BDH2_RAT
ID BDH2_RAT Reviewed; 245 AA.
AC D4A1J4;
DT 05-OCT-2010, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 2.
DT 03-AUG-2022, entry version 69.
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:0000303|PubMed:35150746};
DE EC=1.1.1.104 {ECO:0000269|PubMed:35150746};
DE AltName: Full=Dehydrogenase/reductase SDR family member 6;
DE AltName: Full=R-beta-hydroxybutyrate dehydrogenase;
GN Name=Bdh2; Synonyms=Dhrs6;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF TYR-147.
RX PubMed=35150746; DOI=10.1016/j.jbc.2022.101708;
RA Kwiatkowski S., Bozko M., Zarod M., Witecka A., Kocdemir K.,
RA Jagielski A.K., Drozak J.;
RT "Recharacterization of the Mammalian Cytosolic Type 2 (R)-beta-
RT Hydroxybutyrate Dehydrogenase (BDH2) as 4-Oxo-L-Proline Reductase (EC
RT 1.1.1.104).";
RL J. Biol. Chem. 298:101708-101708(2022).
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 (PubMed:35150746). Mediates
CC the 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 (By
CC similarity). May act as a 3-hydroxybutyrate dehydrogenase (By
CC similarity). {ECO:0000250|UniProtKB:Q8JZV9,
CC ECO:0000250|UniProtKB:Q9BUT1, ECO:0000269|PubMed:35150746}.
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:0000269|PubMed:35150746};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:13603;
CC Evidence={ECO:0000269|PubMed:35150746};
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=387 uM for 4-oxo-L-proline {ECO:0000269|PubMed:35150746};
CC KM=10232 uM for (R)-3-hydroxybutanoate {ECO:0000269|PubMed:35150746};
CC Vmax=28 umol/min/mg enzyme toward 4-oxo-L-proline
CC {ECO:0000269|PubMed:35150746};
CC Vmax=0.04 umol/min/mg enzyme toward (R)-3-hydroxybutanoate
CC {ECO:0000269|PubMed:35150746};
CC Note=kcat is 14 sec(-1) for the NADH-dependent reduction of 4-oxo-L-
CC proline. kcat is 0.02 sec(-1) for the NAD(+)-dependent oxidation of
CC (R)-3-hydroxybutanoate.;
CC pH dependence:
CC Optimum pH is 6.5. Active from 5.5 to 9.0 with 4-oxo-L-proline.
CC {ECO:0000269|PubMed:35150746};
CC -!- PATHWAY: Amino-acid metabolism. {ECO:0000305|PubMed:35150746}.
CC -!- PATHWAY: Siderophore biosynthesis. {ECO:0000250|UniProtKB:Q8JZV9}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:Q9BUT1}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9BUT1}.
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:Q8JZV9,
CC ECO:0000250|UniProtKB:Q9BUT1}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EDL82248.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; CH473952; EDL82248.1; ALT_INIT; Genomic_DNA.
DR RefSeq; NP_001099943.1; NM_001106473.1.
DR RefSeq; XP_006233384.1; XM_006233322.3.
DR AlphaFoldDB; D4A1J4; -.
DR SMR; D4A1J4; -.
DR STRING; 10116.ENSRNOP00000019507; -.
DR iPTMnet; D4A1J4; -.
DR PhosphoSitePlus; D4A1J4; -.
DR PaxDb; D4A1J4; -.
DR PeptideAtlas; D4A1J4; -.
DR PRIDE; D4A1J4; -.
DR GeneID; 295458; -.
DR KEGG; rno:295458; -.
DR CTD; 56898; -.
DR RGD; 1309898; Bdh2.
DR eggNOG; KOG0725; Eukaryota.
DR InParanoid; D4A1J4; -.
DR OrthoDB; 1226147at2759; -.
DR PhylomeDB; D4A1J4; -.
DR TreeFam; TF328795; -.
DR Reactome; R-RNO-77111; Synthesis of Ketone Bodies.
DR PRO; PR:D4A1J4; -.
DR Proteomes; UP000002494; Unplaced.
DR Proteomes; UP000234681; Chromosome 2.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0003858; F:3-hydroxybutyrate dehydrogenase activity; ISO:RGD.
DR GO; GO:0051287; F:NAD binding; ISO:RGD.
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; 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:0030855; P:epithelial cell differentiation; ISO:RGD.
DR GO; GO:0006635; P:fatty acid beta-oxidation; ISO:RGD.
DR GO; GO:0042168; P:heme metabolic process; ISS:UniProtKB.
DR GO; GO:0055072; P:iron ion homeostasis; ISS:UniProtKB.
DR GO; GO:0019290; P:siderophore biosynthetic process; 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 Cytoplasm; Lipid metabolism; NAD; Oxidoreductase; Reference proteome.
FT CHAIN 1..245
FT /note="3-hydroxybutyrate dehydrogenase type 2"
FT /id="PRO_0000398628"
FT ACT_SITE 147
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
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:35150746"
SQ SEQUENCE 245 AA; 26651 MW; 46E513E8F8CF1169 CRC64;
MGRLEGKVIV LTAAAQGIGR ASALAFAREG AKVIATDINE AKLQELENYP GIQTRVLDVT
KKRQIDQFAS EIEKIDVLFN VAGFVHHGTI LDCEEKDWDF SMNLNVRSMY LMIKAFLPKM
LAQKSGNIIN MSSVASSIKG VENRCVYSAT KAAVIGLTKS VAADFIQQGI RCNCVCPGTV
DTPSLQERIQ ARDDPKEALK AFLNRQKTGR FASAEEVALL CVYLASDESA YVTGTPVVID
GGWSL
