Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

P17516 (AK1C4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 160. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
Short name=CDR
EC=1.1.1.225
Dihydrodiol dehydrogenase 4
Short name=DD-4
Short name=DD4
HAKRA
Gene names
Name:AKR1C4
Synonyms:CHDR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length323 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 activity

Chlordecone alcohol + NADP+ = chlordecone + NADPH.

A 3-alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H.

Subunit structure

Monomer.

Subcellular location

Cytoplasm.

Tissue specificity

Liver specific. Ref.2 Ref.6

Post-translational modification

The N-terminus is blocked.

Polymorphism

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.

Involvement in disease

46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.
Note: 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 (Ref.12). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2. Ref.12

Sequence similarities

Belongs to the aldo/keto reductase family.

Sequence caution

The sequence AAA35658.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   LigandNADP
   Molecular functionOxidoreductase
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processandrogen metabolic process

Traceable author statement Ref.2. Source: ProtInc

bile acid and bile salt transport

Traceable author statement Ref.10. Source: ProtInc

bile acid biosynthetic process

Traceable author statement. Source: Reactome

bile acid metabolic process

Traceable author statement. Source: Reactome

cellular response to jasmonic acid stimulus

Inferred from direct assay PubMed 19487289. Source: UniProtKB

daunorubicin metabolic process

Inferred from mutant phenotype PubMed 20837989. Source: UniProtKB

doxorubicin metabolic process

Inferred from mutant phenotype PubMed 20837989. Source: UniProtKB

phototransduction, visible light

Traceable author statement. Source: Reactome

retinoid metabolic process

Traceable author statement. Source: Reactome

small molecule metabolic process

Traceable author statement. Source: Reactome

steroid metabolic process

Traceable author statement Ref.1. Source: ProtInc

   Cellular_componentcytoplasm

Traceable author statement Ref.9. Source: ProtInc

cytosol

Traceable author statement. Source: Reactome

   Molecular_functionaldo-keto reductase (NADP) activity

Traceable author statement Ref.2. Source: ProtInc

androsterone dehydrogenase activity

Inferred from direct assay PubMed 21851338. Source: UniProtKB

bile acid transmembrane transporter activity

Traceable author statement Ref.10. Source: ProtInc

chlordecone reductase activity

Inferred from electronic annotation. Source: UniProtKB-EC

electron carrier activity

Traceable author statement Ref.10. Source: UniProtKB

oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor

Inferred from direct assay PubMed 20837989. Source: UniProtKB

retinal dehydrogenase activity

Inferred from direct assay PubMed 21851338. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 323323Aldo-keto reductase family 1 member C4
PRO_0000124640

Regions

Nucleotide binding20 – 245NADP
Nucleotide binding166 – 1672NADP
Nucleotide binding216 – 2216NADP
Nucleotide binding270 – 28011NADP

Sites

Active site551Proton donor By similarity
Binding site501NADP
Binding site1171Substrate By similarity
Binding site1901NADP
Site541Important for substrate specificity By similarity
Site841Lowers pKa of active site Tyr By similarity

Natural variations

Natural variant1351G → E.
Corresponds to variant rs11253043 [ dbSNP | Ensembl ].
VAR_028240
Natural variant1451S → C. Ref.4
Corresponds to variant rs3829125 [ dbSNP | Ensembl ].
VAR_013290
Natural variant1701C → Y. Ref.8
Corresponds to variant rs17851824 [ dbSNP | Ensembl ].
VAR_028241
Natural variant2501Q → R. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.8 Ref.9 Ref.10
Corresponds to variant rs4880718 [ dbSNP | Ensembl ].
VAR_028242
Natural variant3111L → V. Ref.4
Corresponds to variant rs17134592 [ dbSNP | Ensembl ].
VAR_013291

Secondary structure

.......................................................... 323
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P17516 [UniParc].

Last modified October 5, 2010. Version 3.
Checksum: E728CE4B420E8C58

FASTA32337,067
        10         20         30         40         50         60 
MDPKYQRVEL NDGHFMPVLG FGTYAPPEVP RNRAVEVTKL AIEAGFRHID SAYLYNNEEQ 

        70         80         90        100        110        120 
VGLAIRSKIA DGSVKREDIF YTSKLWCTFF QPQMVQPALE SSLKKLQLDY VDLYLLHFPM 

       130        140        150        160        170        180 
ALKPGETPLP KDENGKVIFD TVDLSATWEV MEKCKDAGLA KSIGVSNFNC RQLEMILNKP 

       190        200        210        220        230        240 
GLKYKPVCNQ VECHPYLNQS KLLDFCKSKD IVLVAHSALG TQRHKLWVDP NSPVLLEDPV 

       250        260        270        280        290        300 
LCALAKKHKQ TPALIALRYQ LQRGVVVLAK SYNEQRIREN IQVFEFQLTS EDMKVLDGLN 

       310        320 
RNYRYVVMDF LMDHPDYPFS DEY 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase."
Qin K.-N., New M.I., Cheng K.-C.
J. Steroid Biochem. Mol. Biol. 46:673-679(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ARG-250.
Tissue: Liver.
[2]"Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases."
Khanna M., Qin K.-N., Wang R.W., Cheng K.-C.
J. Biol. Chem. 270:20162-20168(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY, VARIANT ARG-250.
[3]"Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans."
Khanna M., Qin K.-N., Cheng K.-C.
J. Steroid Biochem. Mol. Biol. 53:41-46(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ARG-250.
[4]"Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver."
Kume T., Iwasa H., Shiraishi H., Yokoi T., Nagashima K., Otsuka M., Terada T., Takagi T., Hara A., Kamataki T.
Pharmacogenetics 9:763-771(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS CYS-145; ARG-250 AND VAL-311.
Tissue: Liver.
[5]"Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes."
Nishizawa M., Nakajima T., Yasuda K., Kanzaki H., Sasaguri Y., Watanabe K., Ito S.
Genes Cells 5:111-125(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT ARG-250.
Tissue: Liver.
[6]"Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution."
Dufort I., Labrie F., Luu-The V.
J. Clin. Endocrinol. Metab. 86:841-846(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION OF 3-ALPHA-HSD ACTIVITY, TISSUE SPECIFICITY, VARIANT ARG-250.
Tissue: Liver.
[7]"The DNA sequence and comparative analysis of human chromosome 10."
Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. expand/collapse author list , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS TYR-170 AND ARG-250.
Tissue: Liver.
[9]"Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase."
Winters C.J., Molowa D.T., Guzelian P.S.
Biochemistry 29:1080-1087(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-323, VARIANT ARG-250.
Tissue: Liver.
[10]"Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder."
Deyashiki Y., Ogasawara A., Nakayama T., Nakanishi M., Miyabe Y., Sato K., Hara A.
Biochem. J. 299:545-552(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 3-323, PROTEIN SEQUENCE OF 5-29; 76-131; 184-201 AND 271-294, VARIANT ARG-250.
Tissue: Liver.
[11]"Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase."
Binstock J.M., Iyer R.B., Hamby C.V., Fried V.A., Schwartz I.S., Weinstein B.I., Southren A.L.
Biochem. Biophys. Res. Commun. 187:760-766(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 40-54; 105-121; 162-175; 184-196; 277-291 AND 307-321, CHARACTERIZATION AS 3-ALPHA-HSD.
[12]"Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation."
Fluck C.E., Meyer-Boni M., Pandey A.V., Kempna P., Miller W.L., Schoenle E.J., Biason-Lauber A.
Am. J. Hum. Genet. 89:201-218(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN SRXY8.
[13]"Crystal structure of human 3-alpha hydroxysteroid/dihydrodiol dehydrogenase (AKR1C4) complexed with NADP+."
Structural genomics consortium (SGC)
Submitted (FEB-2006) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH NADP.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
PIRA57407.
S59620.
RefSeqNP_001809.3. NM_001818.3.
UniGeneHs.567245.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2FVLX-ray2.40A/B/C1-323[»]
ProteinModelPortalP17516.
SMRP17516. Positions 1-323.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107534. 1 interaction.
STRING9606.ENSP00000263126.

Chemistry

BindingDBP17516.
ChEMBLCHEMBL4999.
DrugBankDB00157. NADH.

PTM databases

PhosphoSiteP17516.

Polymorphism databases

DMDM308153631.

Proteomic databases

PaxDbP17516.
PRIDEP17516.

Protocols and materials databases

DNASU1109.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000263126; ENSP00000263126; ENSG00000198610.
ENST00000380448; ENSP00000369814; ENSG00000198610.
ENST00000583238; ENSP00000464270; ENSG00000266359.
GeneID1109.
KEGGhsa:1109.
UCSCuc001ihw.2. human.

Organism-specific databases

CTD1109.
GeneCardsGC10P005228.
HGNCHGNC:387. AKR1C4.
HPAHPA044720.
MIM600451. gene.
614279. phenotype.
neXtProtNX_P17516.
Orphanet90796. 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency.
PharmGKBPA24680.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0656.
HOGENOMHOG000250272.
HOVERGENHBG000020.
InParanoidP17516.
KOK00037.
K00089.
K00092.
K00212.
OMALLHFPMA.
OrthoDBEOG70KGQF.
PhylomeDBP17516.
TreeFamTF106492.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_116125. Disease.
SABIO-RKP17516.

Gene expression databases

ArrayExpressP17516.
BgeeP17516.
CleanExHS_AKR1C4.
GenevestigatorP17516.

Family and domain databases

Gene3D3.20.20.100. 1 hit.
InterProIPR001395. Aldo/ket_red.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase_subgr.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]
PANTHERPTHR11732. PTHR11732. 1 hit.
PfamPF00248. Aldo_ket_red. 1 hit.
[Graphical view]
PIRSFPIRSF000097. AKR. 1 hit.
PRINTSPR00069. ALDKETRDTASE.
SUPFAMSSF51430. SSF51430. 1 hit.
PROSITEPS00798. ALDOKETO_REDUCTASE_1. 1 hit.
PS00062. ALDOKETO_REDUCTASE_2. 1 hit.
PS00063. ALDOKETO_REDUCTASE_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP17516.
GeneWiki3-alpha-HSD.
GenomeRNAi1109.
NextBio4602.
PROP17516.
SOURCESearch...

Entry information

Entry nameAK1C4_HUMAN
AccessionPrimary (citable) accession number: P17516
Secondary accession number(s): Q5T6A3, Q8WW84, Q9NS54
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: October 5, 2010
Last modified: April 16, 2014
This is version 160 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 10

Human chromosome 10: entries, gene names and cross-references to MIM