BDH2_MOUSE
ID BDH2_MOUSE Reviewed; 245 AA.
AC Q8JZV9;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=3-hydroxybutyrate dehydrogenase type 2;
DE EC=1.1.1.30 {ECO:0000250|UniProtKB:Q9BUT1};
DE AltName: Full=4-oxo-L-proline reductase {ECO:0000250|UniProtKB:Q9BUT1};
DE EC=1.1.1.104 {ECO:0000250|UniProtKB:D4A1J4, ECO:0000250|UniProtKB:Q9BUT1};
DE AltName: Full=Dehydrogenase/reductase SDR family member 6;
DE AltName: Full=R-beta-hydroxybutyrate dehydrogenase;
GN Name=Bdh2; Synonyms=Dhrs6;
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 [LARGE SCALE MRNA].
RC STRAIN=FVB/N; 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 [2]
RP FUNCTION, PATHWAY, TISSUE SPECIFICITY, MUTAGENESIS OF TYR-147, AND ACTIVE
RP SITE.
RX PubMed=20550936; DOI=10.1016/j.cell.2010.04.040;
RA Devireddy L.R., Hart D.O., Goetz D.H., Green M.R.;
RT "A mammalian siderophore synthesized by an enzyme with a bacterial homolog
RT involved in enterobactin production.";
RL Cell 141:1006-1017(2010).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
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 [4]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=24863067; DOI=10.1084/jem.20132629;
RA Liu Z., Reba S., Chen W.D., Porwal S.K., Boom W.H., Petersen R.B.,
RA Rojas R., Viswanathan R., Devireddy L.;
RT "Regulation of mammalian siderophore 2,5-DHBA in the innate immune response
RT to infection.";
RL J. Exp. Med. 211:1197-1213(2014).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24777603; DOI=10.1128/mcb.00231-14;
RA Liu Z., Ciocea A., Devireddy L.;
RT "Endogenous siderophore 2,5-dihydroxybenzoic acid deficiency promotes
RT anemia and splenic iron overload in mice.";
RL Mol. Cell. Biol. 34:2533-2546(2014).
CC -!- FUNCTION: NAD(H)-dependent dehydrogenase/reductase with a preference
CC for cyclic substrates (By similarity). Catalyzes stereoselective
CC conversion of 4-oxo-L-proline to cis-4-hydroxy-L-proline, likely a
CC detoxification mechanism for ketoprolines (By similarity). Mediates the
CC formation of 2,5-dihydroxybenzoate (2,5-DHBA), a siderophore that
CC chelates free cytoplasmic iron and associates with LCN2, thereby
CC regulating iron transport and homeostasis while protecting cells
CC against free radical-induced oxidative stress. The iron-siderophore
CC complex is imported into mitochondria, providing an iron source for
CC mitochondrial metabolic processes in particular heme synthesis
CC (PubMed:20550936, PubMed:24863067, PubMed:24777603). May act as a 3-
CC hydroxybutyrate dehydrogenase (By similarity).
CC {ECO:0000250|UniProtKB:D4A1J4, ECO:0000250|UniProtKB:Q9BUT1,
CC ECO:0000269|PubMed:20550936, ECO:0000269|PubMed:24777603,
CC ECO:0000269|PubMed:24863067}.
CC -!- FUNCTION: (Microbial infection) May play a role in susceptibility to
CC bacterial infection by providing an assimilable source of iron that is
CC exploited by pathogenic bacteria. Host iron-siderophore complexes can
CC be used by bacteria to promote their own growth and pathogenicity.
CC {ECO:0000269|PubMed:24863067}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cis-4-hydroxy-L-proline + NAD(+) = 4-oxo-L-proline + H(+) +
CC NADH; Xref=Rhea:RHEA:13601, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:63727, ChEBI:CHEBI:84813;
CC EC=1.1.1.104; Evidence={ECO:0000250|UniProtKB:D4A1J4,
CC ECO:0000250|UniProtKB:Q9BUT1};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:13603;
CC Evidence={ECO:0000250|UniProtKB:D4A1J4,
CC ECO:0000250|UniProtKB:Q9BUT1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-3-hydroxybutanoate + NAD(+) = acetoacetate + H(+) + NADH;
CC Xref=Rhea:RHEA:20521, ChEBI:CHEBI:10983, ChEBI:CHEBI:13705,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.30;
CC Evidence={ECO:0000250|UniProtKB:Q9BUT1};
CC -!- PATHWAY: Amino-acid metabolism. {ECO:0000250|UniProtKB:Q9BUT1}.
CC -!- PATHWAY: Siderophore biosynthesis. {ECO:0000269|PubMed:20550936,
CC ECO:0000269|PubMed:24863067}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:Q9BUT1}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9BUT1}.
CC -!- TISSUE SPECIFICITY: Detected in liver, spleen and macrophages
CC (PubMed:24863067). Widely expressed. {ECO:0000269|PubMed:20550936,
CC ECO:0000269|PubMed:24863067}.
CC -!- INDUCTION: Down-regulated upon E.coli infection to limit access to host
CC iron pool. Down-regulated in macrophages by exposure to bacterial
CC lipopolysaccharide (LPS). {ECO:0000269|PubMed:24863067}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice are born at the expected Mendelian
CC frequency. They display microcytic and hypochromic anemia and iron
CC overload in spleen and liver associated with heme toxicity when kept on
CC high-iron diet. The plasma levels of ketone bodies is normal.
CC {ECO:0000269|PubMed:24777603}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
CC -!- CAUTION: Postulated to act as a 3-hydroxybutyrate dehydrogenase,
CC however its contribution to ketone body formation appears to be
CC physiologically irrelevant since it has very low affinity for the
CC substrate. {ECO:0000250|UniProtKB:Q9BUT1, ECO:0000269|PubMed:24777603}.
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DR EMBL; BC036998; AAH36998.1; -; mRNA.
DR CCDS; CCDS17853.1; -.
DR RefSeq; NP_081484.1; NM_027208.2.
DR AlphaFoldDB; Q8JZV9; -.
DR SMR; Q8JZV9; -.
DR BioGRID; 213669; 1.
DR STRING; 10090.ENSMUSP00000029817; -.
DR iPTMnet; Q8JZV9; -.
DR PhosphoSitePlus; Q8JZV9; -.
DR jPOST; Q8JZV9; -.
DR MaxQB; Q8JZV9; -.
DR PaxDb; Q8JZV9; -.
DR PRIDE; Q8JZV9; -.
DR ProteomicsDB; 273600; -.
DR Antibodypedia; 26090; 207 antibodies from 28 providers.
DR DNASU; 69772; -.
DR Ensembl; ENSMUST00000029817; ENSMUSP00000029817; ENSMUSG00000028167.
DR GeneID; 69772; -.
DR KEGG; mmu:69772; -.
DR UCSC; uc008rla.2; mouse.
DR CTD; 56898; -.
DR MGI; MGI:1917022; Bdh2.
DR VEuPathDB; HostDB:ENSMUSG00000028167; -.
DR eggNOG; KOG0725; Eukaryota.
DR GeneTree; ENSGT00940000156721; -.
DR HOGENOM; CLU_010194_1_0_1; -.
DR InParanoid; Q8JZV9; -.
DR PhylomeDB; Q8JZV9; -.
DR TreeFam; TF328795; -.
DR BRENDA; 1.1.1.30; 3474.
DR Reactome; R-MMU-77111; Synthesis of Ketone Bodies.
DR BioGRID-ORCS; 69772; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Bdh2; mouse.
DR PRO; PR:Q8JZV9; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q8JZV9; protein.
DR Bgee; ENSMUSG00000028167; Expressed in right kidney and 143 other tissues.
DR ExpressionAtlas; Q8JZV9; baseline and differential.
DR Genevisible; Q8JZV9; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:HGNC-UCL.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0003858; F:3-hydroxybutyrate dehydrogenase activity; ISS:HGNC-UCL.
DR GO; GO:0051287; F:NAD binding; ISS:HGNC-UCL.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016628; F:oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor; IMP: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:0030855; P:epithelial cell differentiation; ISO:MGI.
DR GO; GO:0006635; P:fatty acid beta-oxidation; ISS:HGNC-UCL.
DR GO; GO:0042168; P:heme metabolic process; ISS:UniProtKB.
DR GO; GO:0055072; P:iron ion homeostasis; IMP:UniProtKB.
DR GO; GO:0019290; P:siderophore biosynthetic process; IMP: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 Cytoplasm; Lipid metabolism; NAD; Oxidoreductase; Reference proteome.
FT CHAIN 1..245
FT /note="3-hydroxybutyrate dehydrogenase type 2"
FT /id="PRO_0000042581"
FT ACT_SITE 147
FT /note="Proton acceptor"
FT /evidence="ECO:0000269|PubMed:20550936"
FT BINDING 16..18
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q9BUT1"
FT BINDING 37
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q9BUT1"
FT BINDING 58
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q9BUT1"
FT BINDING 144
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 151
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q9BUT1"
FT BINDING 180..184
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q9BUT1"
FT BINDING 188
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 205
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT MUTAGEN 147
FT /note="Y->F: Loss of function."
FT /evidence="ECO:0000269|PubMed:20550936"
SQ SEQUENCE 245 AA; 26753 MW; 343A25B1F56B9CCF CRC64;
MGRLDGKVIV LTAAAQGIGR ASALAFAREG AKVIATDINE SKLQELESYR GIQTRVLDVT
KKRQIDQFAS EIERIDVLFN VAGFVHHGTI LDCEEKDWDF SMNLNVRSMF LMIKAFLPKM
LAQKSGNIIN MSSVASSIKG VENRCVYSAT KAAVIGLTKS VAADFIQQGI RCNCVCPGTV
DTPSLQERIQ ARDNPKEALK TFLNRQKTGR FASAEEVALL CVYLASDESA YVTGNPVIID
GGWSL
