Reviewed, UniProtKB/Swiss-Prot Q8IWW8 (HOT_HUMAN)

Names and origin

Protein names

Recommended name:
    Hydroxyacid-oxoacid transhydrogenase, mitochondrial
      Short name=HOT
    EC=1.1.99.24
Alternative name(s):
    Fe-containing alcohol dehydrogenase
    Alcohol dehydrogenase iron-containing protein 1
    ADHFe1

Gene names

Name:	ADHFE1
ORF Names:	HMFT2263

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG). D,L-3-hydroxyisobutyrate and L-3-hydroxybutyrate (L-3-OHB) are also substrates for HOT with 10-fold lower activities.
Catalytic activity	(S)-3-hydroxybutanoate + 2-oxoglutarate = acetoacetate + (R)-2-hydroxyglutarate. 2-oxoglutaric acid + 4-hydroxybutanoic acid = (R)-2-hydroxyglutaric acid + succinic semialdehyde.
Subcellular location	MitochondrionBy similarity.
Tissue specificity	Only expressed in adult liver.
Sequence similarities	Belongs to the iron-containing alcohol dehydrogenase family. Hydroxyacid-oxoacid transhydrogenase subfamily.
Biophysicochemical properties	Kinetic parameters: KM=0.17 mM for GHB KM=1.2 mM for 2-KG KM=0.12 mM for D-2-HG KM=0.04 mM for SSA KM=0.8 mM for L-3-OHB Vmax=16 nmol/h/mg enzyme with GHB and 2-KG as substrates Vmax=0.5 nmol/h/mg enzyme with SSA and D-2-HG as substrates Vmax=1.8 nmol/h/mg enzyme with L-3-OHB and 2-KG as substrates pH dependence: Optimum pH is 7.5.
Sequence caution	The sequence AAH47492.1 differs from that shown. Reason: Frameshift at position 228.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transit peptide
Molecular function	Oxidoreductase
Gene Ontology (GO)
Biological process	molecular hydrogen transport Ref.6 Inferred from direct assay. Source: UniProtKB
Cellular component	mitochondrion Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	hydroxyacid-oxoacid transhydrogenase activity Ref.6 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8IWW8-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q8IWW8-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-48: Missing.

Isoform 3 (identifier: Q8IWW8-3)

The sequence of this isoform differs from the canonical sequence as follows:
     299-303: RNPDD → NSTDK
     304-467: Missing.

Notes: No experimental confirmation available.

Isoform 4 (identifier: Q8IWW8-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-48: Missing.
     299-303: RNPDD → NSTDK
     304-467: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Transit peptide	1 – ?		Mitochondrion Potential
	Chain	? – 467		Hydroxyacid-oxoacid transhydrogenase, mitochondrial
Natural variations
	Alternative sequence	1 – 48	48	Missing in isoform 2 and isoform 4.
	Alternative sequence	299 – 303	5	RNPDD → NSTDK in isoform 3 and isoform 4.
	Alternative sequence	304 – 467	164	Missing in isoform 3 and isoform 4.
	Natural variant	242	1	D → V in a breast cancer sample; somatic mutation.
Experimental info
	Sequence conflict	141	1	S → C in AAH47492. Ref.4
	Sequence conflict	449	1	C → R in BAB71335. Ref.2
	Sequence conflict	449	1	C → R in BAD38661. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2003. Version 1. Checksum: C66E0EB15610A0E3	FASTA	467	50,308
	10 20 30 40 50 60 MAAAARARVA YLLRQLQRAA CQCPTHSHTY SQAPGLSPSG KTTDYAFEMA VSNIRYGAAV 70 80 90 100 110 120 TKEVGMDLKN MGAKNVCLMT DKNLSKLPPV QVAMDSLVKN GIPFTVYDNV RVEPTDSSFM 130 140 150 160 170 180 EAIEFAQKGA FDAYVAVGGG STMDTCKAAN LYASSPHSDF LDYVSAPIGK GKPVSVPLKP 190 200 210 220 230 240 LIAVPTTSGT GSETTGVAIF DYEHLKVKIG ITSRAIKPTL GLIDPLHTLH MPARVVANSG 250 260 270 280 290 300 FDVLCHALES YTTLPYHLRS PCPSNPITRP AYQGSNPISD IWAIHALRIV AKYLKRAVRN 310 320 330 340 350 360 PDDLEARSHM HLASAFAGIG FGNAGVHLCH GMSYPISGLV KMYKAKDYNV DHPLVPHGLS 370 380 390 400 410 420 VVLTSPAVFT FTAQMFPERH LEMAEILGAD TRTARIQDAG LVLADTLRKF LFDLDVDDGL 430 440 450 460 AAVGYSKADI PALVKGTLPQ ERVTKLAPCP QSEEDLAALF EASMKLY
	Isoform 2 [UniParc]. Checksum: F1EE897BD6B3B278		419	45,129
	10 20 30 40 50 60 MAVSNIRYGA AVTKEVGMDL KNMGAKNVCL MTDKNLSKLP PVQVAMDSLV KNGIPFTVYD 70 80 90 100 110 120 NVRVEPTDSS FMEAIEFAQK GAFDAYVAVG GGSTMDTCKA ANLYASSPHS DFLDYVSAPI 130 140 150 160 170 180 GKGKPVSVPL KPLIAVPTTS GTGSETTGVA IFDYEHLKVK IGITSRAIKP TLGLIDPLHT 190 200 210 220 230 240 LHMPARVVAN SGFDVLCHAL ESYTTLPYHL RSPCPSNPIT RPAYQGSNPI SDIWAIHALR 250 260 270 280 290 300 IVAKYLKRAV RNPDDLEARS HMHLASAFAG IGFGNAGVHL CHGMSYPISG LVKMYKAKDY 310 320 330 340 350 360 NVDHPLVPHG LSVVLTSPAV FTFTAQMFPE RHLEMAEILG ADTRTARIQD AGLVLADTLR 370 380 390 400 410 KFLFDLDVDD GLAAVGYSKA DIPALVKGTL PQERVTKLAP CPQSEEDLAA LFEASMKLY
	Isoform 3 [UniParc]. Checksum: B2F4BA2C5EBB4625		303	32,531
	10 20 30 40 50 60 MAAAARARVA YLLRQLQRAA CQCPTHSHTY SQAPGLSPSG KTTDYAFEMA VSNIRYGAAV 70 80 90 100 110 120 TKEVGMDLKN MGAKNVCLMT DKNLSKLPPV QVAMDSLVKN GIPFTVYDNV RVEPTDSSFM 130 140 150 160 170 180 EAIEFAQKGA FDAYVAVGGG STMDTCKAAN LYASSPHSDF LDYVSAPIGK GKPVSVPLKP 190 200 210 220 230 240 LIAVPTTSGT GSETTGVAIF DYEHLKVKIG ITSRAIKPTL GLIDPLHTLH MPARVVANSG 250 260 270 280 290 300 FDVLCHALES YTTLPYHLRS PCPSNPITRP AYQGSNPISD IWAIHALRIV AKYLKRAVNS TDK
	Isoform 4 [UniParc]. Checksum: 7A5416F035CEB0EB		255	27,353
	10 20 30 40 50 60 MAVSNIRYGA AVTKEVGMDL KNMGAKNVCL MTDKNLSKLP PVQVAMDSLV KNGIPFTVYD 70 80 90 100 110 120 NVRVEPTDSS FMEAIEFAQK GAFDAYVAVG GGSTMDTCKA ANLYASSPHS DFLDYVSAPI 130 140 150 160 170 180 GKGKPVSVPL KPLIAVPTTS GTGSETTGVA IFDYEHLKVK IGITSRAIKP TLGLIDPLHT 190 200 210 220 230 240 LHMPARVVAN SGFDVLCHAL ESYTTLPYHL RSPCPSNPIT RPAYQGSNPI SDIWAIHALR 250 IVAKYLKRAV NSTDK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a novel human alcohol dehydrogenase gene (ADHFe1)." Deng Y., Wang Z., Gu S., Ji C., Ying K., Xie Y., Mao Y. DNA Seq. 13:301-306(2002) [PubMed: 12592711] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY. Tissue: Fetal brain.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Skeletal muscle.
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). Tissue: Brain and Pancreas.
[5]	"Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas." Yamada S., Ohira M., Horie H., Ando K., Takayasu H., Suzuki Y., Sugano S., Hirata T., Goto T., Matsunaga T., Hiyama E., Hayashi Y., Ando H., Suita S., Kaneko M., Sasaki F., Hashizume K., Ohnuma N., Nakagawara A. Oncogene 23:5901-5911(2004) [PubMed: 15221005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 415-467. Tissue: Hepatoblastoma.
[6]	"Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias." Struys E.A., Verhoeven N.M., Ten Brink H.J., Wickenhagen W.V., Gibson K.M., Jakobs C. J. Inherit. Metab. Dis. 28:921-930(2005) [PubMed: 16435184] [Abstract] Cited for: FUNCTION, SUBSTRATE SPECIFICITY, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
[7]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-242.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AY033237 mRNA. Translation: AAK44223.1. AK056992 mRNA. Translation: BAB71335.1. CH471068 Genomic DNA. Translation: EAW86902.1. CH471068 Genomic DNA. Translation: EAW86907.1. BC047492 mRNA. Translation: AAH47492.1. Frameshift. BC064634 mRNA. Translation: AAH64634.1. AB075879 mRNA. Translation: BAD38661.1.
RefSeq	NP_653251.2.
UniGene	Hs.268869
3D structure databases
ModBase	Search...
PTM databases
PhosphoSite	Q8IWW8.
Genome annotation databases
Ensembl	ENSG00000147576. Homo sapiens. [Contig view]
GeneID	137872.
KEGG	hsa:137872.
Organism-specific databases
HGNC	HGNC:16354. ADHFE1.
MIM	611083. gene.
PharmGKB	PA134871493.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	Q8IWW8.
HOVERGEN	Q8IWW8.
Gene expression databases
ArrayExpress	Q8IWW8.
CleanEx	HS_ADHFE1.
Family and domain databases
InterPro	IPR001670. Fe_AlcDHase. [Graphical view]
Pfam	PF00465. Fe-ADH. 1 hit. [Graphical view]
PROSITE	PS00913. ADH_IRON_1. False negative. PS00060. ADH_IRON_2. False negative. [Graphical view]
ProDom	Q8IWW8. [Graphical view] [Entries sharing at least one domain]
BLOCKS	Search...
Other Resources
SOURCE	Search...
ProtoNet	Search...

Entry information

Entry name

HOT_HUMAN

Accession

Primary (citable) accession number: Q8IWW8
Secondary accession number(s): Q49A19 , Q68CI7, Q6P2B6, Q96MF9

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 18, 2008
Last sequence update:	March 1, 2003
Last modified:	July 22, 2008
This is version 30 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)