DHB8_MOUSE
ID DHB8_MOUSE Reviewed; 259 AA.
AC P50171; Q5M9K0; Q60958; Q60959; Q9Z1W2;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=(3R)-3-hydroxyacyl-CoA dehydrogenase;
DE EC=1.1.1.n12 {ECO:0000250|UniProtKB:Q92506};
DE AltName: Full=17-beta-hydroxysteroid dehydrogenase 8;
DE Short=17-beta-HSD 8;
DE AltName: Full=3-ketoacyl-[acyl-carrier-protein] reductase alpha subunit {ECO:0000250|UniProtKB:Q92506};
DE Short=KAR alpha subunit {ECO:0000250|UniProtKB:Q92506};
DE AltName: Full=3-oxoacyl-[acyl-carrier-protein] reductase;
DE AltName: Full=Estradiol 17-beta-dehydrogenase 8;
DE EC=1.1.1.62 {ECO:0000269|PubMed:9712896};
DE AltName: Full=Protein Ke6 {ECO:0000303|PubMed:9712896};
DE Short=Ke-6 {ECO:0000303|PubMed:9712896};
DE AltName: Full=Testosterone 17-beta-dehydrogenase 8;
DE EC=1.1.1.239 {ECO:0000269|PubMed:9712896};
GN Name=Hsd17b8; Synonyms=H2-Ke6, Hke6;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=DBA/2J; TISSUE=Kidney;
RX PubMed=8441417; DOI=10.1128/mcb.13.3.1847-1853.1993;
RA Aziz N., Maxwell M.M., St Jacques B., Brenner B.M.;
RT "Downregulation of Ke 6, a novel gene encoded within the major
RT histocompatibility complex, in murine polycystic kidney disease.";
RL Mol. Cell. Biol. 13:1847-1853(1993).
RN [2]
RP ERRATUM OF PUBMED:8441417.
RA Aziz N., Maxwell M.M., St Jacques B., Brenner B.M.;
RL Mol. Cell. Biol. 13:6614-6614(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=7559658; DOI=10.1074/jbc.270.42.25213;
RA Maxwell M.M., Nearing J., Aziz N.;
RT "Ke 6 gene. Sequence and organization and aberrant regulation in murine
RT polycystic kidney disease.";
RL J. Biol. Chem. 270:25213-25219(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=129/SvJ;
RA Rowen L., Qin S., Madan A., Loretz C., James R., Dors M., Mix L., Hall J.,
RA Lasky S., Hood L.;
RT "Sequence of the mouse major histocomaptibility locus class II region.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
RC TISSUE=Kidney;
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 [6]
RP CATALYTIC ACTIVITY, FUNCTION, PATHWAY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP TISSUE SPECIFICITY.
RX PubMed=9712896; DOI=10.1074/jbc.273.35.22664;
RA Fomitcheva J., Baker M.E., Anderson E., Lee G.Y., Aziz N.;
RT "Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and
RT its expression in gonadal tissues.";
RL J. Biol. Chem. 273:22664-22671(1998).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=15923359; DOI=10.1369/jhc.5a6692.2005;
RA Pelletier G., Luu-The V., Li S., Labrie F.;
RT "Localization of type 8 17beta-hydroxysteroid dehydrogenase mRNA in mouse
RT tissues as studied by in situ hybridization.";
RL J. Histochem. Cytochem. 53:1257-1271(2005).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200;
RA Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.;
RT "Comprehensive identification of phosphorylation sites in postsynaptic
RT density preparations.";
RL Mol. Cell. Proteomics 5:914-922(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-158 AND LYS-171, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23576753; DOI=10.1073/pnas.1302961110;
RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B.,
RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.;
RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria
RT identifies substrates of SIRT3 in metabolic pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013).
CC -!- FUNCTION: Required for the solubility and assembly of the
CC heterotetramer 3-ketoacyl-[acyl carrier protein] (ACP) reductase
CC functional complex (KAR or KAR1) that forms part of the mitochondrial
CC fatty acid synthase (mtFAS). Alpha-subunit of the KAR complex, acts as
CC scaffold protein, required for the stability of carbonyl reductase
CC type-4 (CBR4, beta-subunit of the KAR complex) and for its 3-ketoacyl-
CC ACP reductase activity, thereby participating in mitochondrial fatty
CC acid biosynthesis. Catalyzes the NAD-dependent conversion of (3R)-3-
CC hydroxyacyl-CoA into 3-ketoacyl-CoA (3-oxoacyl-CoA) with no chain
CC length preference, this enzymatic activity is not needed for the KAR
CC function. Prefers (3R)-3-hydroxyacyl-CoA over (3S)-3-hydroxyacyl-CoA
CC and displays enzymatic activity only in the presence of NAD(+)(H).
CC Cooperates with enoyl-CoA hydratase 1 in mitochondria, together they
CC constitute an alternative route to the auxiliary enzyme pathways for
CC the breakdown of Z-PUFA (cis polyunsaturated fatty acid) enoyl-esters
CC (By similarity). NAD-dependent 17-beta-hydroxysteroid dehydrogenase
CC with highest activity towards estradiol. It efficiently catalyzes the
CC oxidation of estradiol (E2), testosterone, and dihydrotestosterone.
CC Primarily an oxidative enzyme, it can switch to a reductive mode
CC determined in the appropriate physiologic milieu and catalyze the
CC reduction of estrone (E1) to form biologically active estradiol (E2)
CC (PubMed:9712896). {ECO:0000250|UniProtKB:Q92506,
CC ECO:0000269|PubMed:9712896}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a (3R)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + H(+) +
CC NADH; Xref=Rhea:RHEA:32711, ChEBI:CHEBI:15378, ChEBI:CHEBI:57319,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:90726;
CC EC=1.1.1.n12; Evidence={ECO:0000250|UniProtKB:Q92506};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32712;
CC Evidence={ECO:0000250|UniProtKB:Q92506};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-estradiol + NAD(+) = estrone + H(+) + NADH;
CC Xref=Rhea:RHEA:24612, ChEBI:CHEBI:15378, ChEBI:CHEBI:16469,
CC ChEBI:CHEBI:17263, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.62;
CC Evidence={ECO:0000269|PubMed:9712896};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24613;
CC Evidence={ECO:0000269|PubMed:9712896};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:24614;
CC Evidence={ECO:0000269|PubMed:9712896};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) + testosterone = androst-4-ene-3,17-dione + H(+) +
CC NADH; Xref=Rhea:RHEA:14929, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422,
CC ChEBI:CHEBI:17347, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC EC=1.1.1.239; Evidence={ECO:0000269|PubMed:9712896};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14930;
CC Evidence={ECO:0000269|PubMed:9712896};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-hydroxy-5alpha-androstan-3-one + NAD(+) = 5alpha-
CC androstan-3,17-dione + H(+) + NADH; Xref=Rhea:RHEA:41992,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15994, ChEBI:CHEBI:16330,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:9712896};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41993;
CC Evidence={ECO:0000269|PubMed:9712896};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.110 uM for estradiol {ECO:0000269|PubMed:9712896};
CC KM=0.422 uM for testosterone {ECO:0000269|PubMed:9712896};
CC KM=0.368 uM for estrone {ECO:0000269|PubMed:9712896};
CC KM=0.360 uM for dihydrotestosterone {ECO:0000269|PubMed:9712896};
CC Vmax=0.405 nmol/min/mg enzyme for estradiol as substrate
CC {ECO:0000269|PubMed:9712896};
CC Vmax=0.123 nmol/min/mg enzyme for testosterone as substrate
CC {ECO:0000269|PubMed:9712896};
CC Vmax=0.186 nmol/min/mg enzyme for estrone as substrate
CC {ECO:0000269|PubMed:9712896};
CC Vmax=0.081 nmol/min/mg enzyme for dihydrotestosterone as substrate
CC {ECO:0000269|PubMed:9712896};
CC -!- PATHWAY: Lipid metabolism; fatty acid biosynthesis.
CC {ECO:0000250|UniProtKB:Q92506}.
CC -!- PATHWAY: Steroid biosynthesis; estrogen biosynthesis.
CC {ECO:0000269|PubMed:9712896}.
CC -!- PATHWAY: Lipid metabolism; mitochondrial fatty acid beta-oxidation.
CC {ECO:0000250|UniProtKB:Q92506}.
CC -!- SUBUNIT: Heterotetramer with CBR4; contains two molecules of HSD17B8
CC and CBR4. {ECO:0000250|UniProtKB:Q92506}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q92506}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Short;
CC IsoId=P50171-1; Sequence=Displayed;
CC Name=Long;
CC IsoId=P50171-2; Sequence=VSP_006030;
CC -!- TISSUE SPECIFICITY: Kidney, liver, testis, ovary and spleen
CC (PubMed:9712896, PubMed:15923359). Oviduct, uterus, mammary gland,
CC vagina, prostate, clitoral gland and moderately heart, dorsal skin,
CC brain and lung (PubMed:15923359). {ECO:0000269|PubMed:15923359,
CC ECO:0000269|PubMed:9712896}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC69902.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; U34072; AAC53573.1; -; Genomic_DNA.
DR EMBL; U34072; AAC53574.1; -; Genomic_DNA.
DR EMBL; AF100956; AAC69902.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC086927; AAH86927.1; -; mRNA.
DR CCDS; CCDS50071.1; -. [P50171-1]
DR PIR; A48154; A48154.
DR RefSeq; NP_038571.2; NM_013543.2. [P50171-1]
DR AlphaFoldDB; P50171; -.
DR SMR; P50171; -.
DR BioGRID; 200159; 4.
DR STRING; 10090.ENSMUSP00000038069; -.
DR iPTMnet; P50171; -.
DR PhosphoSitePlus; P50171; -.
DR REPRODUCTION-2DPAGE; P50171; -.
DR EPD; P50171; -.
DR jPOST; P50171; -.
DR MaxQB; P50171; -.
DR PaxDb; P50171; -.
DR PeptideAtlas; P50171; -.
DR PRIDE; P50171; -.
DR ProteomicsDB; 277329; -. [P50171-1]
DR ProteomicsDB; 277330; -. [P50171-2]
DR Antibodypedia; 28972; 228 antibodies from 28 providers.
DR DNASU; 14979; -.
DR Ensembl; ENSMUST00000045467; ENSMUSP00000038069; ENSMUSG00000073422. [P50171-1]
DR Ensembl; ENSMUST00000237759; ENSMUSP00000157769; ENSMUSG00000073422. [P50171-2]
DR GeneID; 14979; -.
DR KEGG; mmu:14979; -.
DR UCSC; uc008cat.2; mouse. [P50171-1]
DR CTD; 14979; -.
DR MGI; MGI:95911; H2-Ke6.
DR VEuPathDB; HostDB:ENSMUSG00000073422; -.
DR eggNOG; KOG1200; Eukaryota.
DR GeneTree; ENSGT00940000160668; -.
DR HOGENOM; CLU_010194_1_3_1; -.
DR InParanoid; P50171; -.
DR OMA; KMPERDY; -.
DR OrthoDB; 1226147at2759; -.
DR PhylomeDB; P50171; -.
DR TreeFam; TF313099; -.
DR Reactome; R-MMU-75105; Fatty acyl-CoA biosynthesis.
DR SABIO-RK; P50171; -.
DR UniPathway; UPA00094; -.
DR UniPathway; UPA00660; -.
DR UniPathway; UPA00769; -.
DR BioGRID-ORCS; 14979; 3 hits in 75 CRISPR screens.
DR ChiTaRS; H2-Ke6; mouse.
DR PRO; PR:P50171; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; P50171; protein.
DR Bgee; ENSMUSG00000073422; Expressed in adrenal gland and 63 other tissues.
DR ExpressionAtlas; P50171; baseline and differential.
DR Genevisible; P50171; MM.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005740; C:mitochondrial envelope; IDA:MGI.
DR GO; GO:0005759; C:mitochondrial matrix; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:1990204; C:oxidoreductase complex; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0106386; F:(3R)-hydroxyacyl-CoA dehydrogenase (NAD) activity; ISS:UniProtKB.
DR GO; GO:0044594; F:17-beta-hydroxysteroid dehydrogenase (NAD+) activity; IEA:RHEA.
DR GO; GO:0004303; F:estradiol 17-beta-dehydrogenase activity; IDA:MGI.
DR GO; GO:0070404; F:NADH binding; ISS:UniProtKB.
DR GO; GO:0016616; F:oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; IBA:GO_Central.
DR GO; GO:0048038; F:quinone binding; IBA:GO_Central.
DR GO; GO:0047035; F:testosterone dehydrogenase (NAD+) activity; IDA:MGI.
DR GO; GO:0008209; P:androgen metabolic process; IDA:MGI.
DR GO; GO:0006703; P:estrogen biosynthetic process; ISS:UniProtKB.
DR GO; GO:0008210; P:estrogen metabolic process; IDA:MGI.
DR GO; GO:0006633; P:fatty acid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0051290; P:protein heterotetramerization; ISS:UniProtKB.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR PRINTS; PR00081; GDHRDH.
DR PRINTS; PR00080; SDRFAMILY.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism; Mitochondrion;
KW NAD; Oxidoreductase; Phosphoprotein; Reference proteome;
KW Steroid biosynthesis.
FT CHAIN 1..259
FT /note="(3R)-3-hydroxyacyl-CoA dehydrogenase"
FT /id="PRO_0000054599"
FT ACT_SITE 167
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 13..21
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 40..41
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 72..74
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 154
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 167..171
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT BINDING 200..202
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q92506"
FT MOD_RES 58
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 66
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 158
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 171
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT VAR_SEQ 256..259
FT /note="GLFM -> MRPSWGGGQENRTQVVMRK (in isoform Long)"
FT /evidence="ECO:0000305"
FT /id="VSP_006030"
FT CONFLICT 229
FT /note="E -> EG (in Ref. 1; AAC53573/AAC53574)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 259 AA; 26588 MW; C4704F02B63C275F CRC64;
MASQLRLRSA LALVTGAGSG IGRAISVRLA AEGAAVAACD LDGAAAQDTV RLLGSPGSED
GAPRGKHAAF QADVSQGPAA RRLLEEVQAC FSRPPSVVVS CAGITRDEFL LHMSEEDWDR
VIAVNLKGTF LVTQAAAQAL VSSGGRGSII NISSIIGKVG NIGQTNYASS KAGVIGLTQT
AARELGRHGI RCNSVLPGFI ATPMTQKMPE KVKDKVTAMI PLGHMGDPED VADVVAFLAS
EDSGYITGAS VEVSGGLFM
