAB20222.2; -; Genomic_DNA. DR EMBL; AH003707; AAB19268.2; -; Genomic_DNA. DR EMBL; M22221; AAA35590.1; -; mRNA. DR CCDS; CCDS12581.1; -. [P12694-1] DR PIR; S27156; DEHUXA. DR RefSeq; NP_000700.1; NM_000709.3. [P12694-1] DR RefSeq; NP_001158255.1; NM_001164783.1. DR PDB; 1DTW; X-ray; 2.70 A; A=46-445. DR PDB; 1OLS; X-ray; 1.85 A; A=46-445. DR PDB; 1OLU; X-ray; 1.90 A; A=46-445. DR PDB; 1OLX; X-ray; 2.25 A; A=46-445. DR PDB; 1U5B; X-ray; 1.83 A; A=46-445. DR PDB; 1V11; X-ray; 1.95 A; A=46-445. DR PDB; 1V16; X-ray; 1.90 A; A=46-445. DR PDB; 1V1M; X-ray; 2.00 A; A=46-445. DR PDB; 1V1R; X-ray; 1.80 A; A=46-445. DR PDB; 1WCI; X-ray; 1.84 A; A=46-445. DR PDB; 1X7W; X-ray; 1.73 A; A=46-445. DR PDB; 1X7X; X-ray; 2.10 A; A=46-445. DR PDB; 1X7Y; X-ray; 1.57 A; A=46-445. DR PDB; 1X7Z; X-ray; 1.72 A; A=46-445. DR PDB; 1X80; X-ray; 2.00 A; A=46-445. DR PDB; 2BEU; X-ray; 1.89 A; A=46-445. DR PDB; 2BEV; X-ray; 1.80 A; A=46-445. DR PDB; 2BEW; X-ray; 1.79 A; A=46-445. DR PDB; 2BFB; X-ray; 1.77 A; A=46-445. DR PDB; 2BFC; X-ray; 1.64 A; A=46-445. DR PDB; 2BFD; X-ray; 1.39 A; A=46-445. DR PDB; 2BFE; X-ray; 1.69 A; A=46-445. DR PDB; 2BFF; X-ray; 1.46 A; A=46-445. DR PDB; 2J9F; X-ray; 1.88 A; A/C=46-445. DR PDBsum; 1DTW; -. DR PDBsum; 1OLS; -. DR PDBsum; 1OLU; -. DR PDBsum; 1OLX; -. DR PDBsum; 1U5B; -. DR PDBsum; 1V11; -. DR PDBsum; 1V16; -. DR PDBsum; 1V1M; -. DR PDBsum; 1V1R; -. DR PDBsum; 1WCI; -. DR PDBsum; 1X7W; -. DR PDBsum; 1X7X; -. DR PDBsum; 1X7Y; -. DR PDBsum; 1X7Z; -. DR PDBsum; 1X80; -. DR PDBsum; 2BEU; -. DR PDBsum; 2BEV; -. DR PDBsum; 2BEW; -. DR PDBsum; 2BFB; -. DR PDBsum; 2BFC; -. DR PDBsum; 2BFD; -. DR PDBsum; 2BFE; -. DR PDBsum; 2BFF; -. DR PDBsum; 2J9F; -. DR AlphaFoldDB; P12694; -. DR SMR; P12694; -. DR BioGRID; 107065; 207. DR ComplexPortal; CPX-2216; Mitochondrial 2-oxoisovalerate dehydrogenase complex. DR DIP; DIP-6146N; -. DR IntAct; P12694; 55. DR MINT; P12694; -. DR STRING; 9606.ENSP00000269980; -. DR iPTMnet; P12694; -. DR PhosphoSitePlus; P12694; -. DR SwissPalm; P12694; -. DR BioMuta; BCKDHA; -. DR EPD; P12694; -. DR jPOST; P12694; -. DR MassIVE; P12694; -. DR MaxQB; P12694; -. DR PaxDb; 9606-ENSP00000269980; -. DR PeptideAtlas; P12694; -. DR ProteomicsDB; 4756; -. DR ProteomicsDB; 52863; -. [P12694-1] DR Pumba; P12694; -. DR Antibodypedia; 35354; 173 antibodies from 25 providers. DR DNASU; 593; -. DR Ensembl; ENST00000269980.7; ENSP00000269980.2; ENSG00000248098.12. [P12694-1] DR Ensembl; ENST00000457836.6; ENSP00000416000.2; ENSG00000248098.12. [P12694-2] DR GeneID; 593; -. DR KEGG; hsa:593; -. DR MANE-Select; ENST00000269980.7; ENSP00000269980.2; NM_000709.4; NP_000700.1. DR UCSC; uc002oqq.4; human. [P12694-1] DR AGR; HGNC:986; -. DR CTD; 593; -. DR DisGeNET; 593; -. DR GeneCards; BCKDHA; -. DR GeneReviews; BCKDHA; -. DR HGNC; HGNC:986; BCKDHA. DR HPA; ENSG00000248098; Low tissue specificity. DR MalaCards; BCKDHA; -. DR MIM; 248600; phenotype. DR MIM; 608348; gene. DR neXtProt; NX_P12694; -. DR OpenTargets; ENSG00000248098; -. DR Orphanet; 268145; Classic maple syrup urine disease. DR Orphanet; 268162; Intermediate maple syrup urine disease. DR Orphanet; 268173; Intermittent maple syrup urine disease. DR Orphanet; 268184; Thiamine-responsive maple syrup urine disease. DR PharmGKB; PA25297; -. DR VEuPathDB; HostDB:ENSG00000248098; -. DR eggNOG; KOG1182; Eukaryota. DR GeneTree; ENSGT00530000063174; -. DR HOGENOM; CLU_029393_1_0_1; -. DR InParanoid; P12694; -. DR OMA; DWHTGYD; -. DR OrthoDB; 952at2759; -. DR PhylomeDB; P12694; -. DR TreeFam; TF300863; -. DR BioCyc; MetaCyc:MONOMER-12005; -. DR PathwayCommons; P12694; -. DR Reactome; R-HSA-389661; Glyoxylate metabolism and glycine degradation. DR Reactome; R-HSA-70895; Branched-chain amino acid catabolism. DR SABIO-RK; P12694; -. DR SignaLink; P12694; -. DR SIGNOR; P12694; -. DR BioGRID-ORCS; 593; 18 hits in 1160 CRISPR screens. DR ChiTaRS; BCKDHA; human. DR EvolutionaryTrace; P12694; -. DR GeneWiki; BCKDHA; -. DR GenomeRNAi; 593; -. DR Pharos; P12694; Tbio. DR PRO; PR:P12694; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P12694; Protein. DR Bgee; ENSG00000248098; Expressed in lower esophagus mucosa and 99 other cell types or tissues. DR ExpressionAtlas; P12694; baseline and differential. DR GO; GO:0005947; C:mitochondrial alpha-ketoglutarate dehydrogenase complex; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; HDA:UniProtKB. DR GO; GO:0003863; F:3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) activity; IDA:HGNC-UCL. DR GO; GO:0016831; F:carboxy-lyase activity; TAS:HGNC-UCL. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0009083; P:branched-chain amino acid catabolic process; IDA:HGNC-UCL. DR CDD; cd02000; TPP_E1_PDC_ADC_BCADC; 1. DR Gene3D; 3.40.50.970; -; 1. DR InterPro; IPR001017; DH_E1. DR InterPro; IPR029061; THDP-binding. DR PANTHER; PTHR43380; 2-OXOISOVALERATE DEHYDROGENASE SUBUNIT ALPHA, MITOCHONDRIAL; 1. DR PANTHER; PTHR43380:SF1; 2-OXOISOVALERATE DEHYDROGENASE SUBUNIT ALPHA, MITOCHONDRIAL; 1. DR Pfam; PF00676; E1_dh; 1. DR SUPFAM; SSF52518; Thiamin diphosphate-binding fold (THDP-binding); 1. DR Genevisible; P12694; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Direct protein sequencing; KW Disease variant; Maple syrup urine disease; Metal-binding; Mitochondrion; KW Oxidoreductase; Phosphoprotein; Potassium; Reference proteome; KW Thiamine pyrophosphate; Transit peptide. FT TRANSIT 1..45 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:7918575" FT CHAIN 46..445 FT /note="2-oxoisovalerate dehydrogenase subunit alpha, FT mitochondrial" FT /id="PRO_0000020465" FT REGION 33..52 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 37..51 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 158 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 159 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 206 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /ligand_note="structural" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 207 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 208 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /ligand_note="structural" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 211 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /ligand_note="structural" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 212 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /ligand_note="structural" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 238 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 239 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 240 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 265 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 267 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 269 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT BINDING 336 FT /ligand="thiamine diphosphate" FT /ligand_id="ChEBI:CHEBI:58937" FT /ligand_note="ligand shared with beta subunit" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0007744|PDB:1DTW" FT MOD_RES 337 FT /note="Phosphoserine; by BCKDK" FT /evidence="ECO:0000269|PubMed:19411760, FT ECO:0000269|PubMed:22589535" FT MOD_RES 338 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P50136" FT MOD_RES 339 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P50136" FT MOD_RES 347 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P50136" FT MOD_RES 356 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P50136" FT MOD_RES 356 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P50136" FT MOD_RES 380 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P50136" FT VAR_SEQ 19..40 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056156" FT VAR_SEQ 331 FT /note="Y -> YSSSPILPPDPHSREPTLTWGPLPLC (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056157" FT VARIANT 39 FT /note="P -> H (in dbSNP:rs11549936)" FT /id="VAR_034360" FT VARIANT 151 FT /note="T -> M (in dbSNP:rs34442879)" FT /id="VAR_034361" FT VARIANT 159 FT /note="R -> W (in MSUD1A; loss of 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs769688327)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:8161368" FT /id="VAR_004968" FT VARIANT 190 FT /note="Q -> K (in MSUD1A; decreased 3-methyl-2-oxobutanoate FT dehydrogenase activity)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:8161368" FT /id="VAR_004969" FT VARIANT 211 FT /note="T -> M (in MSUD1A; loss of 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs398123503)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:21844576" FT /id="VAR_069748" FT VARIANT 220 FT /note="A -> V (in MSUD1A; dbSNP:rs375785084)" FT /evidence="ECO:0000269|PubMed:21844576" FT /id="VAR_069749" FT VARIANT 249 FT /note="G -> S (in MSUD1A; no effect on solubility; no FT effect on mitochondrial alpha-ketoglutarate dehydrogenase FT complex assembly; loss of 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs137852874)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:9582350" FT /id="VAR_088268" FT VARIANT 253 FT /note="A -> T (in MSUD1A; loss of 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs199599175)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:8161368" FT /id="VAR_004970" FT VARIANT 254 FT /note="A -> D (in MSUD1A; uncertain significance; loss of FT 3-methyl-2-oxobutanoate dehydrogenase activity)" FT /evidence="ECO:0000269|PubMed:10745006" FT /id="VAR_088269" FT VARIANT 265 FT /note="R -> W (in MSUD1A; uncertain significance; no effect FT on solubility; no effect on mitochondrial FT alpha-ketoglutarate dehydrogenase complex assembly; loss of FT 3-methyl-2-oxobutanoate dehydrogenase activity; FT dbSNP:rs137852873)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:9582350" FT /id="VAR_088270" FT VARIANT 267 FT /note="N -> S (in MSUD1A; uncertain significance; no effect FT on solubility; no effect on mitochondrial FT alpha-ketoglutarate dehydrogenase complex assembly; FT decreased affinity for the cofactor thiamine diphosphate; FT decreased 3-methyl-2-oxobutanoate dehydrogenase activity)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:9582350" FT /id="VAR_088271" FT VARIANT 285 FT /note="A -> P (in MSUD1A; no effect on solubility; no FT effect on mitochondrial alpha-ketoglutarate dehydrogenase FT complex assembly; loss of 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs398123508)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:9582350" FT /id="VAR_088272" FT VARIANT 290 FT /note="G -> R (in MSUD1A; no effect on solubility; no FT effect on mitochondrial alpha-ketoglutarate dehydrogenase FT complex assembly; decreased 3-methyl-2-oxobutanoate FT dehydrogenase activity; dbSNP:rs137852871)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:7883996, ECO:0000269|PubMed:9582350" FT /id="VAR_015101" FT VARIANT 297 FT /note="R -> H (in MSUD1A; uncertain significance; decreased FT affinity for the cofactor thiamine diphosphate; decreased FT 3-methyl-2-oxobutanoate dehydrogenase activity; FT dbSNP:rs200137189)" FT /evidence="ECO:0000269|PubMed:10745006" FT /id="VAR_088273" FT VARIANT 310 FT /note="T -> R (in MSUD1A; decreased solubility; changed FT mitochondrial alpha-ketoglutarate dehydrogenase complex FT assembly; loss of 3-methyl-2-oxobutanoate dehydrogenase FT activity; dbSNP:rs137852875)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:9582350" FT /id="VAR_088274" FT VARIANT 326 FT /note="I -> T (in MSUD1A; decreased 3-methyl-2-oxobutanoate FT dehydrogenase activity)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:8161368" FT /id="VAR_004971" FT VARIANT 346 FT /note="R -> C (in MSUD1A; dbSNP:rs182923857)" FT /evidence="ECO:0000269|PubMed:21844576" FT /id="VAR_069750" FT VARIANT 403 FT /note="P -> PKP (in MSUD1A)" FT /id="VAR_069751" FT VARIANT 409 FT /note="F -> C (in MSUD1A; decreased solubility; loss of FT mitochondrial alpha-ketoglutarate dehydrogenase complex FT assembly; loss of 3-methyl-2-oxobutanoate dehydrogenase FT activity; dbSNP:rs137852872)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:7883996, ECO:0000269|PubMed:9582350" FT /id="VAR_015102" FT VARIANT 413 FT /note="Y -> C (in MSUD1A; uncertain significance; decreased FT solubility; changed mitochondrial alpha-ketoglutarate FT dehydrogenase complex assembly; loss of FT 3-methyl-2-oxobutanoate dehydrogenase activity; FT dbSNP:rs398123508)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:8037208, ECO:0000269|PubMed:9582350" FT /id="VAR_004972" FT VARIANT 427..428 FT /note="LA -> P (in MSUD1A)" FT /evidence="ECO:0000269|PubMed:21844576" FT /id="VAR_069752" FT VARIANT 438 FT /note="Y -> N (in MSUD1A; decreased solubility; loss of FT mitochondrial alpha-ketoglutarate dehydrogenase complex FT assembly; loss of 3-methyl-2-oxobutanoate dehydrogenase FT activity; dbSNP:rs137852870)" FT /evidence="ECO:0000269|PubMed:10745006, FT ECO:0000269|PubMed:1867199, ECO:0000269|PubMed:1885764, FT ECO:0000269|PubMed:2060625, ECO:0000269|PubMed:2241958, FT ECO:0000269|PubMed:2703538, ECO:0000269|PubMed:9582350" FT /id="VAR_004973" FT MUTAGEN 337 FT /note="S->A: Substantially decreases the stability of the FT BCKD complex." FT /evidence="ECO:0000269|PubMed:19411760" FT MUTAGEN 347 FT /note="S->A: Does not affect the stability of the BCKD FT complex." FT /evidence="ECO:0000269|PubMed:19411760" FT CONFLICT 3 FT /note="V -> G (in Ref. 6; AAB20222/AAB19268)" FT /evidence="ECO:0000305" FT CONFLICT 36 FT /note="S -> A (in Ref. 5; AAB59549)" FT /evidence="ECO:0000305" FT CONFLICT 248 FT /note="A -> D (in Ref. 8; AAA35590)" FT /evidence="ECO:0000305" FT STRAND 61..64 FT /evidence="ECO:0007829|PDB:2J9F" FT STRAND 88..90 FT /evidence="ECO:0007829|PDB:1DTW" FT HELIX 91..93 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 99..124 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 127..129 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 135..137 FT /evidence="ECO:0007829|PDB:2BFB" FT HELIX 138..146 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 152..155 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 161..166 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 171..179 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 185..188 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 198..201 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 209..211 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 212..226 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 232..237 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 240..242 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 244..255 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 260..266 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 268..270 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 275..277 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 280..282 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 285..287 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 289..291 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 294..299 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 303..320 FT /evidence="ECO:0007829|PDB:2BFD" FT STRAND 324..329 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 342..344 FT /evidence="ECO:0007829|PDB:2BFF" FT HELIX 351..357 FT /evidence="ECO:0007829|PDB:2BFF" FT HELIX 360..368 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 369..372 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 376..399 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 405..408 FT /evidence="ECO:0007829|PDB:2BFD" FT TURN 409..411 FT /evidence="ECO:0007829|PDB:2BEW" FT STRAND 412..415 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 418..434 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 435..437 FT /evidence="ECO:0007829|PDB:2BFD" FT HELIX 440..442 FT /evidence="ECO:0007829|PDB:2BFD" SQ SEQUENCE 445 AA; 50471 MW; 2B4DD658924DB0C3 CRC64; MAVAIAAARV WRLNRGLSQA ALLLLRQPGA RGLARSHPPR QQQQFSSLDD KPQFPGASAE FIDKLEFIQP NVISGIPIYR VMDRQGQIIN PSEDPHLPKE KVLKLYKSMT LLNTMDRILY ESQRQGRISF YMTNYGEEGT HVGSAAALDN TDLVFGQYRE AGVLMYRDYP LELFMAQCYG NISDLGKGRQ MPVHYGCKER HFVTISSPLA TQIPQAVGAA YAAKRANANR VVICYFGEGA ASEGDAHAGF NFAATLECPI IFFCRNNGYA ISTPTSEQYR GDGIAARGPG YGIMSIRVDG NDVFAVYNAT KEARRRAVAE NQPFLIEAMT YRIGHHSTSD DSSAYRSVDE VNYWDKQDHP ISRLRHYLLS QGWWDEEQEK AWRKQSRRKV MEAFEQAERK PKPNPNLLFS DVYQEMPAQL RKQQESLARH LQTYGEHYPL DHFDK //