DLDH_HUMAN
ID DLDH_HUMAN Reviewed; 509 AA.
AC P09622; B2R5X0; B4DHG0; B4DT69; Q14131; Q14167; Q59EV8; Q8WTS4;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 2.
DT 03-AUG-2022, entry version 251.
DE RecName: Full=Dihydrolipoyl dehydrogenase, mitochondrial;
DE EC=1.8.1.4 {ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:20385101};
DE AltName: Full=Dihydrolipoamide dehydrogenase;
DE AltName: Full=Glycine cleavage system L protein;
DE Flags: Precursor;
GN Name=DLD; Synonyms=GCSL, LAD, PHE3;
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), AND VARIANT THR-104.
RX PubMed=3693355; DOI=10.1016/s0021-9258(18)45379-3;
RA Otulakowski G., Robinson B.H.;
RT "Isolation and sequence determination of cDNA clones for porcine and human
RT lipoamide dehydrogenase. Homology to other disulfide oxidoreductases.";
RL J. Biol. Chem. 262:17313-17318(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3278312; DOI=10.1073/pnas.85.5.1422;
RA Pons G., Raefsky-Estrin C., Carothers D.J., Pepin R.A., Javed A.A.,
RA Jesse B.W., Ganapathi M.K., Samols D., Patel M.S.;
RT "Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component
RT human alpha-ketoacid dehydrogenase complexes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:1422-1426(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-104.
RC TISSUE=Liver;
RX PubMed=8406489; DOI=10.1006/geno.1993.1335;
RA Feigenbaum A.S., Robinson B.H.;
RT "The structure of the human dihydrolipoamide dehydrogenase gene (DLD) and
RT its upstream elements.";
RL Genomics 17:376-381(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Brain, Brain cortex, and Pericardium;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [8]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary;
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 [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-13.
RX PubMed=1332063; DOI=10.1073/pnas.89.22.10964;
RA Johanning G.L., Morris J.I., Madhusudhan K.T., Samols D., Patel M.S.;
RT "Characterization of the transcriptional regulatory region of the human
RT dihydrolipoamide dehydrogenase gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:10964-10968(1992).
RN [11]
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 [12]
RP SUBCELLULAR LOCATION.
RX PubMed=15888450; DOI=10.1074/jbc.m500310200;
RA Mitra K., Rangaraj N., Shivaji S.;
RT "Novelty of the pyruvate metabolic enzyme dihydrolipoamide dehydrogenase in
RT spermatozoa: correlation of its localization, tyrosine phosphorylation, and
RT activity during sperm capacitation.";
RL J. Biol. Chem. 280:25743-25753(2005).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, CHARACTERIZATION OF
RP VARIANT DLDD ASP-479, AND MUTAGENESIS OF GLU-466; HIS-485 AND SER-491.
RX PubMed=17404228; DOI=10.1073/pnas.0610618104;
RA Babady N.E., Pang Y.P., Elpeleg O., Isaya G.;
RT "Cryptic proteolytic activity of dihydrolipoamide dehydrogenase.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:6158-6163(2007).
RN [14]
RP CATALYTIC ACTIVITY, INTERACTION WITH PDHX, MUTAGENESIS OF LYS-89; ARG-482;
RP GLU-492 AND LYS-505, AND CHARACTERIZATION OF VARIANTS DLDD GLU-72; LYS-375;
RP LEU-488 AND GLY-495.
RX PubMed=20160912; DOI=10.1016/j.molcatb.2009.05.001;
RA Patel M.S., Korotchkina L.G., Sidhu S.;
RT "Interaction of E1 and E3 components with the core proteins of the human
RT pyruvate dehydrogenase complex.";
RL J. Mol. Catal., B Enzym. 61:2-6(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-143; LYS-410 AND LYS-417, AND
RP IDENTIFICATION BY MASS 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 [16]
RP CATALYTIC ACTIVITY, INTERACTION WITH PDHX, AND MUTAGENESIS OF HIS-383;
RP ASP-448; TYR-473 AND ARG-482.
RX PubMed=20385101; DOI=10.1016/j.bbrc.2010.04.038;
RA Park Y.H., Patel M.S.;
RT "Characterization of interactions of dihydrolipoamide dehydrogenase with
RT its binding protein in the human pyruvate dehydrogenase complex.";
RL Biochem. Biophys. Res. Commun. 395:416-419(2010).
RN [17]
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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22905912; DOI=10.1021/pr300539b;
RA Rosenow A., Noben J.P., Jocken J., Kallendrusch S., Fischer-Posovszky P.,
RA Mariman E.C., Renes J.;
RT "Resveratrol-induced changes of the human adipocyte secretion profile.";
RL J. Proteome Res. 11:4733-4743(2012).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-502, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [21]
RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER TYR-35, 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 [22]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=29211711; DOI=10.1038/nature25003;
RA Wang Y., Guo Y.R., Liu K., Yin Z., Liu R., Xia Y., Tan L., Yang P.,
RA Lee J.H., Li X.J., Hawke D., Zheng Y., Qian X., Lyu J., He J., Xing D.,
RA Tao Y.J., Lu Z.;
RT "KAT2A coupled with the alpha-KGDH complex acts as a histone H3
RT succinyltransferase.";
RL Nature 552:273-277(2017).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 36-509 IN COMPLEXES WITH NAD AND
RP FAD, AND SUBUNIT.
RX PubMed=15946682; DOI=10.1016/j.jmb.2005.05.014;
RA Brautigam C.A., Chuang J.L., Tomchick D.R., Machius M., Chuang D.T.;
RT "Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH
RT binding and the structural basis of disease-causing mutations.";
RL J. Mol. Biol. 350:543-552(2005).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 36-509.
RX PubMed=16263718; DOI=10.1074/jbc.m507850200;
RA Ciszak E.M., Makal A., Hong Y.S., Vettaikkorumakankauv A.K.,
RA Korotchkina L.G., Patel M.S.;
RT "How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide
RT dehydrogenase in the human pyruvate dehydrogenase complex.";
RL J. Biol. Chem. 281:648-655(2006).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.18 ANGSTROMS) OF 36-509 IN COMPLEX WITH PDHX,
RP CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT DLDD GLY-495.
RX PubMed=16442803; DOI=10.1016/j.str.2006.01.001;
RA Brautigam C.A., Wynn R.M., Chuang J.L., Machius M., Tomchick D.R.,
RA Chuang D.T.;
RT "Structural insight into interactions between dihydrolipoamide
RT dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase
RT complex.";
RL Structure 14:611-621(2006).
RN [26]
RP STRUCTURE BY ELECTRON MICROSCOPY (33.3 ANGSTROMS) OF INNER CORE OF THE
RP COMPLEX, AND SUBUNIT.
RX PubMed=20361979; DOI=10.1016/j.jmb.2010.03.043;
RA Vijayakrishnan S., Kelly S.M., Gilbert R.J., Callow P., Bhella D.,
RA Forsyth T., Lindsay J.G., Byron O.;
RT "Solution structure and characterisation of the human pyruvate
RT dehydrogenase complex core assembly.";
RL J. Mol. Biol. 399:71-93(2010).
RN [27]
RP VARIANTS DLDD GLU-72 AND LEU-488.
RX PubMed=8506365; DOI=10.1073/pnas.90.11.5186;
RA Liu T.-C., Kim H., Arizmendi C., Kitano A., Patel M.S.;
RT "Identification of two missense mutations in a dihydrolipoamide
RT dehydrogenase-deficient patient.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:5186-5190(1993).
RN [28]
RP VARIANTS DLDD GLY-136 DEL AND LYS-375.
RX PubMed=9540846; DOI=10.1016/s0925-4439(97)00073-2;
RA Hong Y.S., Kerr D.S., Liu T.C., Lusk M., Powell B.R., Patel M.S.;
RT "Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles
RT (E340K and G101del). Analysis of a family and prenatal testing.";
RL Biochim. Biophys. Acta 1362:160-168(1997).
RN [29]
RP VARIANT DLDD GLY-495.
RX PubMed=8968745; DOI=10.1093/hmg/5.12.1925;
RA Hong Y.S., Kerr D.S., Craigen W.J., Tan J., Pan Y., Lusk M., Patel M.S.;
RT "Identification of two mutations in a compound heterozygous child with
RT dihydrolipoamide dehydrogenase deficiency.";
RL Hum. Mol. Genet. 5:1925-1930(1996).
RN [30]
RP VARIANT DLDD VAL-479.
RX PubMed=10448086; DOI=10.1006/bbrc.1999.1133;
RA Shany E., Saada A., Landau D., Shaag A., Hershkovitz E., Elpeleg O.N.;
RT "Lipoamide dehydrogenase deficiency due to a novel mutation in the
RT interface domain.";
RL Biochem. Biophys. Res. Commun. 262:163-166(1999).
RN [31]
RP VARIANTS DLDD VAL-361 AND LYS-375.
RX PubMed=11687750;
RA Cerna L., Wenchich L., Hansikova H., Kmoch S., Peskova K., Chrastina P.,
RA Brynda J., Zeman J.;
RT "Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency.";
RL Med. Sci. Monit. 7:1319-1325(2001).
RN [32]
RP VARIANT DLDD THR-393.
RX PubMed=12925875; DOI=10.1007/s00431-003-1282-z;
RA Grafakou O., Oexle K., van den Heuvel L., Smeets R., Trijbels F.,
RA Goebel H.H., Bosshard N., Superti-Furga A., Steinmann B., Smeitink J.;
RT "Leigh syndrome due to compound heterozygosity of dihydrolipoamide
RT dehydrogenase gene mutations. Description of the first E3 splice site
RT mutation.";
RL Eur. J. Pediatr. 162:714-718(2003).
RN [33]
RP VARIANT DLDD GLY-482, CHARACTERIZATION OF VARIANT DLDD GLY-482, AND
RP CATALYTIC ACTIVITY.
RX PubMed=15712224; DOI=10.1002/humu.9319;
RA Odievre M.H., Chretien D., Munnich A., Robinson B.H., Dumoulin R.,
RA Masmoudi S., Kadhom N., Roetig A., Rustin P., Bonnefont J.P.;
RT "A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene
RT (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase
RT deficiency.";
RL Hum. Mutat. 25:323-324(2005).
RN [34]
RP VARIANTS DLDD THR-47; CYS-229 AND LYS-375, AND CATALYTIC ACTIVITY.
RX PubMed=16770810; DOI=10.1002/ajmg.a.31313;
RA Cameron J.M., Levandovskiy V., Mackay N., Raiman J., Renaud D.L.,
RA Clarke J.T., Feigenbaum A., Elpeleg O., Robinson B.H.;
RT "Novel mutations in dihydrolipoamide dehydrogenase deficiency in two
RT cousins with borderline-normal PDH complex activity.";
RL Am. J. Med. Genet. A 140:1542-1552(2006).
RN [35]
RP VARIANT DLDD CYS-229.
RX PubMed=9934985;
RX DOI=10.1002/(sici)1096-8628(19990115)82:2<177::aid-ajmg15>3.0.co;2-9;
RA Shaag A., Saada A., Berger I., Mandel H., Joseph A., Feigenbaum A.,
RA Elpeleg O.N.;
RT "Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews.";
RL Am. J. Med. Genet. 82:177-182(1999).
CC -!- FUNCTION: Lipoamide dehydrogenase is a component of the glycine
CC cleavage system as well as an E3 component of three alpha-ketoacid
CC dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-
CC chain amino acid-dehydrogenase complex) (PubMed:15712224,
CC PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912,
CC PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly
CC active in the mitochondrion (PubMed:29211711). A fraction of the 2-
CC oxoglutarate dehydrogenase complex also localizes in the nucleus and is
CC required for lysine succinylation of histones: associates with KAT2A on
CC chromatin and provides succinyl-CoA to histone succinyltransferase
CC KAT2A (PubMed:29211711). In monomeric form may have additional
CC moonlighting function as serine protease (PubMed:17404228). Involved in
CC the hyperactivation of spermatazoa during capacitation and in the
CC spermatazoal acrosome reaction (By similarity).
CC {ECO:0000250|UniProtKB:Q811C4, ECO:0000269|PubMed:15712224,
CC ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810,
CC ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912,
CC ECO:0000269|PubMed:20385101, ECO:0000269|PubMed:29211711}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-N(6)-dihydrolipoyl-L-lysyl-[protein] + NAD(+) = (R)-N(6)-
CC lipoyl-L-lysyl-[protein] + H(+) + NADH; Xref=Rhea:RHEA:15045,
CC Rhea:RHEA-COMP:10474, Rhea:RHEA-COMP:10475, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:83099,
CC ChEBI:CHEBI:83100; EC=1.8.1.4; Evidence={ECO:0000269|PubMed:15712224,
CC ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810,
CC ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912,
CC ECO:0000269|PubMed:20385101};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:15946682, ECO:0000269|PubMed:16442803};
CC Note=Binds 1 FAD per subunit. {ECO:0000269|PubMed:15946682,
CC ECO:0000269|PubMed:16442803};
CC -!- ACTIVITY REGULATION: Disruption of native heterodimer state inhibits
CC primary dihydrolipoamide dehydrogenase activity and induces serine
CC protease activity. {ECO:0000269|PubMed:17404228}.
CC -!- SUBUNIT: Homodimer (PubMed:15946682). Part of the multimeric pyruvate
CC dehydrogenase complex that contains multiple copies of pyruvate
CC dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1),
CC dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide
CC dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to
CC an inner core composed of about 48 DLAT and 12 PDHX molecules (by non
CC covalent bonds) (PubMed:14638692, PubMed:20361979). The 2-oxoglutarate
CC dehydrogenase complex is composed of OGDH (2-oxoglutarate
CC dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and
CC DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies
CC of the three enzymatic components (E1, E2 and E3). In the nucleus, the
CC 2-oxoglutarate dehydrogenase complex associates with KAT2A
CC (PubMed:29211711). Interacts with PDHX (PubMed:20385101,
CC PubMed:16442803, PubMed:20160912, PubMed:20361979).
CC {ECO:0000269|PubMed:14638692, ECO:0000269|PubMed:15946682,
CC ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:20160912,
CC ECO:0000269|PubMed:20361979, ECO:0000269|PubMed:20385101,
CC ECO:0000269|PubMed:29211711}.
CC -!- INTERACTION:
CC P09622; P42858: HTT; NbExp=3; IntAct=EBI-353366, EBI-466029;
CC P09622; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-353366, EBI-2127319;
CC P09622; O00330: PDHX; NbExp=7; IntAct=EBI-353366, EBI-751566;
CC P09622; P30041: PRDX6; NbExp=3; IntAct=EBI-353366, EBI-2255129;
CC P09622; P62258: YWHAE; NbExp=5; IntAct=EBI-353366, EBI-356498;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000305|PubMed:29211711, ECO:0000305|PubMed:3693355}. Nucleus
CC {ECO:0000269|PubMed:29211711}. Cell projection, cilium, flagellum
CC {ECO:0000250|UniProtKB:Q811C4}. Cytoplasmic vesicle, secretory vesicle,
CC acrosome {ECO:0000269|PubMed:15888450}. Note=Mainly localizes in the
CC mitochondrion. A small fraction localizes to the nucleus, where the 2-
CC oxoglutarate dehydrogenase complex is required for histone
CC succinylation. {ECO:0000269|PubMed:29211711}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P09622-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P09622-2; Sequence=VSP_055855;
CC Name=3;
CC IsoId=P09622-3; Sequence=VSP_055856;
CC -!- PTM: Tyrosine phosphorylated. {ECO:0000250|UniProtKB:Q811C4}.
CC -!- DISEASE: Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]:
CC An autosomal recessive metabolic disorder characterized biochemically
CC by a combined deficiency of the branched-chain alpha-keto acid
CC dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC),
CC and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically,
CC affected individuals have lactic acidosis and neurologic deterioration
CC due to sensitivity of the central nervous system to defects in
CC oxidative metabolism. {ECO:0000269|PubMed:10448086,
CC ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875,
CC ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803,
CC ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228,
CC ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365,
CC ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846,
CC ECO:0000269|PubMed:9934985}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The active site is a redox-active disulfide bond.
CC {ECO:0000250|UniProtKB:P09624}.
CC -!- SIMILARITY: Belongs to the class-I pyridine nucleotide-disulfide
CC oxidoreductase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92940.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; J03490; AAA59527.1; -; mRNA.
DR EMBL; J03620; AAA35764.1; -; mRNA.
DR EMBL; L13761; AAB01381.1; -; Genomic_DNA.
DR EMBL; L13749; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13750; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13751; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13752; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13753; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13754; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13748; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13755; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13759; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13760; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13756; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13757; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; L13758; AAB01381.1; JOINED; Genomic_DNA.
DR EMBL; AK295080; BAG58122.1; -; mRNA.
DR EMBL; AK300077; BAG61881.1; -; mRNA.
DR EMBL; AK312346; BAG35267.1; -; mRNA.
DR EMBL; AB209703; BAD92940.1; ALT_INIT; mRNA.
DR EMBL; AC005046; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236947; EAL24389.1; -; Genomic_DNA.
DR EMBL; CH471070; EAW83421.1; -; Genomic_DNA.
DR EMBL; BC018648; AAH18648.1; -; mRNA.
DR EMBL; BC018696; AAH18696.1; -; mRNA.
DR EMBL; M99384; AAA35759.1; -; Genomic_DNA.
DR CCDS; CCDS5749.1; -. [P09622-1]
DR CCDS; CCDS78268.1; -. [P09622-3]
DR PIR; A92622; DEHULP.
DR RefSeq; NP_000099.2; NM_000108.4. [P09622-1]
DR RefSeq; NP_001276679.1; NM_001289750.1. [P09622-2]
DR RefSeq; NP_001276680.1; NM_001289751.1.
DR RefSeq; NP_001276681.1; NM_001289752.1. [P09622-3]
DR PDB; 1ZMC; X-ray; 2.53 A; A/B/C/D/E/F/G/H=36-509.
DR PDB; 1ZMD; X-ray; 2.08 A; A/B/C/D/E/F/G/H=36-509.
DR PDB; 1ZY8; X-ray; 2.59 A; A/B/C/D/E/F/G/H/I/J=36-509.
DR PDB; 2F5Z; X-ray; 2.18 A; A/B/C/D/E/F/G/H/I/J=36-509.
DR PDB; 3RNM; X-ray; 2.40 A; A/B/C/D=36-509.
DR PDB; 5J5Z; X-ray; 1.84 A; A/B=36-509.
DR PDB; 5NHG; X-ray; 2.27 A; A/B/C/D/E/F/G/H=36-509.
DR PDB; 6HG8; X-ray; 1.76 A; A/B=36-509.
DR PDB; 6I4P; X-ray; 1.60 A; A/B=36-509.
DR PDB; 6I4Q; X-ray; 1.75 A; A/B=36-509.
DR PDB; 6I4R; X-ray; 1.44 A; A/B=36-509.
DR PDB; 6I4S; X-ray; 1.75 A; A/B=36-509.
DR PDB; 6I4T; X-ray; 1.82 A; A/B=36-509.
DR PDB; 6I4U; X-ray; 1.84 A; A/B=36-509.
DR PDB; 6I4Z; X-ray; 2.34 A; A/B/C/D/E/F/G/H=36-509.
DR PDBsum; 1ZMC; -.
DR PDBsum; 1ZMD; -.
DR PDBsum; 1ZY8; -.
DR PDBsum; 2F5Z; -.
DR PDBsum; 3RNM; -.
DR PDBsum; 5J5Z; -.
DR PDBsum; 5NHG; -.
DR PDBsum; 6HG8; -.
DR PDBsum; 6I4P; -.
DR PDBsum; 6I4Q; -.
DR PDBsum; 6I4R; -.
DR PDBsum; 6I4S; -.
DR PDBsum; 6I4T; -.
DR PDBsum; 6I4U; -.
DR PDBsum; 6I4Z; -.
DR AlphaFoldDB; P09622; -.
DR SMR; P09622; -.
DR BioGRID; 108082; 448.
DR ComplexPortal; CPX-2216; Mitochondrial 2-oxoisovalerate dehydrogenase complex.
DR ComplexPortal; CPX-6233; Mitochondrial pyruvate dehydrogenase complex, somatic variant.
DR ComplexPortal; CPX-6242; Mitochondrial pyruvate dehydrogenase complex, testis-specific variant.
DR CORUM; P09622; -.
DR DIP; DIP-29027N; -.
DR IntAct; P09622; 358.
DR MINT; P09622; -.
DR STRING; 9606.ENSP00000205402; -.
DR DrugBank; DB03147; Flavin adenine dinucleotide.
DR DrugBank; DB00145; Glycine.
DR DrugBank; DB00157; NADH.
DR GlyGen; P09622; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P09622; -.
DR PhosphoSitePlus; P09622; -.
DR SwissPalm; P09622; -.
DR BioMuta; DLD; -.
DR DMDM; 269849557; -.
DR REPRODUCTION-2DPAGE; IPI00015911; -.
DR UCD-2DPAGE; P09622; -.
DR EPD; P09622; -.
DR jPOST; P09622; -.
DR MassIVE; P09622; -.
DR MaxQB; P09622; -.
DR PaxDb; P09622; -.
DR PeptideAtlas; P09622; -.
DR PRIDE; P09622; -.
DR ProteomicsDB; 4221; -.
DR ProteomicsDB; 5080; -.
DR ProteomicsDB; 52254; -. [P09622-1]
DR Antibodypedia; 17237; 536 antibodies from 36 providers.
DR DNASU; 1738; -.
DR Ensembl; ENST00000205402.10; ENSP00000205402.3; ENSG00000091140.15. [P09622-1]
DR Ensembl; ENST00000417551.5; ENSP00000390667.1; ENSG00000091140.15. [P09622-1]
DR Ensembl; ENST00000437604.6; ENSP00000387542.2; ENSG00000091140.15. [P09622-3]
DR GeneID; 1738; -.
DR KEGG; hsa:1738; -.
DR MANE-Select; ENST00000205402.10; ENSP00000205402.3; NM_000108.5; NP_000099.2.
DR UCSC; uc003vet.5; human. [P09622-1]
DR CTD; 1738; -.
DR DisGeNET; 1738; -.
DR GeneCards; DLD; -.
DR GeneReviews; DLD; -.
DR HGNC; HGNC:2898; DLD.
DR HPA; ENSG00000091140; Tissue enhanced (tongue).
DR MalaCards; DLD; -.
DR MIM; 238331; gene.
DR MIM; 246900; phenotype.
DR neXtProt; NX_P09622; -.
DR OpenTargets; ENSG00000091140; -.
DR Orphanet; 2394; Pyruvate dehydrogenase E3 deficiency.
DR PharmGKB; PA27352; -.
DR VEuPathDB; HostDB:ENSG00000091140; -.
DR eggNOG; KOG1335; Eukaryota.
DR GeneTree; ENSGT00550000074844; -.
DR HOGENOM; CLU_016755_0_1_1; -.
DR InParanoid; P09622; -.
DR OMA; DAKYGEW; -.
DR PhylomeDB; P09622; -.
DR TreeFam; TF300414; -.
DR BioCyc; MetaCyc:HS01727-MON; -.
DR BRENDA; 1.2.1.104; 2681.
DR BRENDA; 1.2.1.105; 2681.
DR BRENDA; 1.4.1.27; 2681.
DR BRENDA; 1.8.1.4; 2681.
DR PathwayCommons; P09622; -.
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-6783984; Glycine degradation.
DR Reactome; R-HSA-70268; Pyruvate metabolism.
DR Reactome; R-HSA-70895; Branched-chain amino acid catabolism.
DR Reactome; R-HSA-71064; Lysine catabolism.
DR Reactome; R-HSA-71403; Citric acid cycle (TCA cycle).
DR SABIO-RK; P09622; -.
DR SignaLink; P09622; -.
DR SIGNOR; P09622; -.
DR BioGRID-ORCS; 1738; 206 hits in 1086 CRISPR screens.
DR ChiTaRS; DLD; human.
DR EvolutionaryTrace; P09622; -.
DR GeneWiki; Dihydrolipoamide_dehydrogenase; -.
DR GenomeRNAi; 1738; -.
DR Pharos; P09622; Tbio.
DR PRO; PR:P09622; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; P09622; protein.
DR Bgee; ENSG00000091140; Expressed in heart right ventricle and 213 other tissues.
DR ExpressionAtlas; P09622; baseline and differential.
DR Genevisible; P09622; HS.
DR GO; GO:0043159; C:acrosomal matrix; IEA:Ensembl.
DR GO; GO:0005947; C:mitochondrial alpha-ketoglutarate dehydrogenase complex; IPI:ComplexPortal.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005967; C:mitochondrial pyruvate dehydrogenase complex; IPI:ComplexPortal.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0031514; C:motile cilium; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0045252; C:oxoglutarate dehydrogenase complex; IDA:UniProtKB.
DR GO; GO:0045254; C:pyruvate dehydrogenase complex; IDA:MGI.
DR GO; GO:0004148; F:dihydrolipoyl dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IBA:GO_Central.
DR GO; GO:0006086; P:acetyl-CoA biosynthetic process from pyruvate; IDA:ComplexPortal.
DR GO; GO:0009083; P:branched-chain amino acid catabolic process; IDA:ComplexPortal.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:InterPro.
DR GO; GO:0007369; P:gastrulation; IEA:Ensembl.
DR GO; GO:0106077; P:histone succinylation; IDA:UniProtKB.
DR GO; GO:0061732; P:mitochondrial acetyl-CoA biosynthetic process from pyruvate; IC:MGI.
DR GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; IEA:Ensembl.
DR GO; GO:0042391; P:regulation of membrane potential; IEA:Ensembl.
DR GO; GO:0048240; P:sperm capacitation; IEA:Ensembl.
DR Gene3D; 3.30.390.30; -; 1.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR InterPro; IPR016156; FAD/NAD-linked_Rdtase_dimer_sf.
DR InterPro; IPR006258; Lipoamide_DH.
DR InterPro; IPR001100; Pyr_nuc-diS_OxRdtase.
DR InterPro; IPR004099; Pyr_nucl-diS_OxRdtase_dimer.
DR InterPro; IPR012999; Pyr_OxRdtase_I_AS.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR Pfam; PF02852; Pyr_redox_dim; 1.
DR PIRSF; PIRSF000350; Mercury_reductase_MerA; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR SUPFAM; SSF55424; SSF55424; 1.
DR TIGRFAMs; TIGR01350; lipoamide_DH; 1.
DR PROSITE; PS00076; PYRIDINE_REDOX_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell projection; Cilium;
KW Cytoplasmic vesicle; Disease variant; Disulfide bond; FAD; Flagellum;
KW Flavoprotein; Mitochondrion; NAD; Nucleus; Oxidoreductase; Phosphoprotein;
KW Redox-active center; Reference proteome; Transit peptide.
FT TRANSIT 1..35
FT /note="Mitochondrion"
FT /evidence="ECO:0007744|PubMed:25944712"
FT CHAIN 36..509
FT /note="Dihydrolipoyl dehydrogenase, mitochondrial"
FT /id="PRO_0000030295"
FT ACT_SITE 487
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P09624"
FT BINDING 71..80
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 89
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 154
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 183..185
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 220..227
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 243
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 278
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 314
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 355
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT BINDING 361..364
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:15946682"
FT SITE 448
FT /note="Important for interaction with PDHX and activity of
FT multienzyme pyruvate dehydrogenase complex"
FT /evidence="ECO:0000269|PubMed:20385101"
FT SITE 473
FT /note="Important for interaction with PDHX and activity of
FT multienzyme pyruvate dehydrogenase complex"
FT /evidence="ECO:0000269|PubMed:20385101"
FT MOD_RES 66
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 66
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 104
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 104
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 122
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 122
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 132
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 132
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 143
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 143
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 159
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 166
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 273
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 277
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 285
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 297
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P6R2"
FT MOD_RES 346
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 410
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 410
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 417
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 420
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 430
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 502
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 505
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT MOD_RES 505
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O08749"
FT DISULFID 80..85
FT /note="Redox-active"
FT /evidence="ECO:0000250|UniProtKB:P09624"
FT VAR_SEQ 1..99
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055855"
FT VAR_SEQ 147..194
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055856"
FT VARIANT 47
FT /note="I -> T (in DLDD; dbSNP:rs397514651)"
FT /evidence="ECO:0000269|PubMed:16770810"
FT /id="VAR_076985"
FT VARIANT 72
FT /note="K -> E (in DLDD; reduced dihydrolipoyl dehydrogenase
FT activity; no effect on interaction with PDHX;
FT dbSNP:rs121964987)"
FT /evidence="ECO:0000269|PubMed:20160912,
FT ECO:0000269|PubMed:8506365"
FT /id="VAR_006907"
FT VARIANT 104
FT /note="K -> T (in dbSNP:rs1130477)"
FT /evidence="ECO:0000269|PubMed:3693355,
FT ECO:0000269|PubMed:8406489"
FT /id="VAR_031922"
FT VARIANT 136
FT /note="Missing (in DLDD)"
FT /evidence="ECO:0000269|PubMed:9540846"
FT /id="VAR_076986"
FT VARIANT 229
FT /note="G -> C (in DLDD; dbSNP:rs121964990)"
FT /evidence="ECO:0000269|PubMed:16770810,
FT ECO:0000269|PubMed:9934985"
FT /id="VAR_015820"
FT VARIANT 331
FT /note="L -> V (in dbSNP:rs17624)"
FT /id="VAR_014555"
FT VARIANT 361
FT /note="M -> V (in DLDD; dbSNP:rs121964993)"
FT /evidence="ECO:0000269|PubMed:11687750"
FT /id="VAR_076987"
FT VARIANT 375
FT /note="E -> K (in DLDD; loss of enzyme activity; abolished
FT interaction with PDHX; dbSNP:rs121964992)"
FT /evidence="ECO:0000269|PubMed:11687750,
FT ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:20160912,
FT ECO:0000269|PubMed:9540846"
FT /id="VAR_076988"
FT VARIANT 393
FT /note="I -> T (in DLDD; dbSNP:rs121964991)"
FT /evidence="ECO:0000269|PubMed:12925875"
FT /id="VAR_076989"
FT VARIANT 479
FT /note="D -> V (in DLDD; reduced dehydrogenase activity;
FT increased proteolytic activity; dbSNP:rs397514649)"
FT /evidence="ECO:0000269|PubMed:10448086,
FT ECO:0000269|PubMed:17404228"
FT /id="VAR_076990"
FT VARIANT 482
FT /note="R -> G (in DLDD; reduced enzyme activity;
FT dbSNP:rs397514650)"
FT /id="VAR_076991"
FT VARIANT 488
FT /note="P -> L (in DLDD; no effect on interaction with PDHX;
FT dbSNP:rs121964988)"
FT /evidence="ECO:0000269|PubMed:20160912,
FT ECO:0000269|PubMed:8506365"
FT /id="VAR_006908"
FT VARIANT 495
FT /note="R -> G (in DLDD; loss of enzyme activity; reduced
FT interaction with PDHX; dbSNP:rs121964989)"
FT /evidence="ECO:0000269|PubMed:16442803,
FT ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8968745"
FT /id="VAR_015821"
FT MUTAGEN 89
FT /note="K->E: Abolishes dihydrolipoyl dehydrogenase
FT activity. Does not affect interaction with PDHX."
FT /evidence="ECO:0000269|PubMed:20160912"
FT MUTAGEN 383
FT /note="H->A: Reduces dihydrolipoyl dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 383
FT /note="H->L: Reduces dihydrolipoyl dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 448
FT /note="D->A: Reduces interaction with PDHX. Inhibits
FT multienzyme pyruvate dehydrogenase complex activity. Does
FT not affect dihydrolipoyl dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 448
FT /note="D->N: Does not affect dihydrolipoyl dehydrogenase
FT activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 466
FT /note="E->A: Decreases dehydrogenase activity. Loss of
FT proteolytic activity."
FT /evidence="ECO:0000269|PubMed:17404228"
FT MUTAGEN 473
FT /note="Y->A: Reduces interaction with PDHX. Inhibits
FT multienzyme pyruvate dehydrogenase complex activity. Does
FT not affect dihydrolipoyl dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 473
FT /note="Y->F: Does not affect dihydrolipoyl dehydrogenase
FT activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 473
FT /note="Y->H: Reduces interaction with PDHX. Inhibits
FT multienzyme pyruvate dehydrogenase complex activity. Does
FT not affect dihydrolipoyl dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 482
FT /note="R->A: Does not affect dihydrolipoyl dehydrogenase
FT activity."
FT /evidence="ECO:0000269|PubMed:20385101"
FT MUTAGEN 482
FT /note="R->M: Does not affect interaction with PDHX."
FT /evidence="ECO:0000269|PubMed:20160912"
FT MUTAGEN 485
FT /note="H->A: Loss of dehydrogenase activity. Increases
FT proteolytic activity."
FT /evidence="ECO:0000269|PubMed:17404228"
FT MUTAGEN 491
FT /note="S->A: Loss of proteolytic activity. Does not affect
FT dehydrogenase activity."
FT /evidence="ECO:0000269|PubMed:17404228"
FT MUTAGEN 492
FT /note="E->Q: Reduces dihydrolipoyl dehydrogenase activity.
FT Does not affect interaction with PDHX."
FT /evidence="ECO:0000269|PubMed:20160912"
FT MUTAGEN 505
FT /note="K->M: Reduces dihydrolipoyl dehydrogenase activity.
FT Does not affect interaction with PDHX."
FT /evidence="ECO:0000269|PubMed:20160912"
FT CONFLICT 154
FT /note="G -> R (in Ref. 2; AAA35764)"
FT /evidence="ECO:0000305"
FT CONFLICT 209
FT /note="L -> F (in Ref. 5; BAD92940)"
FT /evidence="ECO:0000305"
FT CONFLICT 493
FT /note="A -> AEA (in Ref. 3; AAB01381)"
FT /evidence="ECO:0000305"
FT STRAND 40..47
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 51..62
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 67..71
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 73..77
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 78..83
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 85..102
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 105..108
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 111..114
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 116..118
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 120..144
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 148..158
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 171..181
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 197..201
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 203..206
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 214..219
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 223..235
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 238..242
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 244..249
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 255..268
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 271..273
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 275..283
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 289..295
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 302..311
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 315..317
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 324..327
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 350..352
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 354..356
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 363..377
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 386..388
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 391..393
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 395..403
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 406..412
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 416..422
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 423..425
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 427..432
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 438..444
FT /evidence="ECO:0007829|PDB:6I4R"
FT TURN 445..447
FT /evidence="ECO:0007829|PDB:6I4R"
FT STRAND 449..457
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 460..473
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 477..482
FT /evidence="ECO:0007829|PDB:6I4R"
FT HELIX 491..503
FT /evidence="ECO:0007829|PDB:6I4R"
SQ SEQUENCE 509 AA; 54177 MW; 7613492C516F3835 CRC64;
MQSWSRVYCS LAKRGHFNRI SHGLQGLSAV PLRTYADQPI DADVTVIGSG PGGYVAAIKA
AQLGFKTVCI EKNETLGGTC LNVGCIPSKA LLNNSHYYHM AHGKDFASRG IEMSEVRLNL
DKMMEQKSTA VKALTGGIAH LFKQNKVVHV NGYGKITGKN QVTATKADGG TQVIDTKNIL
IATGSEVTPF PGITIDEDTI VSSTGALSLK KVPEKMVVIG AGVIGVELGS VWQRLGADVT
AVEFLGHVGG VGIDMEISKN FQRILQKQGF KFKLNTKVTG ATKKSDGKID VSIEAASGGK
AEVITCDVLL VCIGRRPFTK NLGLEELGIE LDPRGRIPVN TRFQTKIPNI YAIGDVVAGP
MLAHKAEDEG IICVEGMAGG AVHIDYNCVP SVIYTHPEVA WVGKSEEQLK EEGIEYKVGK
FPFAANSRAK TNADTDGMVK ILGQKSTDRV LGAHILGPGA GEMVNEAALA LEYGASCEDI
ARVCHAHPTL SEAFREANLA ASFGKSINF
