ECHB_HUMAN
ID ECHB_HUMAN Reviewed; 474 AA.
AC P55084; B2RB16; B4E2W0; O14969; Q53TA6; Q96C77; Q9H3F5; Q9T2V8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=Trifunctional enzyme subunit beta, mitochondrial;
DE AltName: Full=TP-beta;
DE Includes:
DE RecName: Full=3-ketoacyl-CoA thiolase;
DE EC=2.3.1.155 {ECO:0000269|PubMed:7958339, ECO:0000269|PubMed:8135828, ECO:0000269|PubMed:8163672, ECO:0000269|PubMed:8651282};
DE EC=2.3.1.16 {ECO:0000269|PubMed:1550553, ECO:0000269|PubMed:7958339, ECO:0000269|PubMed:8135828, ECO:0000269|PubMed:8163672, ECO:0000269|PubMed:8651282};
DE AltName: Full=Acetyl-CoA acyltransferase;
DE AltName: Full=Beta-ketothiolase;
DE Flags: Precursor;
GN Name=HADHB; ORFNames=MSTP029;
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), FUNCTION, CATALYTIC ACTIVITY, AND
RP PATHWAY.
RX PubMed=8135828; DOI=10.1006/bbrc.1994.1302;
RA Kamijo T., Aoyama T., Komiyama A., Hashimoto T.;
RT "Structural analysis of cDNAs for subunits of human mitochondrial fatty
RT acid beta-oxidation trifunctional protein.";
RL Biochem. Biophys. Res. Commun. 199:818-825(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MTPD LYS-444.
RC TISSUE=Blood;
RX PubMed=9259266; DOI=10.1093/hmg/6.8.1215;
RA Orii K.E., Aoyama T., Wakui K., Fukushima Y., Miyajima H., Yamaguchi S.,
RA Orii T., Kondo N., Hashimoto T.;
RT "Genomic and mutational analysis of the mitochondrial trifunctional protein
RT beta-subunit (HADHB) gene in patients with trifunctional protein
RT deficiency.";
RL Hum. Mol. Genet. 6:1215-1224(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Liu B., Liu Y.Q., Wang X.Y., Zhao B., Sheng H., Zhao X.W., Liu S., Xu Y.Y.,
RA Ye J., Song L., Gao Y., Zhang C.L., Zhang J., Wei Y.J., Cao H.Q., Zhao Y.,
RA Liu L.S., Ding J.F., Gao R.L., Wu Q.Y., Qiang B.Q., Yuan J.G., Liew C.C.,
RA Zhao M.S., Hui R.T.;
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Stomach, and Tongue;
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 GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT SER-209.
RC TISSUE=Colon, Hypothalamus, Skeletal muscle, and Urinary bladder;
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 [7]
RP PROTEIN SEQUENCE OF 34-52.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass spectrometric
RT identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [8]
RP PROTEIN SEQUENCE OF 48-63, AND CATALYTIC ACTIVITY.
RC TISSUE=Liver;
RX PubMed=7958339; DOI=10.1042/bst0220427;
RA Middleton B.;
RT "The mitochondrial long-chain trifunctional enzyme: 2-enoyl-CoA hydratase,
RT 3-hydroxyacyl-CoA dehydrogenase and 3-oxoacyl-CoA thiolase.";
RL Biochem. Soc. Trans. 22:427-431(1994).
RN [9]
RP PROTEIN SEQUENCE OF 62-72 AND 96-111.
RC TISSUE=Adipocyte;
RX PubMed=15242332; DOI=10.1042/bj20040647;
RA Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.;
RT "Vectorial proteomics reveal targeting, phosphorylation and specific
RT fragmentation of polymerase I and transcript release factor (PTRF) at the
RT surface of caveolae in human adipocytes.";
RL Biochem. J. 383:237-248(2004).
RN [10]
RP CATALYTIC ACTIVITY.
RX PubMed=1550553; DOI=10.1016/0006-291x(92)90501-b;
RA Carpenter K., Pollitt R.J., Middleton B.;
RT "Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a
RT multifunctional membrane-bound beta-oxidation enzyme of mitochondria.";
RL Biochem. Biophys. Res. Commun. 183:443-448(1992).
RN [11]
RP CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=8163672; DOI=10.1172/jci117158;
RA Kamijo T., Wanders R.J., Saudubray J.-M., Aoyama T., Komiyama A.,
RA Hashimoto T.;
RT "Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of
RT the mutant enzyme in two patients.";
RL J. Clin. Invest. 93:1740-1747(1994).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-72 AND LYS-188, 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 [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND INTERACTION
RP WITH RSAD2.
RX PubMed=21527675; DOI=10.1126/science.1202007;
RA Seo J.Y., Yaneva R., Hinson E.R., Cresswell P.;
RT "Human cytomegalovirus directly induces the antiviral protein viperin to
RT enhance infectivity.";
RL Science 332:1093-1097(2011).
RN [15]
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 [16]
RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER ARG-33, 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 [17]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.20 ANGSTROMS), FUNCTION, SUBUNIT,
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=29915090; DOI=10.1073/pnas.1801252115;
RA Liang K., Li N., Wang X., Dai J., Liu P., Wang C., Chen X.W., Gao N.,
RA Xiao J.;
RT "Cryo-EM structure of human mitochondrial trifunctional protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:7039-7044(2018).
RN [18]
RP INTERACTION WITH MTLN.
RX PubMed=32243843; DOI=10.1016/j.stemcr.2020.03.002;
RA Friesen M., Warren C.R., Yu H., Toyohara T., Ding Q., Florido M.H.C.,
RA Sayre C., Pope B.D., Goff L.A., Rinn J.L., Cowan C.A.;
RT "Mitoregulin Controls beta-Oxidation in Human and Mouse Adipocytes.";
RL Stem Cell Reports 14:590-602(2020).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (3.60 ANGSTROMS) OF 34-474, FUNCTION, SUBUNIT, AND
RP ACTIVE SITE.
RX PubMed=30850536; DOI=10.1073/pnas.1816317116;
RA Xia C., Fu Z., Battaile K.P., Kim J.P.;
RT "Crystal structure of human mitochondrial trifunctional protein, a fatty
RT acid beta-oxidation metabolon.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:6069-6074(2019).
RN [20]
RP VARIANTS MTPD HIS-61; HIS-247 AND GLY-263, AND CATALYTIC ACTIVITY.
RX PubMed=8651282;
RA Ushikubo S., Aoyama T., Kamijo T., Wanders R.J.A., Rinaldo P., Vockley J.,
RA Hashimoto T.;
RT "Molecular characterization of mitochondrial trifunctional protein
RT deficiency: formation of the enzyme complex is important for stabilization
RT of both alpha- and beta-subunits.";
RL Am. J. Hum. Genet. 58:979-988(1996).
RN [21]
RP VARIANTS MTPD ASP-59; CYS-61; HIS-61; GLY-117; PRO-121; PRO-133; GLY-242;
RP HIS-247; 259-GLY--PRO-270 DEL; GLY-263; ASP-280; ARG-294; LEU-294; SER-301
RP AND LYS-444.
RX PubMed=12754706; DOI=10.1002/humu.10211;
RA Spiekerkoetter U., Sun B., Khuchua Z., Bennett M.J., Strauss A.W.;
RT "Molecular and phenotypic heterogeneity in mitochondrial trifunctional
RT protein deficiency due to beta-subunit mutations.";
RL Hum. Mutat. 21:598-607(2003).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-119.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Mitochondrial trifunctional enzyme catalyzes the last three
CC of the four reactions of the mitochondrial beta-oxidation pathway
CC (PubMed:8135828, PubMed:29915090, PubMed:30850536). The mitochondrial
CC beta-oxidation pathway is the major energy-producing process in tissues
CC and is performed through four consecutive reactions breaking down fatty
CC acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in
CC this pathway, the trifunctional enzyme exhibits specificity for long-
CC chain fatty acids (PubMed:30850536). Mitochondrial trifunctional enzyme
CC is a heterotetrameric complex composed of two proteins, the
CC trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA
CC hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the
CC trifunctional enzyme subunit beta/HADHB described here bears the 3-
CC ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090,
CC PubMed:30850536). {ECO:0000269|PubMed:29915090,
CC ECO:0000269|PubMed:30850536, ECO:0000269|PubMed:8135828,
CC ECO:0000303|PubMed:29915090, ECO:0000303|PubMed:30850536}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + an acyl-CoA = a 3-oxoacyl-CoA + CoA;
CC Xref=Rhea:RHEA:21564, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:58342, ChEBI:CHEBI:90726; EC=2.3.1.16;
CC Evidence={ECO:0000269|PubMed:7958339, ECO:0000269|PubMed:8135828,
CC ECO:0000269|PubMed:8163672, ECO:0000269|PubMed:8651282};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:21566;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + butanoyl-CoA = 3-oxohexanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:31111, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57371, ChEBI:CHEBI:62418;
CC Evidence={ECO:0000269|PubMed:1550553};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31113;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + hexanoyl-CoA = 3-oxooctanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:31203, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:62619, ChEBI:CHEBI:62620;
CC Evidence={ECO:0000269|PubMed:8163672};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31205;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + octanoyl-CoA = 3-oxodecanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:31087, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57386, ChEBI:CHEBI:62548;
CC Evidence={ECO:0000269|PubMed:1550553};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31089;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + decanoyl-CoA = 3-oxododecanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:31183, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:61430, ChEBI:CHEBI:62615;
CC Evidence={ECO:0000269|PubMed:8163672};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31185;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + dodecanoyl-CoA = 3-oxotetradecanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:31091, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57375, ChEBI:CHEBI:62543;
CC Evidence={ECO:0000269|PubMed:1550553};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:31093;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + tetradecanoyl-CoA = 3-oxohexadecanoyl-CoA + CoA;
CC Xref=Rhea:RHEA:18161, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57349, ChEBI:CHEBI:57385; EC=2.3.1.155;
CC Evidence={ECO:0000269|PubMed:1550553, ECO:0000269|PubMed:7958339,
CC ECO:0000269|PubMed:8135828, ECO:0000269|PubMed:8163672,
CC ECO:0000269|PubMed:8651282};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18163;
CC Evidence={ECO:0000269|PubMed:8135828};
CC -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC {ECO:0000269|PubMed:8135828}.
CC -!- SUBUNIT: Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits;
CC forms the mitochondrial trifunctional enzyme (PubMed:29915090,
CC PubMed:30850536). Also purified as higher order heterooligomers
CC including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which
CC physiological significance remains unclear (PubMed:8163672,
CC PubMed:29915090). The mitochondrial trifunctional enzyme interacts with
CC MTLN (PubMed:32243843). Interacts with RSAD2/viperin (PubMed:21527675).
CC {ECO:0000269|PubMed:21527675, ECO:0000269|PubMed:29915090,
CC ECO:0000269|PubMed:30850536, ECO:0000269|PubMed:32243843,
CC ECO:0000269|PubMed:8163672}.
CC -!- INTERACTION:
CC P55084; Q9H0R8: GABARAPL1; NbExp=4; IntAct=EBI-356635, EBI-746969;
CC P55084; P40939: HADHA; NbExp=7; IntAct=EBI-356635, EBI-356720;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:21527675}.
CC Mitochondrion inner membrane {ECO:0000269|PubMed:21527675}.
CC Mitochondrion outer membrane {ECO:0000269|PubMed:21527675}. Endoplasmic
CC reticulum {ECO:0000269|PubMed:21527675}. Note=Protein stability and
CC association with membranes require HADHA.
CC {ECO:0000269|PubMed:29915090}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P55084-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P55084-2; Sequence=VSP_054426;
CC -!- DISEASE: Mitochondrial trifunctional protein deficiency (MTPD)
CC [MIM:609015]: A disease biochemically characterized by loss of all
CC enzyme activities of the mitochondrial trifunctional protein complex.
CC Variable clinical manifestations include hypoglycemia, cardiomyopathy,
CC delayed psychomotor development, sensorimotor axonopathy, generalized
CC weakness, hepatic dysfunction, respiratory failure. Sudden infant death
CC may occur. Most patients die from heart failure.
CC {ECO:0000269|PubMed:12754706, ECO:0000269|PubMed:8651282,
CC ECO:0000269|PubMed:9259266}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the thiolase-like superfamily. Thiolase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA22061.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; D16481; BAA03942.1; -; mRNA.
DR EMBL; D86850; BAA22061.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF113209; AAG39280.1; -; mRNA.
DR EMBL; AK304455; BAG65272.1; -; mRNA.
DR EMBL; AK314455; BAG37063.1; -; mRNA.
DR EMBL; AC010896; AAY14644.1; -; Genomic_DNA.
DR EMBL; BC014572; AAH14572.1; -; mRNA.
DR EMBL; BC017564; AAH17564.1; -; mRNA.
DR EMBL; BC030824; AAH30824.1; -; mRNA.
DR EMBL; BC066963; AAH66963.1; -; mRNA.
DR CCDS; CCDS1722.1; -. [P55084-1]
DR CCDS; CCDS62872.1; -. [P55084-2]
DR PIR; JC2109; JC2109.
DR RefSeq; NP_000174.1; NM_000183.2. [P55084-1]
DR RefSeq; NP_001268441.1; NM_001281512.1.
DR RefSeq; NP_001268442.1; NM_001281513.1. [P55084-2]
DR RefSeq; XP_011531105.1; XM_011532803.1. [P55084-1]
DR PDB; 5ZQZ; EM; 4.20 A; B/D=1-474.
DR PDB; 5ZRV; EM; 7.70 A; B/D/F/H=1-474.
DR PDB; 6DV2; X-ray; 3.60 A; A/B/C/D/E/F=34-474.
DR PDBsum; 5ZQZ; -.
DR PDBsum; 5ZRV; -.
DR PDBsum; 6DV2; -.
DR AlphaFoldDB; P55084; -.
DR SMR; P55084; -.
DR BioGRID; 109282; 371.
DR ComplexPortal; CPX-6245; Mitochondrial trifunctional enzyme complex.
DR CORUM; P55084; -.
DR IntAct; P55084; 126.
DR MINT; P55084; -.
DR STRING; 9606.ENSP00000325136; -.
DR ChEMBL; CHEMBL4523245; -.
DR MoonProt; P55084; -.
DR GlyGen; P55084; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P55084; -.
DR MetOSite; P55084; -.
DR PhosphoSitePlus; P55084; -.
DR SwissPalm; P55084; -.
DR BioMuta; HADHB; -.
DR DMDM; 116241345; -.
DR UCD-2DPAGE; P55084; -.
DR EPD; P55084; -.
DR jPOST; P55084; -.
DR MassIVE; P55084; -.
DR MaxQB; P55084; -.
DR PaxDb; P55084; -.
DR PeptideAtlas; P55084; -.
DR PRIDE; P55084; -.
DR ProteomicsDB; 56786; -. [P55084-1]
DR ProteomicsDB; 5856; -.
DR Antibodypedia; 27848; 249 antibodies from 30 providers.
DR DNASU; 3032; -.
DR Ensembl; ENST00000317799.10; ENSP00000325136.5; ENSG00000138029.14. [P55084-1]
DR Ensembl; ENST00000545822.2; ENSP00000442665.1; ENSG00000138029.14. [P55084-2]
DR GeneID; 3032; -.
DR KEGG; hsa:3032; -.
DR MANE-Select; ENST00000317799.10; ENSP00000325136.5; NM_000183.3; NP_000174.1.
DR UCSC; uc002rgz.4; human. [P55084-1]
DR CTD; 3032; -.
DR DisGeNET; 3032; -.
DR GeneCards; HADHB; -.
DR HGNC; HGNC:4803; HADHB.
DR HPA; ENSG00000138029; Tissue enhanced (skeletal muscle, tongue).
DR MalaCards; HADHB; -.
DR MIM; 143450; gene.
DR MIM; 609015; phenotype.
DR neXtProt; NX_P55084; -.
DR OpenTargets; ENSG00000138029; -.
DR Orphanet; 746; Mitochondrial trifunctional protein deficiency.
DR PharmGKB; PA29177; -.
DR VEuPathDB; HostDB:ENSG00000138029; -.
DR eggNOG; KOG1392; Eukaryota.
DR GeneTree; ENSGT01030000234626; -.
DR InParanoid; P55084; -.
DR OMA; MTAFPEP; -.
DR OrthoDB; 1129049at2759; -.
DR PhylomeDB; P55084; -.
DR TreeFam; TF315243; -.
DR BioCyc; MetaCyc:HS06436-MON; -.
DR PathwayCommons; P55084; -.
DR Reactome; R-HSA-1482798; Acyl chain remodeling of CL.
DR Reactome; R-HSA-77285; Beta oxidation of myristoyl-CoA to lauroyl-CoA.
DR Reactome; R-HSA-77288; mitochondrial fatty acid beta-oxidation of unsaturated fatty acids.
DR Reactome; R-HSA-77305; Beta oxidation of palmitoyl-CoA to myristoyl-CoA.
DR Reactome; R-HSA-77310; Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA.
DR Reactome; R-HSA-77346; Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA.
DR Reactome; R-HSA-77348; Beta oxidation of octanoyl-CoA to hexanoyl-CoA.
DR Reactome; R-HSA-77350; Beta oxidation of hexanoyl-CoA to butanoyl-CoA.
DR SignaLink; P55084; -.
DR UniPathway; UPA00659; -.
DR BioGRID-ORCS; 3032; 7 hits in 1074 CRISPR screens.
DR ChiTaRS; HADHB; human.
DR GeneWiki; HADHB; -.
DR GenomeRNAi; 3032; -.
DR Pharos; P55084; Tbio.
DR PRO; PR:P55084; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P55084; protein.
DR Bgee; ENSG00000138029; Expressed in heart right ventricle and 207 other tissues.
DR ExpressionAtlas; P55084; baseline and differential.
DR Genevisible; P55084; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005740; C:mitochondrial envelope; TAS:ProtInc.
DR GO; GO:0016507; C:mitochondrial fatty acid beta-oxidation multienzyme complex; IPI:ComplexPortal.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB.
DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0003857; F:3-hydroxyacyl-CoA dehydrogenase activity; TAS:ProtInc.
DR GO; GO:0003985; F:acetyl-CoA C-acetyltransferase activity; IEA:Ensembl.
DR GO; GO:0003988; F:acetyl-CoA C-acyltransferase activity; TAS:ProtInc.
DR GO; GO:0050633; F:acetyl-CoA C-myristoyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0004300; F:enoyl-CoA hydratase activity; TAS:ProtInc.
DR GO; GO:0106222; F:lncRNA binding; IEA:Ensembl.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IDA:ComplexPortal.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR CDD; cd00751; thiolase; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR002155; Thiolase.
DR InterPro; IPR016039; Thiolase-like.
DR InterPro; IPR020615; Thiolase_acyl_enz_int_AS.
DR InterPro; IPR020610; Thiolase_AS.
DR InterPro; IPR020617; Thiolase_C.
DR InterPro; IPR020613; Thiolase_CS.
DR InterPro; IPR020616; Thiolase_N.
DR Pfam; PF02803; Thiolase_C; 1.
DR Pfam; PF00108; Thiolase_N; 1.
DR SUPFAM; SSF53901; SSF53901; 2.
DR TIGRFAMs; TIGR01930; AcCoA-C-Actrans; 1.
DR PROSITE; PS00098; THIOLASE_1; 1.
DR PROSITE; PS00737; THIOLASE_2; 1.
DR PROSITE; PS00099; THIOLASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Acyltransferase; Alternative splicing;
KW Direct protein sequencing; Disease variant; Endoplasmic reticulum;
KW Fatty acid metabolism; Lipid metabolism; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Mitochondrion outer membrane;
KW Reference proteome; Transferase; Transit peptide.
FT TRANSIT 1..33
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:12665801,
FT ECO:0007744|PubMed:25944712"
FT CHAIN 34..474
FT /note="Trifunctional enzyme subunit beta, mitochondrial"
FT /id="PRO_0000034080"
FT INTRAMEM 173..220
FT /evidence="ECO:0000305|PubMed:29915090"
FT ACT_SITE 138
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000305|PubMed:30850536"
FT ACT_SITE 458
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000305|PubMed:30850536"
FT SITE 428
FT /note="Increases nucleophilicity of active site Cys"
FT /evidence="ECO:0000305|PubMed:30850536"
FT MOD_RES 72
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 72
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 188
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 188
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 190
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 272
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 291
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 293
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 293
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 298
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 332
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 332
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 348
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT MOD_RES 361
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99JY0"
FT VAR_SEQ 1..36
FT /note="MTILTYPFKNLPTASKWALRFSIRPLSCSSQLRAAP -> MTLVSGWLLYGW
FT II (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054426"
FT VARIANT 59
FT /note="G -> D (in MTPD)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021128"
FT VARIANT 61
FT /note="R -> C (in MTPD; dbSNP:rs780351691)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021129"
FT VARIANT 61
FT /note="R -> H (in MTPD; dbSNP:rs121913132)"
FT /evidence="ECO:0000269|PubMed:12754706,
FT ECO:0000269|PubMed:8651282"
FT /id="VAR_007493"
FT VARIANT 117
FT /note="R -> G (in MTPD)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021130"
FT VARIANT 119
FT /note="A -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035705"
FT VARIANT 121
FT /note="L -> P (in MTPD; dbSNP:rs773127211)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021131"
FT VARIANT 133
FT /note="T -> P (in MTPD; dbSNP:rs371159065)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021132"
FT VARIANT 209
FT /note="P -> S (in dbSNP:rs17851200)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_028231"
FT VARIANT 242
FT /note="D -> G (in MTPD; dbSNP:rs1166120479)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021133"
FT VARIANT 247
FT /note="R -> H (in MTPD; dbSNP:rs121913133)"
FT /evidence="ECO:0000269|PubMed:12754706,
FT ECO:0000269|PubMed:8651282"
FT /id="VAR_007494"
FT VARIANT 259..270
FT /note="Missing (in MTPD)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021134"
FT VARIANT 263
FT /note="D -> G (in MTPD; dbSNP:rs121913131)"
FT /evidence="ECO:0000269|PubMed:12754706,
FT ECO:0000269|PubMed:8651282"
FT /id="VAR_007495"
FT VARIANT 277
FT /note="K -> R (in dbSNP:rs57969630)"
FT /id="VAR_061897"
FT VARIANT 280
FT /note="G -> D (in MTPD; dbSNP:rs751772298)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021135"
FT VARIANT 294
FT /note="P -> L (in MTPD)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021136"
FT VARIANT 294
FT /note="P -> R (in MTPD; dbSNP:rs1558357879)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021137"
FT VARIANT 301
FT /note="G -> S (in MTPD; dbSNP:rs891954464)"
FT /evidence="ECO:0000269|PubMed:12754706"
FT /id="VAR_021138"
FT VARIANT 444
FT /note="R -> K (in MTPD; dbSNP:rs121913134)"
FT /evidence="ECO:0000269|PubMed:12754706,
FT ECO:0000269|PubMed:9259266"
FT /id="VAR_017409"
FT CONFLICT 1
FT /note="M -> MT (in Ref. 3; AAG39280 and 6; AAH14572/
FT AAH17564/AAH30824/AAH66963)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 474 AA; 51294 MW; A7B41C37BEC1E6AD CRC64;
MTILTYPFKN LPTASKWALR FSIRPLSCSS QLRAAPAVQT KTKKTLAKPN IRNVVVVDGV
RTPFLLSGTS YKDLMPHDLA RAALTGLLHR TSVPKEVVDY IIFGTVIQEV KTSNVAREAA
LGAGFSDKTP AHTVTMACIS ANQAMTTGVG LIASGQCDVI VAGGVELMSD VPIRHSRKMR
KLMLDLNKAK SMGQRLSLIS KFRFNFLAPE LPAVSEFSTS ETMGHSADRL AAAFAVSRLE
QDEYALRSHS LAKKAQDEGL LSDVVPFKVP GKDTVTKDNG IRPSSLEQMA KLKPAFIKPY
GTVTAANSSF LTDGASAMLI MAEEKALAMG YKPKAYLRDF MYVSQDPKDQ LLLGPTYATP
KVLEKAGLTM NDIDAFEFHE AFSGQILANF KAMDSDWFAE NYMGRKTKVG LPPLEKFNNW
GGSLSLGHPF GATGCRLVMA AANRLRKEGG QYGLVAACAA GGQGHAMIVE AYPK
