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   24-JAN-2024, entry version 162.
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}, SDR9C8
GN   {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=androsterone + NAD(+) = 5alpha-androstan-3,17-dione + H(+) +
CC         NADH; Xref=Rhea:RHEA:20381, ChEBI:CHEBI:15378, ChEBI:CHEBI:15994,
CC         ChEBI:CHEBI:16032, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         EC=1.1.1.209; Evidence={ECO:0000269|PubMed:12534290,
CC         ECO:0000269|PubMed:29541409, 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=0.8 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; 9606-ENSP00000381206; -.
DR   PeptideAtlas; O75452; -.
DR   ProteomicsDB; 50019; -.
DR   Antibodypedia; 28411; 111 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   AGR; HGNC:29674; -.
DR   CTD; 8608; -.
DR   DisGeNET; 8608; -.
DR   GeneCards; RDH16; -.
DR   HGNC; HGNC:29674; RDH16.
DR   HPA; ENSG00000139547; Tissue enriched (liver).
DR   MIM; 620043; gene.
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; HLRDKCV; -.
DR   OrthoDB; 5403248at2759; -.
DR   PhylomeDB; O75452; -.
DR   TreeFam; TF325617; -.
DR   BioCyc; MetaCyc:ENSG00000139547-MONOMER; -.
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 1146 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 104 other cell types or tissues.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:UniProtKB.
DR   GO; GO:0106429; F:11-cis-retinol dehydrogenase; IEA:UniProtKB-EC.
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: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   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR   InterPro; IPR002347; SDR_fam.
DR   PANTHER; PTHR43313:SF11; RETINOL DEHYDROGENASE 16; 1.
DR   PANTHER; PTHR43313; SHORT-CHAIN DEHYDROGENASE/REDUCTASE FAMILY 9C; 1.
DR   Pfam; PF00106; adh_short; 1.
DR   PRINTS; PR00081; GDHRDH.
DR   PRINTS; PR00080; SDRFAMILY.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00061; ADH_SHORT; 1.
DR   Genevisible; O75452; HS.
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
//