Reviewed, UniProtKB/Swiss-Prot P52895 (AK1C2_HUMAN)

Names and origin

Protein names

Recommended name:
    Aldo-keto reductase family 1 member C2
    EC=1.-.-.-
Alternative name(s):
    Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
    EC=1.3.1.20
    Type III 3-alpha-hydroxysteroid dehydrogenase
    EC=1.1.1.213
    3-alpha-HSD3
    Dihydrodiol dehydrogenase 2
      Short name=DD-2
      Short name=DD2
    Dihydrodiol dehydrogenase/bile acid-binding protein
      Short name=DD/BABP
    Chlordecone reductase homolog HAKRD

Gene names

Name:	AKR1C2
Synonyms:	DDH2

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.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability. Ref.11
Catalytic activity	Trans-1,2-dihydrobenzene-1,2-diol + NADP+ = catechol + NADPH. Ref.11 Androsterone + NAD(P)+ = 5-alpha-androstane-3,17-dione + NAD(P)H. Ref.11
Enzyme regulation	Inhibited by hexestrol with an IC50 of 2.8 µM, 1,10-phenanthroline with an IC50 of 2100 µM, 1,7-phenanthroline with an IC50 of 1500 µM, flufenamic acid with an IC50 of 0.9 µM, indomethacin with an IC50 of 75 µM, ibuprofen with an IC50 of 6.9 µM, lithocholic acid with an IC50 of 0.07 µM, ursodeoxycholic acid with an IC50 of 0.08 µM and chenodeoxycholic acid with an IC50 of 0.13 µM. Ref.11
Subcellular location	Cytoplasm Potential.
Sequence similarities	Belongs to the aldo/keto reductase family.
Biophysicochemical properties	Kinetic parameters: KM=260 µM for (s)-tetralol KM=520 µM for (s)-indan-1-ol KM=5000 µM for benzene dihydrodiol KM=1 µM for 5-beta-pregnane-3-alpha,20-alpha-diol KM=208 µM for 9-alpha,11-beta-PGF2 KM=0.3 µM for 5-beta-androstane-3,17-dione KM=79 µM for PGD2

Ontologies

Keywords
Biological process	Lipid metabolism Steroid metabolism
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	digestion Ref.11 Inferred from direct assay. Source: UniProtKB oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW prostaglandin metabolic process Ref.11 Inferred from direct assay. Source: UniProtKB steroid metabolic process Ref.11 Inferred from direct assay. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	3-alpha-hydroxysteroid dehydrogenase (A-specific) activity Inferred from electronic annotation. Source: EC bile acid binding Ref.11 Inferred from direct assay. Source: UniProtKB trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity Ref.11 Inferred from direct assay. 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 C2

PRO_0000124637

Regions

Nucleotide binding

216 – 280

65

NADP

Sites

Active site

55

1

Proton donor

Binding site

117

1

Substrate

Site

84

1

Lowers pKa of active site Tyr By similarity

Amino acid modifications

Modified residue

4

1

N6-acetyllysine Ref.14

Modified residue

161

1

N6-acetyllysine Ref.14

Modified residue

179

1

N6-acetyllysine Ref.14

Natural variations

Natural variant

46

1

F → Y: dbSNP rs2854482. Ref.3

VAR_048216

Natural variant

172

1

L → Q: dbSNP rs11474.

VAR_014748

Experimental info

Sequence conflict

76

1

R → S AA sequence Ref.12

Sequence conflict

87

1

S → C AA sequence Ref.12

Sequence conflict

93

1

E → EE AA sequence Ref.12

Sequence conflict

111

1

V → A in AAB38486. Ref.3

Sequence conflict

164

1

G → R in BAF82993. Ref.7

Sequence conflict

179

1

K → E in AAD14013. Ref.1

Sequence conflict

179

1

K → E in AAB38486. Ref.3

Sequence conflict

185

1

K → E in AAD14013. Ref.1

Sequence conflict

185

1

K → E in AAB38486. Ref.3

Sequence conflict

188

1

C → H AA sequence Ref.12

Sequence conflict

193

1

C → H AA sequence Ref.12

Sequence conflict

319

1

F → I in AAD14013. Ref.1

Sequence conflict

319

1

F → I in AAB38486. Ref.3

Secondary structure

1

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323

Helix Strand Turn

Details...

Beta strand

7 – 9

3

Beta strand

15 – 22

8

Helix

32 – 44

13

Beta strand

48 – 50

3

Helix

53 – 55

3

Helix

58 – 70

13

Helix

76 – 78

3

Beta strand

80 – 85

6

Helix

87 – 89

3

Helix

92 – 94

3

Helix

95 – 106

12

Beta strand

111 – 116

6

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 – 248

10

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

Sequences

	Sequence		Length	Mass (Da)
	P52895-1 [UniParc]. Last modified May 10, 2002. Version 3. Checksum: 0D7B6F983FCE85E1	FASTA	323	36,735
	10 20 30 40 50 60 MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEAVKL AIEAGFHHID SAHVYNNEEQ 70 80 90 100 110 120 VGLAIRSKIA DGSVKREDIF YTSKLWSNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV 130 140 150 160 170 180 SVKPGEEVIP KDENGKILFD TVDLCATWEA MEKCKDAGLA KSIGVSNFNH RLLEMILNKP 190 200 210 220 230 240 GLKYKPVCNQ VECHPYFNQR KLLDFCKSKD IVLVAYSALG SHREEPWVDP NSPVLLEDPV 250 260 270 280 290 300 LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTS EEMKAIDGLN 310 320 RNVRYLTLDI FAGPPNYPFS 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]	"cDNA and deduced amino acid sequences of a human colon dihydrodiol dehydrogenase." Ciaccio P.J., Tew K.D. Biochim. Biophys. Acta 1186:129-132(1994) [PubMed: 8011662] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Colon.
[3]	"Structure of a gene coding for human dihydrodiol dehydrogenase/bile acid-binding protein." Qin K.-N., Khanna M., Cheng K.-C. Gene 149:357-361(1994) [PubMed: 7959017] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT TYR-46.
[4]	"Molecular cloning of human type 3 3 alpha-hydroxysteroid dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase by seven amino acids." Dufort I., Soucy P., Labrie F., Luu-The V. Biochem. Biophys. Res. Commun. 228:474-479(1996) [PubMed: 8920937] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Prostate.
[5]	"Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA." Shiraishi H., Ishikura S., Matsuura K., Deyashiki Y., Ninomiya M., Sakai S., Hara A. Biochem. J. 334:399-405(1998) [PubMed: 9716498] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[6]	"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 [GENOMIC DNA / MRNA]. Tissue: Liver.
[7]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Tongue.
[8]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[9]	"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].
[10]	"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]. Tissue: Lung and Urinary bladder.
[11]	"Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells." Hara A., Matsuura K., Tamada Y., Sato K., Miyabe Y., Deyashiki Y., Ishida N. Biochem. J. 313:373-376(1996) [PubMed: 8573067] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-31; 40-62; 69-100; 105-131; 137-153; 162-206; 209-231; 250-269 AND 271-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[12]	"cDNA cloning and expression of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family." Stolz A., Hammond L., Lou H., Takikawa H., Ronk M., Shively J.E. J. Biol. Chem. 268:10448-10457(1993) [PubMed: 8486699] [Abstract] Cited for: PROTEIN SEQUENCE OF 10-29; 40-55; 76-101; 105-128; 137-146; 162-197; 208-223; 259-270 AND 305-322. Tissue: Liver.
[13]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[14]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-4; LYS-161 AND LYS-179, MASS SPECTROMETRY.
[15]	"Crystal structure of human type III 3alpha-hydroxysteroid dehydrogenase/bile acid binding protein complexed with NADP(+) and ursodeoxycholate." Jin Y., Stayrook S.E., Albert R.H., Palackal N.T., Penning T.M., Lewis M. Biochemistry 40:10161-10168(2001) [PubMed: 11513593] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH NADP AND URSODEOXYCHOLATE.
[16]	"Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution." Nahoum V., Gangloff A., Legrand P., Zhu D.-W., Cantin L., Zhorov B.S., Luu-The V., Labrie F., Breton R., Lin S.X. J. Biol. Chem. 276:42091-42098(2001) [PubMed: 11514561] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) IN COMPLEX WITH NADP AND TESTOSTERONE.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

S68330 mRNA. Translation: AAD14013.1.
U05598 mRNA. Translation: AAA20937.1.
L32592 Genomic DNA. Translation: AAB38486.1.
AB021654 mRNA. Translation: BAA36169.1.
AB031084 mRNA. Translation: BAA92884.1.
AB032153 Genomic DNA. Translation: BAA92891.1.
AK290304 mRNA. Translation: BAF82993.1.
BT006653 mRNA. Translation: AAP35299.1.
AL391427, AL713867 Genomic DNA. Translation: CAI14726.1.
AL713867, AL391427 Genomic DNA. Translation: CAI16408.1.
BC007024 mRNA. Translation: AAH07024.1.
BC063574 mRNA. Translation: AAH63574.1.

IPI

IPI00005668.

PIR

I73676.
JC5240.
S61516.

RefSeq

NP_001345.1.
NP_995317.1.

UniGene

Hs.460260
Hs.567256

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IHI	X-ray	3.00	A/B	1-323	[»]
1J96	X-ray	1.25	A/B	2-323	[»]
1XJB	X-ray	1.90	A/B	2-323	[»]
2HDJ	X-ray	2.00	A/B	1-323	[»]
2IPJ	X-ray	1.80	A/B	3-323	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P52895.

PTM databases

PhosphoSite

P52895.

Proteomic databases

PRIDE

P52895.

Genome annotation databases

Ensembl

ENST00000380753; ENSP00000370129; ENSG00000151632; Homo sapiens. [Genome view]
ENST00000407674; ENSP00000385221; ENSG00000151632; Homo sapiens. [Genome view]
ENST00000455179; ENSP00000397161; ENSG00000151632; Homo sapiens. [Genome view]

GeneID

1646.

UCSC

uc001ihs.1. human.

Organism-specific databases

CTD

1646.

GeneCards

GC10M005021.

H-InvDB

HIX0008604.

HGNC

HGNC:385. AKR1C2.

MIM

600450. gene.

PharmGKB

PA24678.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG16138.

HOGENOM

HBG605727.

HOVERGEN

P52895.

InParanoid

P52895.

OMA

EDMETIN.

OrthoDB

EOG9B2WGJ.

PhylomeDB

P52895.

Enzyme and pathway databases

BRENDA

1.1.1.213. 247.
1.3.1.20. 247.

Gene expression databases

ArrayExpress

P52895.

Bgee

P52895.

CleanEx

HS_AKR1C2.

Genevestigator

P52895.

GermOnline

ENSG00000151632. Homo sapiens.

Family and domain databases

InterPro

IPR001395. Aldo/ket_red.
IPR018170. Aldo/ket_reductase_CS.
IPR020471. Aldo/keto_reductase_sg.
[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]

PRINTS

PR00069. ALDKETRDTASE.

PROSITE

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

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.
DB01586. Ursodeoxycholic acid.

NextBio

6772.

SOURCE

Search...

Entry information

Entry name

AK1C2_HUMAN

Accession

Primary (citable) accession number: P52895
Secondary accession number(s): A8K2N9 , Q14133, Q5SR16, Q7M4N1, Q96A71

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	May 10, 2002
Last modified:	February 9, 2010
This is version 101 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.