HOT_HUMAN
ID HOT_HUMAN Reviewed; 467 AA.
AC Q8IWW8; B4DTJ8; Q49A19; Q68CI7; Q6P2B6; Q96MF9;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Hydroxyacid-oxoacid transhydrogenase, mitochondrial;
DE Short=HOT;
DE EC=1.1.99.24 {ECO:0000269|PubMed:16435184};
DE AltName: Full=Alcohol dehydrogenase iron-containing protein 1;
DE Short=ADHFe1;
DE AltName: Full=Fe-containing alcohol dehydrogenase;
DE Flags: Precursor;
GN Name=ADHFE1; ORFNames=HMFT2263;
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] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=12592711; DOI=10.1080/1042517021000011636;
RA Deng Y., Wang Z., Gu S., Ji C., Ying K., Xie Y., Mao Y.;
RT "Cloning and characterization of a novel human alcohol dehydrogenase gene
RT (ADHFe1).";
RL DNA Seq. 13:301-306(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), AND VARIANT
RP ARG-449.
RC TISSUE=Placenta, and Skeletal muscle;
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].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Pancreas;
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 [LARGE SCALE MRNA] OF 415-467, AND VARIANT ARG-449.
RC TISSUE=Hepatoblastoma;
RX PubMed=15221005; DOI=10.1038/sj.onc.1207782;
RA Yamada S., Ohira M., Horie H., Ando K., Takayasu H., Suzuki Y., Sugano S.,
RA Hirata T., Goto T., Matsunaga T., Hiyama E., Hayashi Y., Ando H., Suita S.,
RA Kaneko M., Sasaki F., Hashizume K., Ohnuma N., Nakagawara A.;
RT "Expression profiling and differential screening between hepatoblastomas
RT and the corresponding normal livers: identification of high expression of
RT the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas.";
RL Oncogene 23:5901-5911(2004).
RN [6]
RP FUNCTION, SUBSTRATE SPECIFICITY, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=16435184; DOI=10.1007/s10545-005-0114-x;
RA Struys E.A., Verhoeven N.M., Ten Brink H.J., Wickenhagen W.V., Gibson K.M.,
RA Jakobs C.;
RT "Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase:
RT relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias.";
RL J. Inherit. Metab. Dis. 28:921-930(2005).
RN [7]
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 [8]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-242.
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: Catalyzes the cofactor-independent reversible oxidation of
CC gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to
CC reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG).
CC D,L-3-hydroxyisobutyrate and L-3-hydroxybutyrate (L-3-OHB) are also
CC substrates for HOT with 10-fold lower activities.
CC {ECO:0000269|PubMed:16435184}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-3-hydroxybutanoate + 2-oxoglutarate = (R)-2-
CC hydroxyglutarate + acetoacetate; Xref=Rhea:RHEA:23048,
CC ChEBI:CHEBI:11047, ChEBI:CHEBI:13705, ChEBI:CHEBI:15801,
CC ChEBI:CHEBI:16810; EC=1.1.99.24;
CC Evidence={ECO:0000269|PubMed:16435184};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + 4-hydroxybutanoate = (R)-2-hydroxyglutarate +
CC succinate semialdehyde; Xref=Rhea:RHEA:24734, ChEBI:CHEBI:15801,
CC ChEBI:CHEBI:16724, ChEBI:CHEBI:16810, ChEBI:CHEBI:57706;
CC EC=1.1.99.24; Evidence={ECO:0000269|PubMed:16435184};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.17 mM for GHB {ECO:0000269|PubMed:16435184};
CC KM=1.2 mM for 2-KG {ECO:0000269|PubMed:16435184};
CC KM=0.12 mM for D-2-HG {ECO:0000269|PubMed:16435184};
CC KM=0.04 mM for SSA {ECO:0000269|PubMed:16435184};
CC KM=0.8 mM for L-3-OHB {ECO:0000269|PubMed:16435184};
CC Vmax=16 nmol/h/mg enzyme with GHB and 2-KG as substrates
CC {ECO:0000269|PubMed:16435184};
CC Vmax=0.5 nmol/h/mg enzyme with SSA and D-2-HG as substrates
CC {ECO:0000269|PubMed:16435184};
CC Vmax=1.8 nmol/h/mg enzyme with L-3-OHB and 2-KG as substrates
CC {ECO:0000269|PubMed:16435184};
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:16435184};
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8IWW8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IWW8-2; Sequence=VSP_031984;
CC Name=3;
CC IsoId=Q8IWW8-3; Sequence=VSP_031985, VSP_031986;
CC Name=4;
CC IsoId=Q8IWW8-4; Sequence=VSP_031984, VSP_031985, VSP_031986;
CC -!- TISSUE SPECIFICITY: Only expressed in adult liver.
CC {ECO:0000269|PubMed:12592711}.
CC -!- SIMILARITY: Belongs to the iron-containing alcohol dehydrogenase
CC family. Hydroxyacid-oxoacid transhydrogenase subfamily. {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; AY033237; AAK44223.1; -; mRNA.
DR EMBL; AK056992; BAB71335.1; -; mRNA.
DR EMBL; AK300243; BAG62010.1; -; mRNA.
DR EMBL; CH471068; EAW86902.1; -; Genomic_DNA.
DR EMBL; CH471068; EAW86903.1; -; Genomic_DNA.
DR EMBL; CH471068; EAW86907.1; -; Genomic_DNA.
DR EMBL; BC064634; AAH64634.1; -; mRNA.
DR EMBL; AB075879; BAD38661.1; -; mRNA.
DR CCDS; CCDS6190.2; -. [Q8IWW8-1]
DR RefSeq; NP_653251.2; NM_144650.2. [Q8IWW8-1]
DR AlphaFoldDB; Q8IWW8; -.
DR SMR; Q8IWW8; -.
DR BioGRID; 126489; 3.
DR IntAct; Q8IWW8; 3.
DR STRING; 9606.ENSP00000379865; -.
DR ChEMBL; CHEMBL4947; -.
DR DrugBank; DB09072; Sodium oxybate.
DR iPTMnet; Q8IWW8; -.
DR PhosphoSitePlus; Q8IWW8; -.
DR BioMuta; ADHFE1; -.
DR DMDM; 74714449; -.
DR MassIVE; Q8IWW8; -.
DR PaxDb; Q8IWW8; -.
DR PeptideAtlas; Q8IWW8; -.
DR PRIDE; Q8IWW8; -.
DR ProteomicsDB; 70916; -. [Q8IWW8-1]
DR ProteomicsDB; 70917; -. [Q8IWW8-2]
DR ProteomicsDB; 70918; -. [Q8IWW8-3]
DR ProteomicsDB; 70919; -. [Q8IWW8-4]
DR Antibodypedia; 11986; 120 antibodies from 23 providers.
DR DNASU; 137872; -.
DR Ensembl; ENST00000396623.8; ENSP00000379865.3; ENSG00000147576.17. [Q8IWW8-1]
DR Ensembl; ENST00000415254.5; ENSP00000407115.1; ENSG00000147576.17. [Q8IWW8-2]
DR Ensembl; ENST00000424777.6; ENSP00000410883.2; ENSG00000147576.17. [Q8IWW8-3]
DR GeneID; 137872; -.
DR KEGG; hsa:137872; -.
DR MANE-Select; ENST00000396623.8; ENSP00000379865.3; NM_144650.3; NP_653251.2.
DR UCSC; uc003xwb.5; human. [Q8IWW8-1]
DR CTD; 137872; -.
DR DisGeNET; 137872; -.
DR GeneCards; ADHFE1; -.
DR HGNC; HGNC:16354; ADHFE1.
DR HPA; ENSG00000147576; Tissue enhanced (liver, skeletal muscle, tongue).
DR MIM; 611083; gene.
DR neXtProt; NX_Q8IWW8; -.
DR OpenTargets; ENSG00000147576; -.
DR PharmGKB; PA134871493; -.
DR VEuPathDB; HostDB:ENSG00000147576; -.
DR eggNOG; KOG3857; Eukaryota.
DR GeneTree; ENSGT00390000003849; -.
DR HOGENOM; CLU_007207_0_7_1; -.
DR InParanoid; Q8IWW8; -.
DR OMA; IRFGPGC; -.
DR OrthoDB; 776004at2759; -.
DR PhylomeDB; Q8IWW8; -.
DR TreeFam; TF105710; -.
DR BRENDA; 1.1.99.24; 2681.
DR PathwayCommons; Q8IWW8; -.
DR Reactome; R-HSA-880009; Interconversion of 2-oxoglutarate and 2-hydroxyglutarate.
DR SignaLink; Q8IWW8; -.
DR BioGRID-ORCS; 137872; 24 hits in 1068 CRISPR screens.
DR GenomeRNAi; 137872; -.
DR Pharos; Q8IWW8; Tbio.
DR PRO; PR:Q8IWW8; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q8IWW8; protein.
DR Bgee; ENSG00000147576; Expressed in right lobe of liver and 169 other tissues.
DR ExpressionAtlas; Q8IWW8; baseline and differential.
DR Genevisible; Q8IWW8; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0004022; F:alcohol dehydrogenase (NAD+) activity; IBA:GO_Central.
DR GO; GO:0047988; F:hydroxyacid-oxoacid transhydrogenase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:InterPro.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; TAS:Reactome.
DR GO; GO:0006539; P:glutamate catabolic process via 2-oxoglutarate; IDA:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR CDD; cd08190; HOT; 1.
DR InterPro; IPR001670; ADH_Fe/GldA.
DR InterPro; IPR039697; Alcohol_dehydrogenase_Fe.
DR InterPro; IPR042157; HOT.
DR PANTHER; PTHR11496; PTHR11496; 1.
DR Pfam; PF00465; Fe-ADH; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Lipid metabolism; Mitochondrion;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..467
FT /note="Hydroxyacid-oxoacid transhydrogenase, mitochondrial"
FT /id="PRO_0000322996"
FT MOD_RES 445
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8R0N6"
FT MOD_RES 452
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8R0N6"
FT VAR_SEQ 1..48
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:12592711,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334"
FT /id="VSP_031984"
FT VAR_SEQ 299..303
FT /note="RNPDD -> NSTDK (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_031985"
FT VAR_SEQ 304..467
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_031986"
FT VARIANT 242
FT /note="D -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_039470"
FT VARIANT 449
FT /note="C -> R (in dbSNP:rs1060242)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15221005"
FT /id="VAR_054015"
SQ SEQUENCE 467 AA; 50308 MW; C66E0EB15610A0E3 CRC64;
MAAAARARVA YLLRQLQRAA CQCPTHSHTY SQAPGLSPSG KTTDYAFEMA VSNIRYGAAV
TKEVGMDLKN MGAKNVCLMT DKNLSKLPPV QVAMDSLVKN GIPFTVYDNV RVEPTDSSFM
EAIEFAQKGA FDAYVAVGGG STMDTCKAAN LYASSPHSDF LDYVSAPIGK GKPVSVPLKP
LIAVPTTSGT GSETTGVAIF DYEHLKVKIG ITSRAIKPTL GLIDPLHTLH MPARVVANSG
FDVLCHALES YTTLPYHLRS PCPSNPITRP AYQGSNPISD IWAIHALRIV AKYLKRAVRN
PDDLEARSHM HLASAFAGIG FGNAGVHLCH GMSYPISGLV KMYKAKDYNV DHPLVPHGLS
VVLTSPAVFT FTAQMFPERH LEMAEILGAD TRTARIQDAG LVLADTLRKF LFDLDVDDGL
AAVGYSKADI PALVKGTLPQ ERVTKLAPCP QSEEDLAALF EASMKLY
