Reviewed, UniProtKB/Swiss-Prot P17516 (AK1C4_HUMAN)

Names and origin

Protein names

Recommended name:
    Aldo-keto reductase family 1 member C4
    EC=1.1.1.-
Alternative name(s):
    Chlordecone reductase
      Short name=CDR
    EC=1.1.1.225
    3-alpha-hydroxysteroid dehydrogenase type I
    EC=1.1.1.50
    3-alpha-HSD1
    Dihydrodiol dehydrogenase 4
      Short name=DD-4
      Short name=DD4
    HAKRA

Gene names

Name:	AKR1C4
Synonyms:	CHDR

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	323 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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. Androsterone + NAD(P)+ = 5-alpha-androstane-3,17-dione + 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.
Sequence similarities	Belongs to the aldo/keto reductase family.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	androgen metabolic process Ref.2 Traceable author statement. Source: ProtInc bile acid and bile salt transport Ref.10 Traceable author statement. Source: ProtInc oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Ref.6 Inferred from Experiment. Source: Reactome
Molecular function	3-alpha-hydroxysteroid dehydrogenase (B-specific) activity Inferred from electronic annotation. Source: EC aldo-keto reductase activity Ref.2 Ref.6 Inferred from Experiment. Source: Reactome bile acid transmembrane transporter activity Ref.10 Traceable author statement. Source: ProtInc chlordecone reductase activity Inferred from electronic annotation. Source: EC electron carrier activity Ref.10 Traceable author statement. 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

Amino acid modifications

Modified residue

196

1

Phosphotyrosine Ref.12

Natural variations

Natural variant

135

1

G → E: dbSNP rs11253043.

VAR_028240

Natural variant

145

1

S → C: dbSNP rs3829125. Ref.4

VAR_013290

Natural variant

170

1

C → Y: dbSNP rs17851824. Ref.8

VAR_028241

Natural variant

250

1

R → Q: dbSNP rs4880718. Ref.7

VAR_028242

Natural variant

311

1

L → V: dbSNP rs17134592. Ref.4

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)
	P17516-1 [UniParc]. Last modified October 1, 1996. Version 2. Checksum: E72B028441C24358	FASTA	323	37,095
	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 LCALAKKHKR 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: 8274401] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. 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: 7650035] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY.
[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: 7626489] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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: 10634139] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS CYS-145 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: 10672042] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. 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: 11158055] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION OF 3-ALPHA-HSD ACTIVITY, TISSUE SPECIFICITY. 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: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLN-250.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT TYR-170. 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: 2187532] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-323. 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: 8172617] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 3-323, PROTEIN SEQUENCE OF 5-29; 76-131; 184-201 AND 271-294. 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: 1530633] [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]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-196, MASS SPECTROMETRY. Tissue: Epithelium.
[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

EMBLGenBankDDBJ

S68287 mRNA. Translation: AAD14010.1.
AB045829 mRNA. Translation: BAA99542.1.
AB031085 mRNA. Translation: BAA92885.1.
AB032163 Genomic DNA. Translation: BAA92893.1.
AL355303 Genomic DNA. Translation: CAI14202.1.
BC020744 mRNA. Translation: AAH20744.1.
M33375 mRNA. Translation: AAA35658.1. Different initiation.
D26125 mRNA. Translation: BAA05122.1.

IPI

IPI00289524.

PIR

A57407.
S59620.

RefSeq

NP_001809.2.

UniGene

Hs.567245

3D structure databases

PDBPDBe

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

ModBase

Search...

PTM databases

PhosphoSite

P17516.

Proteomic databases

PRIDE

P17516.

Genome annotation databases

Ensembl

ENSG00000198610. Homo sapiens. [Contig view]

GeneID

1109.

KEGG

hsa:1109.

UCSC

uc001ihw.1. human.

Organism-specific databases

GeneCards

GC10P005228.

H-InvDB

HIX0008607.

HGNC

HGNC:387. AKR1C4.

HPA

CAB006258.

MIM

600451. gene.

PharmGKB

PA24680.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P17516.

HOVERGEN

P17516.

Enzyme and pathway databases

BRENDA

1.1.1.225. 247.
1.1.1.50. 247.

Reactome

REACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P17516.

Bgee

P17516.

CleanEx

HS_AKR1C4.

GermOnline

ENSG00000198610. Homo sapiens.

Family and domain databases

InterPro

IPR001395. Aldo/ket_red.
IPR018170. Aldo/ket_reductase_CS.
[Graphical view]

Gene3D

G3DSA:3.20.20.100. Aldo/ket_red. 1 hit.

PANTHER

PTHR11732. Aldo/ket_red. 1 hit.

Pfam

PF00248. Aldo_ket_red. 1 hit.
[Graphical view]

ProDom

PD000288. Aldo/ket_red. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

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

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.

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 1, 1996
Last modified:	July 7, 2009
This is version 112 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)