P17516 (AK1C4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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=1.1.1.50
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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	323 AA.
Sequence status	Complete.
Protein existence	Evidence 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 component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	androgen metabolic process Traceable author statement Ref.2. Source: ProtInc bile acid biosynthetic 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
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	aldo-keto reductase (NADP) activity Traceable author statement Ref.2. Source: ProtInc androsterone dehydrogenase (B-specific) activity Inferred from electronic annotation. Source: EC 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: 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 323

323

Aldo-keto reductase family 1 member C4

PRO_0000124640

Regions

Nucleotide binding

13 – 22

10

NADP By similarity

Nucleotide binding

217 – 280

64

NADP

Sites

Active site

55

1

Proton donor By similarity

Binding site

50

1

NADP

Binding site

117

1

NADP By similarity

Binding site

117

1

Substrate By similarity

Site

54

1

Important for substrate specificity By similarity

Site

84

1

Lowers pKa of active site Tyr By similarity

Natural variations

Natural variant

135

1

G → E.
Corresponds to variant rs11253043 [ dbSNP | Ensembl ].

VAR_028240

Natural variant

145

1

S → C. Ref.4
Corresponds to variant rs3829125 [ dbSNP | Ensembl ].

VAR_013290

Natural variant

170

1

C → Y. Ref.8
Corresponds to variant rs17851824 [ dbSNP | Ensembl ].

VAR_028241

Natural variant

250

1

Q → 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 variant

311

1

L → V. Ref.4
Corresponds to variant rs17134592 [ dbSNP | Ensembl ].

VAR_013291

Secondary structure

1

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323

Helix Strand Turn

Details...

Helix

3 – 5

3

Beta strand

7 – 9

3

Beta strand

15 – 22

8

Helix

33 – 44

12

Beta strand

48 – 50

3

Helix

53 – 55

3

Helix

58 – 71

14

Helix

76 – 78

3

Beta strand

80 – 85

6

Helix

87 – 89

3

Helix

92 – 106

15

Beta strand

111 – 117

7

Beta strand

124 – 126

3

Helix

144 – 156

13

Beta strand

159 – 167

9

Helix

170 – 177

8

Beta strand

187 – 192

6

Helix

200 – 208

9

Beta strand

212 – 217

6

Turn

225 – 227

3

Helix

235 – 237

3

Helix

239 – 247

9

Helix

252 – 262

11

Beta strand

266 – 270

5

Helix

274 – 280

7

Helix

281 – 285

5

Helix

290 – 297

8

Helix

309 – 311

3

Beta strand

318 – 321

4

Sequences

	Sequence		Length	Mass (Da)
	P17516 [UniParc]. Last modified October 5, 2010. Version 3. Checksum: E728CE4B420E8C58	FASTA	323	37,067
	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

References

	« Hide 'large scale' referencesShow '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. , 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.

IPI

IPI00289524.

PIR

A57407.
S59620.

RefSeq

NP_001809.3. NM_001818.3.

UniGene

Hs.567245.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2FVL	X-ray	2.40	A/B/C	1-323	[»]

ProteinModelPortal

P17516.

SMR

P17516. Positions 1-323.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000263126.

PTM databases

PhosphoSite

P17516.

Polymorphism databases

DMDM

308153631.

Proteomic databases

PaxDb

P17516.

PRIDE

P17516.

Protocols and materials databases

DNASU

1109.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263126; ENSP00000263126; ENSG00000198610.
ENST00000380448; ENSP00000369814; ENSG00000198610.
ENST00000579965; ENSP00000463709; ENSG00000266359.
ENST00000583238; ENSP00000464270; ENSG00000266359.

GeneID

1109.

KEGG

hsa:1109.

UCSC

uc001ihw.2. human.

Organism-specific databases

CTD

1109.

GeneCards

GC10P005228.

HGNC

HGNC:387. AKR1C4.

HPA

HPA044720.

MIM

600451. gene.
614279. phenotype.

neXtProt

NX_P17516.

Orphanet

90796. 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency.

PharmGKB

PA24680.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0656.

HOGENOM

HOG000250272.

HOVERGEN

HBG000020.

InParanoid

P17516.

KO

K00037.
K00089.
K00092.
K00212.

OMA

NNGFHEP.

OrthoDB

EOG4Q2DG2.

PhylomeDB

P17516.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

P17516.

Gene expression databases

ArrayExpress

P17516.

Bgee

P17516.

CleanEx

HS_AKR1C4.

Genevestigator

P17516.

GermOnline

ENSG00000198610. Homo sapiens.

Family and domain databases

Gene3D

3.20.20.100. 1 hit.

InterPro

IPR001395. Aldo/ket_red.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase_subgr.
IPR023210. NADP_OxRdtase_dom.
[Graphical view]

PANTHER

PTHR11732. PTHR11732. 1 hit.

Pfam

PF00248. Aldo_ket_red. 1 hit.
[Graphical view]

PIRSF

PIRSF000097. AKR. 1 hit.

PRINTS

PR00069. ALDKETRDTASE.

SUPFAM

SSF51430. Aldo/ket_red. 1 hit.

PROSITE

PS00798. ALDOKETO_REDUCTASE_1. 1 hit.
PS00062. ALDOKETO_REDUCTASE_2. 1 hit.
PS00063. ALDOKETO_REDUCTASE_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P17516.

ChEMBL

CHEMBL4999.

DrugBank

DB00157. NADH.

EvolutionaryTrace

P17516.

GenomeRNAi

1109.

NextBio

4602.

SOURCE

Search...

Entry information

Entry name

AK1C4_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 151 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.