RDH16_HUMAN
ID RDH16_HUMAN Reviewed; 317 AA.
AC O75452; Q9UNV2;
DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 23-OCT-2007, sequence version 2.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Retinol dehydrogenase 16;
DE EC=1.1.1.105 {ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:12534290, ECO:0000269|PubMed:9677409};
DE EC=1.1.1.209 {ECO:0000269|PubMed:12534290, ECO:0000269|PubMed:29541409, ECO:0000269|PubMed:9677409};
DE EC=1.1.1.315 {ECO:0000250|UniProtKB:O54909};
DE EC=1.1.1.53 {ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:9677409};
DE AltName: Full=Human epidermal retinol dehydrogenase {ECO:0000303|PubMed:10329026};
DE Short=hRDH-E {ECO:0000303|PubMed:10329026};
DE AltName: Full=Microsomal NAD(+)-dependent retinol dehydrogenase 4 {ECO:0000303|PubMed:12534290};
DE Short=RoDH-4 {ECO:0000303|PubMed:12534290};
DE AltName: Full=Short chain dehydrogenase/reductase family 9C member 8 {ECO:0000303|PubMed:19027726};
DE AltName: Full=Sterol/retinol dehydrogenase;
GN Name=RDH16 {ECO:0000312|HGNC:HGNC:29674};
GN Synonyms=RODH4 {ECO:0000303|PubMed:12534290},
GN SDR9C8 {ECO:0000303|PubMed:19027726};
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], FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES,
RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP CATALYTIC ACTIVITY.
RC TISSUE=Liver;
RX PubMed=9677409; DOI=10.1074/jbc.273.31.19778;
RA Gough W.H., VanOoteghem S., Sint T., Kedishvili N.Y.;
RT "cDNA cloning and characterization of a new human microsomal NAD+-dependent
RT dehydrogenase that oxidizes all-trans-retinol and 3alpha-hydroxysteroids.";
RL J. Biol. Chem. 273:19778-19785(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INDUCTION, TISSUE SPECIFICITY, AND
RP CATALYTIC ACTIVITY.
RC TISSUE=Keratinocyte;
RX PubMed=10329026; DOI=10.1006/mgme.1999.2840;
RA Jurukovski V., Markova N.G., Karaman-Jurukovska N., Randolph R.K., Su J.,
RA Napoli J.L., Simon M.;
RT "Cloning and characterization of retinol dehydrogenase transcripts
RT expressed in human epidermal keratinocytes.";
RL Mol. Genet. Metab. 67:62-73(1999).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=11967490; DOI=10.1067/mob.2002.122127;
RA Cain J.M., Zaino R., Shearer D., Bennett R.A., Olt G., Weisz J.;
RT "Expression of a retinol dehydrogenase (hRoDH-4), a member of the
RT retinol/steroid dehydrogenase family implicated in retinoic acid
RT biosynthesis, in normal and neoplastic endometria.";
RL Am. J. Obstet. Gynecol. 186:675-683(2002).
RN [4]
RP FUNCTION, LACK OF GLYCOSYLATION, SUBCELLULAR LOCATION, TOPOLOGY, CATALYTIC
RP ACTIVITY, AND CAUTION.
RX PubMed=12534290; DOI=10.1021/bi026836r;
RA Lapshina E.A., Belyaeva O.V., Chumakova O.V., Kedishvili N.Y.;
RT "Differential recognition of the free versus bound retinol by human
RT microsomal retinol/sterol dehydrogenases: characterization of the holo-CRBP
RT dehydrogenase activity of RoDH-4.";
RL Biochemistry 42:776-784(2003).
RN [5]
RP GENE FAMILY, AND NOMENCLATURE.
RX PubMed=19027726; DOI=10.1016/j.cbi.2008.10.040;
RA Persson B., Kallberg Y., Bray J.E., Bruford E., Dellaporta S.L.,
RA Favia A.D., Duarte R.G., Joernvall H., Kavanagh K.L., Kedishvili N.,
RA Kisiela M., Maser E., Mindnich R., Orchard S., Penning T.M., Thornton J.M.,
RA Adamski J., Oppermann U.;
RT "The SDR (short-chain dehydrogenase/reductase and related enzymes)
RT nomenclature initiative.";
RL Chem. Biol. Interact. 178:94-98(2009).
RN [6]
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 [7]
RP MUTAGENESIS OF TYR-176 AND LYS-180, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=29541409; DOI=10.18632/oncotarget.24107;
RA Fiandalo M.V., Stocking J.J., Pop E.A., Wilton J.H., Mantione K.M., Li Y.,
RA Attwood K.M., Azabdaftari G., Wu Y., Watt D.S., Wilson E.M., Mohler J.L.;
RT "Inhibition of dihydrotestosterone synthesis in prostate cancer by combined
RT frontdoor and backdoor pathway blockade.";
RL Oncotarget 9:11227-11242(2018).
CC -!- FUNCTION: Oxidoreductase with a preference for NAD. Oxidizes all-trans-
CC retinol, 9-cis-retinol, 11-cis-retinol and 13-cis-retinol to the
CC corresponding aldehydes (PubMed:10329026, PubMed:12534290,
CC PubMed:9677409). Has higher activity towards CRBP-bound retinol than
CC with free retinol (PubMed:12534290). Oxidizes also 3-alpha-
CC hydroxysteroids. Oxidizes androstanediol and androsterone to
CC dihydrotestosterone and androstanedione. Can also catalyze the reverse
CC reaction (PubMed:10329026, PubMed:9677409, PubMed:29541409).
CC {ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:12534290,
CC ECO:0000269|PubMed:29541409, ECO:0000269|PubMed:9677409}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=all-trans-retinol--[retinol-binding protein] + NAD(+) = all-
CC trans-retinal--[retinol-binding protein] + H(+) + NADH;
CC Xref=Rhea:RHEA:48488, Rhea:RHEA-COMP:14428, Rhea:RHEA-COMP:14430,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17336, ChEBI:CHEBI:17898,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:83228;
CC EC=1.1.1.105; Evidence={ECO:0000269|PubMed:10329026,
CC ECO:0000269|PubMed:12534290, ECO:0000269|PubMed:9677409};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=all-trans-retinol + NAD(+) = all-trans-retinal + H(+) + NADH;
CC Xref=Rhea:RHEA:21284, ChEBI:CHEBI:15378, ChEBI:CHEBI:17336,
CC ChEBI:CHEBI:17898, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC EC=1.1.1.105; Evidence={ECO:0000269|PubMed:10329026,
CC ECO:0000269|PubMed:9677409};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=13-cis-retinol + NAD(+) = 13-cis-retinal + H(+) + NADH;
CC Xref=Rhea:RHEA:42056, ChEBI:CHEBI:15378, ChEBI:CHEBI:45479,
CC ChEBI:CHEBI:45487, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:9677409};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=11-cis-retinol + NAD(+) = 11-cis-retinal + H(+) + NADH;
CC Xref=Rhea:RHEA:42060, ChEBI:CHEBI:15378, ChEBI:CHEBI:16066,
CC ChEBI:CHEBI:16302, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC EC=1.1.1.315; Evidence={ECO:0000250|UniProtKB:O54909};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=9-cis-retinol + NAD(+) = 9-cis-retinal + H(+) + NADH;
CC Xref=Rhea:RHEA:42052, ChEBI:CHEBI:15378, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:78272, ChEBI:CHEBI:78273;
CC Evidence={ECO:0000250|UniProtKB:O54909};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5alpha-androstane-3alpha,17beta-diol + NAD(+) = 17beta-
CC hydroxy-5alpha-androstan-3-one + H(+) + NADH; Xref=Rhea:RHEA:42004,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16330, ChEBI:CHEBI:36713,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.53;
CC Evidence={ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:9677409};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3alpha-hydroxy-5alpha-androstan-17-one + NAD(+) = 5alpha-
CC androstan-3,17-dione + H(+) + NADH; Xref=Rhea:RHEA:20381,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15994, ChEBI:CHEBI:16032,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.209;
CC Evidence={ECO:0000269|PubMed:12534290, ECO:0000269|PubMed:29541409,
CC ECO:0000269|PubMed:9677409};
CC -!- ACTIVITY REGULATION: Inhibited by citral, perillyl alcohol, geraniol,
CC farnesol and geranyl geraniol. {ECO:0000269|PubMed:9677409}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.14 uM for 3alpha-hydroxy-5alpha-androstan-17-one (androsterone)
CC {ECO:0000269|PubMed:12534290, ECO:0000269|PubMed:9677409};
CC KM=0.22 uM for 5alpha-androstane-3,17-dione (androstanediol)
CC {ECO:0000269|PubMed:9677409};
CC KM=0.80 uM for 17beta-hydroxy-5alpha-androstan-3-one
CC (dihydrotestosterone) {ECO:0000269|PubMed:9677409};
CC KM=0.13 uM for NAD {ECO:0000269|PubMed:9677409};
CC KM=190 uM for NADP {ECO:0000269|PubMed:9677409};
CC KM=5.8 uM for all-trans-retinol {ECO:0000269|PubMed:9677409};
CC KM=3.5 uM for 13-cis-retinol {ECO:0000269|PubMed:9677409};
CC KM=3.6 uM for CRBP-all-trans-retinol {ECO:0000269|PubMed:9677409};
CC -!- PATHWAY: Cofactor metabolism; retinol metabolism.
CC {ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:9677409}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O54909}.
CC -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:9677409}.
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:O54909}; Single-
CC pass membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Highly expressed in adult liver (at protein level)
CC (PubMed:9677409). Detected in endometrium, liver and foreskin
CC (PubMed:10329026, PubMed:11967490). Detected in the spineous layers of
CC adult skin, and at lower levels in basal and granular skin layers
CC (PubMed:10329026). Detected in fetal liver and lung.
CC {ECO:0000269|PubMed:10329026, ECO:0000269|PubMed:11967490,
CC ECO:0000269|PubMed:9677409}.
CC -!- INDUCTION: Transiently up-regulated by retinoic acid.
CC {ECO:0000269|PubMed:10329026}.
CC -!- DOMAIN: The C-terminal region plays a crucial role in controlling the
CC activity of RDH16 and its required for endoplasmic reticulum (ER)
CC retention. {ECO:0000250|UniProtKB:O54909}.
CC -!- PTM: Not N-glycosylated. {ECO:0000269|PubMed:12534290}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
CC -!- CAUTION: Membrane topology is controversial (PubMed:12534290). Membrane
CC topology structure with endoplasmic reticulum lumen orientation of the
CC catalytic domains while the C-terminus is in the cytosol have been
CC suggested (By similarity). Others investigators have argued for a
CC reverse orientation, with a membrane-embedded N-terminal domain but no
CC C-terminal transmembrane segment, and a cytosolic orientation of the
CC catalytic domain (PubMed:12534290). These contradictory results are
CC probably because of differences in the assay systems.
CC {ECO:0000250|UniProtKB:O54909, ECO:0000269|PubMed:12534290,
CC ECO:0000305}.
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DR EMBL; AF057034; AAC39922.1; -; mRNA.
DR EMBL; AF086735; AAC72923.1; -; mRNA.
DR CCDS; CCDS41797.1; -.
DR RefSeq; NP_003699.3; NM_003708.4.
DR AlphaFoldDB; O75452; -.
DR SMR; O75452; -.
DR BioGRID; 114167; 1.
DR STRING; 9606.ENSP00000381206; -.
DR SwissLipids; SLP:000000801; -.
DR iPTMnet; O75452; -.
DR PhosphoSitePlus; O75452; -.
DR BioMuta; RDH16; -.
DR EPD; O75452; -.
DR MassIVE; O75452; -.
DR PaxDb; O75452; -.
DR PeptideAtlas; O75452; -.
DR PRIDE; O75452; -.
DR ProteomicsDB; 50019; -.
DR Antibodypedia; 28411; 107 antibodies from 17 providers.
DR DNASU; 8608; -.
DR Ensembl; ENST00000398138.5; ENSP00000381206.3; ENSG00000139547.8.
DR GeneID; 8608; -.
DR KEGG; hsa:8608; -.
DR MANE-Select; ENST00000398138.5; ENSP00000381206.3; NM_003708.5; NP_003699.3.
DR UCSC; uc001smi.6; human.
DR CTD; 8608; -.
DR DisGeNET; 8608; -.
DR GeneCards; RDH16; -.
DR HGNC; HGNC:29674; RDH16.
DR HPA; ENSG00000139547; Tissue enriched (liver).
DR neXtProt; NX_O75452; -.
DR OpenTargets; ENSG00000139547; -.
DR PharmGKB; PA142671089; -.
DR VEuPathDB; HostDB:ENSG00000139547; -.
DR eggNOG; KOG1610; Eukaryota.
DR GeneTree; ENSGT00940000154118; -.
DR HOGENOM; CLU_010194_2_0_1; -.
DR InParanoid; O75452; -.
DR OMA; FRWYQER; -.
DR OrthoDB; 942985at2759; -.
DR PhylomeDB; O75452; -.
DR TreeFam; TF325617; -.
DR BioCyc; MetaCyc:ENSG00000139547-MON; -.
DR BRENDA; 1.1.1.105; 2681.
DR PathwayCommons; O75452; -.
DR Reactome; R-HSA-2453902; The canonical retinoid cycle in rods (twilight vision).
DR Reactome; R-HSA-5365859; RA biosynthesis pathway.
DR SABIO-RK; O75452; -.
DR UniPathway; UPA00912; -.
DR BioGRID-ORCS; 8608; 7 hits in 1066 CRISPR screens.
DR ChiTaRS; RDH16; human.
DR GenomeRNAi; 8608; -.
DR Pharos; O75452; Tbio.
DR PRO; PR:O75452; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; O75452; protein.
DR Bgee; ENSG00000139547; Expressed in right lobe of liver and 103 other tissues.
DR Genevisible; O75452; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:UniProtKB.
DR GO; GO:0047044; F:androstan-3-alpha,17-beta-diol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0047023; F:androsterone dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0009055; F:electron transfer activity; TAS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0004745; F:NAD-retinol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR GO; GO:0042572; P:retinol metabolic process; IBA:GO_Central.
DR GO; GO:0008202; P:steroid metabolic process; IDA:UniProtKB.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
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 Endoplasmic reticulum; Lipid metabolism; Membrane; Microsome; NAD;
KW Oxidoreductase; Reference proteome; Steroid metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..317
FT /note="Retinol dehydrogenase 16"
FT /id="PRO_0000307693"
FT TRANSMEM 289..309
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ACT_SITE 176
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001,
FT ECO:0000305|PubMed:29541409"
FT BINDING 33..57
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 164
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT MUTAGEN 176
FT /note="Y->F: Decreases androsterone dehydrogenase activity;
FT when associated with R-180."
FT /evidence="ECO:0000269|PubMed:29541409"
FT MUTAGEN 180
FT /note="K->R: Decreases androsterone dehydrogenase activity;
FT when associated with F-176."
FT /evidence="ECO:0000269|PubMed:29541409"
FT CONFLICT 130..131
FT /note="FV -> LL (in Ref. 2; AAC72923)"
FT /evidence="ECO:0000305"
FT CONFLICT 147
FT /note="S -> N (in Ref. 2; AAC72923)"
FT /evidence="ECO:0000305"
FT CONFLICT 154
FT /note="R -> K (in Ref. 1; AAC39922)"
FT /evidence="ECO:0000305"
FT CONFLICT 163
FT /note="S -> F (in Ref. 2; AAC72923)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 317 AA; 35673 MW; F9208C22B0515CFD CRC64;
MWLYLAVFVG LYYLLHWYRE RQVLSHLRDK YVFITGCDSG FGKLLARQLD ARGLRVLAAC
LTEKGAEQLR GQTSDRLETV TLDVTKTESV AAAAQWVKEC VRDKGLWGLV NNAGISLPTA
PNELLTKQDF VTILDVNLLG VIDVTLSLLP LVRRARGRVV NVSSVMGRVS LFGGGYCISK
YGVEAFSDSL RRELSYFGVK VAMIEPGYFK TAVTSKERFL KSFLEIWDRS SPEVKEAYGE
KFVADYKKSA EQMEQKCTQD LSLVTNCMEH ALIACHPRTR YSAGWDAKLL YLPMSYMPTF
LVDAIMYWVS PSPAKAL
