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Protein

Aldo-keto reductase family 1 member C4

Gene

AKR1C4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

  • aldo-keto reductase (NADP) activity Source: Reactome
  • androsterone dehydrogenase activity Source: UniProtKB
  • bile acid transmembrane transporter activity Source: ProtInc
  • chlordecone reductase activity Source: UniProtKB-EC
  • electron carrier activity Source: UniProtKB
  • oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor Source: UniProtKB
  • retinal dehydrogenase activity Source: UniProtKB

GO - Biological processi

  • androgen metabolic process Source: ProtInc
  • bile acid and bile salt transport Source: ProtInc
  • bile acid biosynthetic process Source: Reactome
  • cellular response to jasmonic acid stimulus Source: UniProtKB
  • daunorubicin metabolic process Source: UniProtKB
  • doxorubicin metabolic process Source: UniProtKB
  • retinoid metabolic process Source: Reactome
  • steroid metabolic process Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Ligandi

NADP

Enzyme and pathway databases

BioCyciMetaCyc:HS10739-MONOMER.
ZFISH: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-RKP17516.
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

HGNCiHGNC:387. AKR1C4.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: ProtInc
  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
Complete GO annotation...

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.

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.

PTM databases

iPTMnetiP17516.
PhosphoSitePlusiP17516.

Expressioni

Tissue specificityi

Liver specific.2 Publications

Gene expression databases

BgeeiENSG00000198610.
CleanExiHS_AKR1C4.
GenevisibleiP17516. HS.

Organism-specific databases

HPAiHPA044720.

Interactioni

Subunit structurei

Monomer.1 Publication

Protein-protein interaction databases

BioGridi107534. 4 interactors.
STRINGi9606.ENSP00000263126.

Chemistry databases

BindingDBiP17516.

Structurei

Secondary structure

1323
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi3 – 5Combined sources3
Beta strandi7 – 9Combined sources3
Beta strandi15 – 22Combined sources8
Helixi33 – 44Combined sources12
Beta strandi48 – 50Combined sources3
Helixi53 – 55Combined sources3
Helixi58 – 71Combined sources14
Helixi76 – 78Combined sources3
Beta strandi80 – 85Combined sources6
Helixi87 – 89Combined sources3
Helixi92 – 106Combined sources15
Beta strandi111 – 117Combined sources7
Beta strandi124 – 126Combined sources3
Helixi144 – 156Combined sources13
Beta strandi159 – 167Combined sources9
Helixi170 – 177Combined sources8
Beta strandi187 – 192Combined sources6
Helixi200 – 208Combined sources9
Beta strandi212 – 217Combined sources6
Turni225 – 227Combined sources3
Helixi235 – 237Combined sources3
Helixi239 – 247Combined sources9
Helixi252 – 262Combined sources11
Beta strandi266 – 270Combined sources5
Helixi274 – 280Combined sources7
Helixi281 – 285Combined sources5
Helixi290 – 297Combined sources8
Helixi309 – 311Combined sources3
Beta strandi318 – 321Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2FVLX-ray2.40A/B/C1-323[»]
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.
OMAiLLHFPMA.
OrthoDBiEOG091G0D69.
PhylomeDBiP17516.
TreeFamiTF106492.

Family and domain databases

CDDicd06660. Aldo_ket_red. 1 hit.
Gene3Di3.20.20.100. 1 hit.
InterProiIPR001395. Aldo/ket_red/Kv-b.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]
PANTHERiPTHR11732. PTHR11732. 2 hits.
PfamiPF00248. Aldo_ket_red. 1 hit.
[Graphical view]
PIRSFiPIRSF000097. AKR. 1 hit.
PRINTSiPR00069. ALDKETRDTASE.
SUPFAMiSSF51430. SSF51430. 1 hit.
PROSITEiPS00798. ALDOKETO_REDUCTASE_1. 1 hit.
PS00062. ALDOKETO_REDUCTASE_2. 1 hit.
PS00063. ALDOKETO_REDUCTASE_3. 1 hit.
[Graphical view]

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 rs11253043dbSNPEnsembl.1
Natural variantiVAR_013290145S → C.1 PublicationCorresponds to variant rs3829125dbSNPEnsembl.1
Natural variantiVAR_028241170C → Y.1 PublicationCorresponds to variant rs17851824dbSNPEnsembl.1
Natural variantiVAR_028242250Q → R.9 PublicationsCorresponds to variant rs4880718dbSNPEnsembl.1
Natural variantiVAR_013291311L → V.1 PublicationCorresponds to variant rs17134592dbSNPEnsembl.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

Cross-referencesi

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.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2FVLX-ray2.40A/B/C1-323[»]
ProteinModelPortaliP17516.
SMRiP17516.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107534. 4 interactors.
STRINGi9606.ENSP00000263126.

Chemistry databases

BindingDBiP17516.
ChEMBLiCHEMBL4999.
SwissLipidsiSLP:000000805.

PTM databases

iPTMnetiP17516.
PhosphoSitePlusiP17516.

Polymorphism and mutation databases

BioMutaiAKR1C4.
DMDMi308153631.

Proteomic databases

EPDiP17516.
MaxQBiP17516.
PaxDbiP17516.
PeptideAtlasiP17516.
PRIDEiP17516.

Protocols and materials databases

DNASUi1109.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi1109.
DisGeNETi1109.
GeneCardsiAKR1C4.
HGNCiHGNC:387. AKR1C4.
HPAiHPA044720.
MalaCardsiAKR1C4.
MIMi600451. gene.
614279. phenotype.
neXtProtiNX_P17516.
OpenTargetsiENSG00000198610.
Orphaneti90796. 46,XY disorder of sex development due to isolated 17,20 lyase deficiency.
PharmGKBiPA24680.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BioCyciMetaCyc:HS10739-MONOMER.
ZFISH: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-RKP17516.
SIGNORiP17516.

Miscellaneous databases

EvolutionaryTraceiP17516.
GeneWikii3-alpha-HSD.
GenomeRNAii1109.
PROiP17516.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000198610.
CleanExiHS_AKR1C4.
GenevisibleiP17516. HS.

Family and domain databases

CDDicd06660. Aldo_ket_red. 1 hit.
Gene3Di3.20.20.100. 1 hit.
InterProiIPR001395. Aldo/ket_red/Kv-b.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]
PANTHERiPTHR11732. PTHR11732. 2 hits.
PfamiPF00248. Aldo_ket_red. 1 hit.
[Graphical view]
PIRSFiPIRSF000097. AKR. 1 hit.
PRINTSiPR00069. ALDKETRDTASE.
SUPFAMiSSF51430. SSF51430. 1 hit.
PROSITEiPS00798. ALDOKETO_REDUCTASE_1. 1 hit.
PS00062. ALDOKETO_REDUCTASE_2. 1 hit.
PS00063. ALDOKETO_REDUCTASE_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiAK1C4_HUMAN
AccessioniPrimary (citable) accession number: P17516
Secondary accession number(s): Q5T6A3, Q8WW84, Q9NS54
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: October 5, 2010
Last modified: November 2, 2016
This is version 184 of the entry and version 3 of the sequence. [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

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.