ID ETHE1_HUMAN Reviewed; 254 AA. AC O95571; Q96HR0; Q9H001; DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 2. DT 18-JUL-2018, entry version 142. DE RecName: Full=Persulfide dioxygenase ETHE1, mitochondrial; DE EC=1.13.11.18 {ECO:0000269|PubMed:19136963, ECO:0000269|PubMed:23144459, ECO:0000269|PubMed:25596185}; DE AltName: Full=Ethylmalonic encephalopathy protein 1; DE AltName: Full=Hepatoma subtracted clone one protein; DE AltName: Full=Sulfur dioxygenase ETHE1; DE Flags: Precursor; GN Name=ETHE1; Synonyms=HSCO; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, INTERACTION WITH RP RELA, FUNCTION, AND ABSENCE OF GLYOXALASE II ACTIVITY. RC TISSUE=Liver; RX PubMed=12398897; DOI=10.1016/S1535-6108(02)00152-6; RA Higashitsuji H., Higashitsuji H., Nagao T., Nonoguchi K., Fujii S., RA Itoh K., Fujita J.; RT "A novel protein overexpressed in hepatoma accelerates export of NF- RT kappa B from the nucleus and inhibits p53-dependent apoptosis."; RL Cancer Cell 2:335-346(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP FUNCTION, ABSENCE OF GLYOXALASE II ACTIVITY, AND VARIANTS EE CYS-38; RP ALA-136; TRP-163 AND ARG-185. RX PubMed=14732903; DOI=10.1086/381653; RA Tiranti V., D'Adamo P., Briem E., Ferrari G., Mineri R., Lamantea E., RA Mandel H., Balestri P., Garcia-Silva M.-T., Vollmer B., Rinaldo P., RA Hahn S.H., Leonard J., Rahman S., Dionisi-Vici C., Garavaglia B., RA Gasparini P., Zeviani M.; RT "Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene RT encoding a mitochondrial matrix protein."; RL Am. J. Hum. Genet. 74:239-252(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., RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M., RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., RA 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]. RC TISSUE=Eye; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ROLE IN DISEASE, SUBCELLULAR RP LOCATION, TRANSIT PEPTIDE CLEAVAGE SITE, IDENTIFICATION BY MASS RP SPECTROMETRY, AND INTERACTION WITH TST. RX PubMed=19136963; DOI=10.1038/nm.1907; RA Tiranti V., Viscomi C., Hildebrandt T., Di Meo I., Mineri R., RA Tiveron C., Levitt M.D., Prelle A., Fagiolari G., Rimoldi M., RA Zeviani M.; RT "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide RT toxicity in ethylmalonic encephalopathy."; RL Nat. Med. 15:200-205(2009). RN [6] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66, AND IDENTIFICATION BY RP 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., RA Walther T.C., 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 [7] 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., RA Buerckstuemmer T., 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 [8] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, RP SUBUNIT, ENZYME REGULATION, AND CHARACTERIZATION OF VARIANTS EE RP ILE-152 AND ASN-196. RX PubMed=23144459; DOI=10.1074/jbc.M112.407411; RA Kabil O., Banerjee R.; RT "Characterization of patient mutations in human persulfide dioxygenase RT (ETHE1) involved in H2S catabolism."; RL J. Biol. Chem. 287:44561-44567(2012). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19, AND IDENTIFICATION RP 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., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [10] 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., RA Ayoub D., 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 [11] {ECO:0000244|PDB:4CHL} RP X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) OF 21-254 IN COMPLEX WITH IRON, RP CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, AND DISULFIDE BONDS. RX PubMed=25596185; DOI=10.1093/HMG/DDV007; RA Pettinati I., Brem J., McDonough M.A., Schofield C.J.; RT "Crystal structure of human persulfide dioxygenase: structural basis RT of ethylmalonic encephalopathy."; RL Hum. Mol. Genet. 24:2458-2469(2015). RN [12] RP VARIANTS EE PRO-55; ALA-136; ILE-152; GLN-163; TRP-163; LYS-164; RP ARG-185 AND ASN-196, AND CHARACTERIZATION OF VARIANTS EE PRO-55 AND RP LYS-164. RX PubMed=18593870; DOI=10.1136/jmg.2008.058271; RA Mineri R., Rimoldi M., Burlina A.B., Koskull S., Perletti C., RA Heese B., von Dobeln U., Mereghetti P., Di Meo I., Invernizzi F., RA Zeviani M., Uziel G., Tiranti V.; RT "Identification of new mutations in the ETHE1 gene in a cohort of 14 RT patients presenting with ethylmalonic encephalopathy."; RL J. Med. Genet. 45:473-478(2008). CC -!- FUNCTION: Sulfur dioxygenase that plays an essential role in CC hydrogen sulfide catabolism in the mitochondrial matrix. Hydrogen CC sulfide (H(2)S) is first oxidized by SQRDL, giving rise to CC cysteine persulfide residues. ETHE1 consumes molecular oxygen to CC catalyze the oxidation of the persulfide, once it has been CC transferred to a thiophilic acceptor, such as glutathione (R-SSH). CC Plays an important role in metabolic homeostasis in mitochondria CC by metabolizing hydrogen sulfide and preventing the accumulation CC of supraphysiological H(2)S levels that have toxic effects, due to CC the inhibition of cytochrome c oxidase. First described as a CC protein that can shuttle between the nucleus and the cytoplasm and CC suppress p53-induced apoptosis by sequestering the transcription CC factor RELA/NFKB3 in the cytoplasm and preventing its accumulation CC in the nucleus (PubMed:12398897). {ECO:0000269|PubMed:12398897, CC ECO:0000269|PubMed:14732903, ECO:0000269|PubMed:19136963, CC ECO:0000269|PubMed:23144459}. CC -!- CATALYTIC ACTIVITY: S-sulfanylglutathione + O(2) + H(2)O = CC glutathione + sulfite + 2 H(+). {ECO:0000269|PubMed:19136963, CC ECO:0000269|PubMed:23144459, ECO:0000269|PubMed:25596185}. CC -!- COFACTOR: CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033; CC Evidence={ECO:0000269|PubMed:19136963, CC ECO:0000269|PubMed:23144459, ECO:0000269|PubMed:25596185}; CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:19136963, CC ECO:0000269|PubMed:23144459, ECO:0000269|PubMed:25596185}; CC -!- ENZYME REGULATION: Glutathione increases enzyme activity. CC {ECO:0000269|PubMed:23144459}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.34 mM for glutathione persulfide (GSSH) CC {ECO:0000269|PubMed:23144459}; CC Vmax=113 umol/min/mg enzyme (in the presence of equimolar CC amounts of GSSH and GSH and at 22 degrees Celsius) CC {ECO:0000269|PubMed:23144459}; CC -!- SUBUNIT: Homodimer (PubMed:25596185). Monomer (PubMed:23144459). CC Interacts with TST (PubMed:19136963). May interact with RELA CC (PubMed:12398897). {ECO:0000269|PubMed:12398897, CC ECO:0000269|PubMed:19136963, ECO:0000269|PubMed:23144459, CC ECO:0000269|PubMed:25596185}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12398897}. CC Nucleus {ECO:0000269|PubMed:12398897}. Mitochondrion matrix CC {ECO:0000269|PubMed:14732903}. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:14732903}. CC -!- DISEASE: Ethylmalonic encephalopathy (EE) [MIM:602473]: Autosomal CC recessive disorder characterized by neurodevelopmental delay and CC regression, recurrent petechiae, acrocyanosis, diarrhea, leading CC to death in the first decade of life. It is also associated with CC persistent lactic acidemia and ethylmalonic and methylsuccinic CC aciduria. {ECO:0000269|PubMed:14732903, CC ECO:0000269|PubMed:18593870, ECO:0000269|PubMed:23144459}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the metallo-beta-lactamase superfamily. CC Glyoxalase II family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG09063.1; Type=Erroneous gene model prediction; 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; D83198; BAA34595.2; -; mRNA. DR EMBL; AC018758; AAG09063.1; ALT_SEQ; Genomic_DNA. DR EMBL; BC008250; AAH08250.1; -; mRNA. DR CCDS; CCDS12622.1; -. DR RefSeq; NP_001307796.1; NM_001320867.1. DR RefSeq; NP_001307797.1; NM_001320868.1. DR RefSeq; NP_001307798.1; NM_001320869.1. DR RefSeq; NP_055112.2; NM_014297.4. DR RefSeq; XP_005258744.1; XM_005258687.3. DR UniGene; Hs.7486; -. DR PDB; 4CHL; X-ray; 2.61 A; A/B=21-254. DR PDBsum; 4CHL; -. DR ProteinModelPortal; O95571; -. DR SMR; O95571; -. DR BioGrid; 117034; 9. DR IntAct; O95571; 11. DR MINT; O95571; -. DR STRING; 9606.ENSP00000292147; -. DR iPTMnet; O95571; -. DR PhosphoSitePlus; O95571; -. DR SwissPalm; O95571; -. DR BioMuta; ETHE1; -. DR UCD-2DPAGE; O95571; -. DR EPD; O95571; -. DR MaxQB; O95571; -. DR PaxDb; O95571; -. DR PeptideAtlas; O95571; -. DR PRIDE; O95571; -. DR ProteomicsDB; 50945; -. DR DNASU; 23474; -. DR Ensembl; ENST00000292147; ENSP00000292147; ENSG00000105755. DR GeneID; 23474; -. DR KEGG; hsa:23474; -. DR UCSC; uc002owp.3; human. DR CTD; 23474; -. DR DisGeNET; 23474; -. DR EuPathDB; HostDB:ENSG00000105755.7; -. DR GeneCards; ETHE1; -. DR HGNC; HGNC:23287; ETHE1. DR HPA; HPA028360; -. DR HPA; HPA029028; -. DR HPA; HPA029029; -. DR MalaCards; ETHE1; -. DR MIM; 602473; phenotype. DR MIM; 608451; gene. DR neXtProt; NX_O95571; -. DR OpenTargets; ENSG00000105755; -. DR Orphanet; 51188; Ethylmalonic encephalopathy. DR PharmGKB; PA134879650; -. DR eggNOG; KOG0814; Eukaryota. DR eggNOG; COG0491; LUCA. DR GeneTree; ENSGT00530000063033; -. DR HOGENOM; HOG000058040; -. DR HOVERGEN; HBG053310; -. DR InParanoid; O95571; -. DR KO; K17725; -. DR PhylomeDB; O95571; -. DR TreeFam; TF312952; -. DR BioCyc; MetaCyc:ENSG00000105755-MONOMER; -. DR Reactome; R-HSA-1614517; Sulfide oxidation to sulfate. DR ChiTaRS; ETHE1; human. DR GeneWiki; ETHE1; -. DR GenomeRNAi; 23474; -. DR PRO; PR:O95571; -. DR Proteomes; UP000005640; Chromosome 19. DR Bgee; ENSG00000105755; -. DR CleanEx; HS_ETHE1; -. DR ExpressionAtlas; O95571; baseline and differential. DR Genevisible; O95571; HS. DR GO; GO:0005737; C:cytoplasm; IDA:LIFEdb. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB. DR GO; GO:0050313; F:sulfur dioxygenase activity; IDA:UniProtKB. DR GO; GO:0006749; P:glutathione metabolic process; IDA:UniProtKB. DR GO; GO:0070813; P:hydrogen sulfide metabolic process; IDA:UniProtKB. DR GO; GO:0070221; P:sulfide oxidation, using sulfide:quinone oxidoreductase; TAS:Reactome. DR Gene3D; 3.60.15.10; -; 1. DR InterPro; IPR001279; Metallo-B-lactamas. DR InterPro; IPR036866; RibonucZ/Hydroxyglut_hydro. DR Pfam; PF00753; Lactamase_B; 1. DR SMART; SM00849; Lactamase_B; 1. DR SUPFAM; SSF56281; SSF56281; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Dioxygenase; KW Disease mutation; Metal-binding; Mitochondrion; Nucleus; KW Oxidoreductase; Phosphoprotein; Reference proteome; Transit peptide. FT TRANSIT 1 7 Mitochondrion. FT {ECO:0000269|PubMed:19136963}. FT CHAIN 8 254 Persulfide dioxygenase ETHE1, FT mitochondrial. FT /FTId=PRO_0000012289. FT METAL 79 79 Iron; catalytic. {ECO:0000244|PDB:4CHL, FT ECO:0000269|PubMed:25596185}. FT METAL 135 135 Iron; catalytic. {ECO:0000244|PDB:4CHL, FT ECO:0000269|PubMed:25596185}. FT METAL 154 154 Iron; catalytic. {ECO:0000244|PDB:4CHL, FT ECO:0000269|PubMed:25596185}. FT MOD_RES 14 14 Phosphoserine. FT {ECO:0000250|UniProtKB:Q9DCM0}. FT MOD_RES 19 19 Phosphoserine. FT {ECO:0000244|PubMed:24275569}. FT MOD_RES 66 66 N6-acetyllysine. FT {ECO:0000244|PubMed:19608861}. FT MOD_RES 172 172 N6-acetyllysine; alternate. FT {ECO:0000250|UniProtKB:Q9DCM0}. FT MOD_RES 172 172 N6-succinyllysine; alternate. FT {ECO:0000250|UniProtKB:Q9DCM0}. FT VARIANT 38 38 Y -> C (in EE). FT {ECO:0000269|PubMed:14732903}. FT /FTId=VAR_023395. FT VARIANT 55 55 L -> P (in EE; reduces protein stability; FT dbSNP:rs182983506). FT {ECO:0000269|PubMed:18593870}. FT /FTId=VAR_069507. FT VARIANT 136 136 T -> A (in EE). FT {ECO:0000269|PubMed:14732903, FT ECO:0000269|PubMed:18593870}. FT /FTId=VAR_023396. FT VARIANT 152 152 T -> I (in EE; reduces protein stability, FT iron content and enzyme activity). FT {ECO:0000269|PubMed:18593870, FT ECO:0000269|PubMed:23144459}. FT /FTId=VAR_069508. FT VARIANT 163 163 R -> Q (in EE; dbSNP:rs745656120). FT {ECO:0000269|PubMed:18593870}. FT /FTId=VAR_069509. FT VARIANT 163 163 R -> W (in EE; dbSNP:rs28940289). FT {ECO:0000269|PubMed:14732903, FT ECO:0000269|PubMed:18593870}. FT /FTId=VAR_023397. FT VARIANT 164 164 T -> K (in EE; reduces protein FT stability). FT {ECO:0000269|PubMed:18593870}. FT /FTId=VAR_069510. FT VARIANT 185 185 L -> R (in EE; dbSNP:rs387906987). FT {ECO:0000269|PubMed:14732903, FT ECO:0000269|PubMed:18593870}. FT /FTId=VAR_023398. FT VARIANT 196 196 D -> N (in EE; reduces protein stability FT and affinity for substrate; FT dbSNP:rs763799125). FT {ECO:0000269|PubMed:18593870, FT ECO:0000269|PubMed:23144459}. FT /FTId=VAR_069511. FT STRAND 24 30 {ECO:0000244|PDB:4CHL}. FT TURN 31 34 {ECO:0000244|PDB:4CHL}. FT STRAND 35 41 {ECO:0000244|PDB:4CHL}. FT TURN 43 45 {ECO:0000244|PDB:4CHL}. FT STRAND 47 52 {ECO:0000244|PDB:4CHL}. FT HELIX 55 57 {ECO:0000244|PDB:4CHL}. FT HELIX 58 68 {ECO:0000244|PDB:4CHL}. FT STRAND 71 76 {ECO:0000244|PDB:4CHL}. FT STRAND 82 84 {ECO:0000244|PDB:4CHL}. FT HELIX 88 94 {ECO:0000244|PDB:4CHL}. FT STRAND 99 103 {ECO:0000244|PDB:4CHL}. FT HELIX 104 106 {ECO:0000244|PDB:4CHL}. FT STRAND 111 114 {ECO:0000244|PDB:4CHL}. FT STRAND 119 122 {ECO:0000244|PDB:4CHL}. FT STRAND 125 131 {ECO:0000244|PDB:4CHL}. FT STRAND 134 136 {ECO:0000244|PDB:4CHL}. FT STRAND 140 144 {ECO:0000244|PDB:4CHL}. FT STRAND 147 153 {ECO:0000244|PDB:4CHL}. FT HELIX 171 181 {ECO:0000244|PDB:4CHL}. FT TURN 182 184 {ECO:0000244|PDB:4CHL}. FT STRAND 190 195 {ECO:0000244|PDB:4CHL}. FT STRAND 197 199 {ECO:0000244|PDB:4CHL}. FT HELIX 205 211 {ECO:0000244|PDB:4CHL}. FT TURN 213 216 {ECO:0000244|PDB:4CHL}. FT HELIX 219 228 {ECO:0000244|PDB:4CHL}. FT HELIX 237 245 {ECO:0000244|PDB:4CHL}. FT TURN 246 248 {ECO:0000244|PDB:4CHL}. SQ SEQUENCE 254 AA; 27873 MW; 52073D52A487ACD4 CRC64; MAEAVLRVAR RQLSQRGGSG APILLRQMFE PVSCTFTYLL GDRESREAVL IDPVLETAPR DAQLIKELGL RLLYAVNTHC HADHITGSGL LRSLLPGCQS VISRLSGAQA DLHIEDGDSI RFGRFALETR ASPGHTPGCV TFVLNDHSMA FTGDALLIRG CGRTDFQQGC AKTLYHSVHE KIFTLPGDCL IYPAHDYHGF TVSTVEEERT LNPRLTLSCE EFVKIMGNLN LPKPQQIDFA VPANMRCGVQ TPTA //