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Protein

Aldo-keto reductase family 1 member C4

Gene

AKR1C4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol). Also has some 20-alpha-hydroxysteroid dehydrogenase activity. The biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leads to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route.

Catalytic activityi

Chlordecone alcohol + NADP+ = chlordecone + NADPH.
A 3-alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei50NADP1 Publication1
Sitei54Important for substrate specificityBy similarity1
Active sitei55Proton donorBy similarity1
Sitei84Lowers pKa of active site TyrBy similarity1
Binding sitei117SubstrateBy similarity1
Binding sitei190NADP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi20 – 24NADP1 Publication5
Nucleotide bindingi166 – 167NADP1 Publication2
Nucleotide bindingi216 – 221NADP1 Publication6
Nucleotide bindingi270 – 280NADP1 PublicationAdd BLAST11

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionOxidoreductase
LigandNADP

Enzyme and pathway databases

BioCyciMetaCyc:HS10739-MONOMER
BRENDAi1.1.1.357 2681
ReactomeiR-HSA-193368 Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
R-HSA-193775 Synthesis of bile acids and bile salts via 24-hydroxycholesterol
R-HSA-193807 Synthesis of bile acids and bile salts via 27-hydroxycholesterol
R-HSA-975634 Retinoid metabolism and transport
SABIO-RKiP17516
SIGNORiP17516

Chemistry databases

SwissLipidsiSLP:000000805

Names & Taxonomyi

Protein namesi
Recommended name:
Aldo-keto reductase family 1 member C4 (EC:1.1.1.-)
Alternative name(s):
3-alpha-HSD1
3-alpha-hydroxysteroid dehydrogenase type I (EC:1.1.1.357)
Chlordecone reductase (EC:1.1.1.225)
Short name:
CDR
Dihydrodiol dehydrogenase 4
Short name:
DD-4
Short name:
DD4
HAKRA
Gene namesi
Name:AKR1C4
Synonyms:CHDR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000198610.10
HGNCiHGNC:387 AKR1C4
MIMi600451 gene
neXtProtiNX_P17516

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Involvement in diseasei

46,XY sex reversal 8 (SRXY8)1 Publication
The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2 (PubMed:21802064). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2.1 Publication
Disease descriptionA disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.
See also OMIM:614279

Organism-specific databases

DisGeNETi1109
MalaCardsiAKR1C4
MIMi614279 phenotype
OpenTargetsiENSG00000198610
Orphaneti90796 46,XY disorder of sex development due to isolated 17,20 lyase deficiency
PharmGKBiPA24680

Chemistry databases

ChEMBLiCHEMBL4999
DrugBankiDB00157 NADH

Polymorphism and mutation databases

BioMutaiAKR1C4
DMDMi308153631

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001246401 – 323Aldo-keto reductase family 1 member C4Add BLAST323

Post-translational modificationi

The N-terminus is blocked.

Proteomic databases

EPDiP17516
MaxQBiP17516
PaxDbiP17516
PeptideAtlasiP17516
PRIDEiP17516
ProteomicsDBi53480

PTM databases

iPTMnetiP17516
PhosphoSitePlusiP17516

Expressioni

Tissue specificityi

Liver specific.2 Publications

Gene expression databases

BgeeiENSG00000198610 Expressed in 41 organ(s), highest expression level in right lobe of liver
CleanExiHS_AKR1C4
GenevisibleiP17516 HS

Organism-specific databases

HPAiHPA044720
HPA068265

Interactioni

Subunit structurei

Monomer.1 Publication

Protein-protein interaction databases

BioGridi107534, 5 interactors
STRINGi9606.ENSP00000263126

Chemistry databases

BindingDBiP17516

Structurei

Secondary structure

1323
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP17516
SMRiP17516
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP17516

Family & Domainsi

Sequence similaritiesi

Belongs to the aldo/keto reductase family.Curated

Phylogenomic databases

eggNOGiKOG1577 Eukaryota
COG0656 LUCA
GeneTreeiENSGT00760000119041
HOGENOMiHOG000250272
HOVERGENiHBG000020
InParanoidiP17516
KOiK00037
OMAiNPKEDHY
OrthoDBiEOG091G0D69
PhylomeDBiP17516
TreeFamiTF106492

Family and domain databases

CDDicd06660 Aldo_ket_red, 1 hit
Gene3Di3.20.20.100, 1 hit
InterProiView protein in InterPro
IPR018170 Aldo/ket_reductase_CS
IPR020471 Aldo/keto_reductase
IPR023210 NADP_OxRdtase_dom
IPR036812 NADP_OxRdtase_dom_sf
PANTHERiPTHR11732 PTHR11732, 1 hit
PfamiView protein in Pfam
PF00248 Aldo_ket_red, 1 hit
PIRSFiPIRSF000097 AKR, 1 hit
PRINTSiPR00069 ALDKETRDTASE
SUPFAMiSSF51430 SSF51430, 1 hit
PROSITEiView protein in PROSITE
PS00798 ALDOKETO_REDUCTASE_1, 1 hit
PS00062 ALDOKETO_REDUCTASE_2, 1 hit
PS00063 ALDOKETO_REDUCTASE_3, 1 hit

Sequencei

Sequence statusi: Complete.

P17516-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MDPKYQRVEL NDGHFMPVLG FGTYAPPEVP RNRAVEVTKL AIEAGFRHID
60 70 80 90 100
SAYLYNNEEQ VGLAIRSKIA DGSVKREDIF YTSKLWCTFF QPQMVQPALE
110 120 130 140 150
SSLKKLQLDY VDLYLLHFPM ALKPGETPLP KDENGKVIFD TVDLSATWEV
160 170 180 190 200
MEKCKDAGLA KSIGVSNFNC RQLEMILNKP GLKYKPVCNQ VECHPYLNQS
210 220 230 240 250
KLLDFCKSKD IVLVAHSALG TQRHKLWVDP NSPVLLEDPV LCALAKKHKQ
260 270 280 290 300
TPALIALRYQ LQRGVVVLAK SYNEQRIREN IQVFEFQLTS EDMKVLDGLN
310 320
RNYRYVVMDF LMDHPDYPFS DEY
Length:323
Mass (Da):37,067
Last modified:October 5, 2010 - v3
Checksum:iE728CE4B420E8C58
GO

Sequence cautioni

The sequence AAA35658 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Polymorphismi

The allele with Cys-145/Val-311 shows a three- to five-fold decrease in catalytic efficiency for xenobiotic and steroidal substrates compared to the Ser-145/Leu-311 allele.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_028240135G → E. Corresponds to variant dbSNP:rs11253043Ensembl.1
Natural variantiVAR_013290145S → C1 PublicationCorresponds to variant dbSNP:rs3829125Ensembl.1
Natural variantiVAR_028241170C → Y1 PublicationCorresponds to variant dbSNP:rs17851824Ensembl.1
Natural variantiVAR_028242250Q → R9 PublicationsCorresponds to variant dbSNP:rs4880718Ensembl.1
Natural variantiVAR_013291311L → V1 PublicationCorresponds to variant dbSNP:rs17134592Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S68287 mRNA Translation: AAD14010.1
AB045829 mRNA Translation: BAA99542.1
AB031085 mRNA Translation: BAA92885.1
AB032163 Genomic DNA Translation: BAA92893.1
AL355303 Genomic DNA No translation available.
BC020744 mRNA Translation: AAH20744.1
M33375 mRNA Translation: AAA35658.1 Different initiation.
D26125 mRNA Translation: BAA05122.1
CCDSiCCDS7064.1
PIRiA57407
S59620
RefSeqiNP_001809.3, NM_001818.3
UniGeneiHs.567245

Genome annotation databases

EnsembliENST00000263126; ENSP00000263126; ENSG00000198610
ENST00000380448; ENSP00000369814; ENSG00000198610
GeneIDi1109
KEGGihsa:1109
UCSCiuc001ihw.2 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiAK1C4_HUMAN
AccessioniPrimary (citable) accession number: P17516
Secondary accession number(s): Q5T6A3, Q8WW84, Q9NS54
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: October 5, 2010
Last modified: September 12, 2018
This is version 194 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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