Reviewed, UniProtKB/Swiss-Prot Q04828 (AK1C1_HUMAN)

Names and origin

Protein names

Recommended name:
    Aldo-keto reductase family 1 member C1
    EC=1.1.1.-
Alternative name(s):
    20-alpha-hydroxysteroid dehydrogenase
      Short name=20-alpha-HSD
    EC=1.1.1.149
    Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
    EC=1.3.1.20
    Dihydrodiol dehydrogenase 1/2
      Short name=DD1/DD2
    Chlordecone reductase homolog HAKRC
    High-affinity hepatic bile acid-binding protein
      Short name=HBAB

Gene names

Name:	AKR1C1
Synonyms:	DDH, DDH1

Organism

Homo sapiens (Human)

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	Converts progesterone to its inactive form, 20-alpha-dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation.
Catalytic activity	17-alpha,20-alpha-dihydroxypregn-4-en-3-one + NAD(P)(+) = 17-alpha-hydroxyprogesterone + NAD(P)H. Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) = catechol + NADPH.
Enzyme regulation	Inhibited by hexestrol with an IC50 of 9.5 µM, 1,10-phenanthroline with an IC50 of 55 µM, 1,7-phenanthroline with an IC50 of 72 µM, flufenamic acid with an IC50 of 6.0 µM, indomethacin with an IC50 of 140 µM, ibuprofen with an IC50 of 950 µM, lithocholic acid with an IC50 of 25 µM, ursodeoxycholic acid with an IC50 of 340 µM and chenodeoxycholic acid with an IC50 of 570 µM.
Subunit structure	Monomer.
Subcellular location	Cytoplasm.
Tissue specificity	Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain.
Sequence similarities	Belongs to the aldo/keto reductase family.
Biophysicochemical properties	Kinetic parameters: KM=5 µM for (s)-tetralol KM=38 µM for (s)-indan-1-ol KM=580 µM for benzene dihydrodiol KM=3 µM for 5-beta-pregnane-3-alpha,20-alpha-diol KM=3 µM for 5-beta-pregnan-20-alpha-ol-3-one KM=12 µM for 4-pregnen-20-alpha-ol-3-one KM=133 µM for 9-alpha,11-beta-PGF2 KM=2 µM for 5-beta-pregnan-3-alpha-ol-20-one KM=1 µM for 5-beta-androstane-3,17-dione KM=12 µM for PGD2 KM=0.6 µM for 20-alpha-hydroxyprogesterone (with NADH)

Ontologies

Keywords
Cellular component	Cytoplasm
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	bile acid and bile salt transport Ref.1 Traceable author statement. Source: UniProtKB bile acid metabolic process Ref.1 Inferred from direct assay. Source: UniProtKB cholesterol absorption Ref.1 Traceable author statement. Source: UniProtKB cholesterol homeostasis Ref.1 Traceable author statement. Source: UniProtKB oxidation reduction Ref.1 Inferred from direct assay. Source: UniProtKB protein homooligomerization Ref.1 Inferred from direct assay. Source: UniProtKB xenobiotic metabolic process Ref.1 Non-traceable author statement. Source: UniProtKB
Cellular component	cytosol Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	20-alpha-hydroxysteroid dehydrogenase activity Inferred from electronic annotation. Source: EC 3-alpha-hydroxysteroid dehydrogenase (B-specific) activity Ref.1 Inferred from direct assay. Source: UniProtKB aldo-keto reductase activity Traceable author statement. Source: UniProtKB bile acid binding Ref.1 Inferred from direct assay. Source: UniProtKB trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity Ref.1 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 C1

PRO_0000124633

Regions

Nucleotide binding

13 – 22

10

NADP Potential

Nucleotide binding

217 – 280

64

NADP By similarity

Sites

Active site

55

1

Proton donor By similarity

Binding site

117

1

Substrate By similarity

Binding site

304

1

Progesterone

Site

54

1

Important for substrate specificity By similarity

Site

84

1

Lowers pKa of active site Tyr By similarity

Site

222

1

May be involved in the mediating step between the transformation of progesterone and the release of the cofactor

Experimental info

Mutagenesis

127

1

E → D: 30-fold decrease in k(cat)/K(m) value for progesterone reduction; no effect on the K(m) value

Mutagenesis

222

1

H → I: Marked decrease in k(cat)/K(m) value for progesterone; 24-fold decrease for progesterone reduction; 18-fold decrease for 20alpha-OHProg oxidation. 95-fold decrease in K(m) value for NADPH

Mutagenesis

222

1

H → S: Marked decrease in k(cat)/K(m) value for progesterone; 10-fold decrease for progesterone reduction; 3-fold decrease for 20alpha-OHProg oxidation. 10-fold decrease in K(m) value for NADPH

Mutagenesis

304

1

R → L: 70-fold decrease in progesterone reduction. No effect on DHT reduction

Mutagenesis

305

1

Y → F: No effect on progesterone reduction

Mutagenesis

307

1

T → V: No effect on progesterone reduction

Mutagenesis

309

1

D → V: No effect on progesterone reduction

Sequence conflict

3

1

S → A Ref.4

Sequence conflict

95

1

V → D in AAD14012. Ref.4 Ref.10

Sequence conflict

158

1

G → E in AAD14012. Ref.4 Ref.10

Sequence conflict

171 – 172

2

RQ → ST in AAD14012. Ref.4 Ref.10

Sequence conflict

183 – 184

2

KY → QV in AAD14012. Ref.4 Ref.10

Sequence conflict

222

1

H → L in AAD14012. Ref.4 Ref.10

Sequence conflict

319

1

F → I in AAD14012. Ref.4 Ref.10

Secondary structure

1

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323

Helix Strand Turn

Details...

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 – 70

13

Helix

76 – 78

3

Beta strand

80 – 85

6

Helix

87 – 89

3

Helix

92 – 106

15

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)
	Q04828-1 [UniParc]. Last modified October 1, 1993. Version 1. Checksum: 9CB215478FBD29D5	FASTA	323	36,788
	10 20 30 40 50 60 MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEATKL AIEAGFRHID SAHLYNNEEQ 70 80 90 100 110 120 VGLAIRSKIA DGSVKREDIF YTSKLWCNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV 130 140 150 160 170 180 SVKPGEEVIP KDENGKILFD TVDLCATWEA VEKCKDAGLA KSIGVSNFNR RQLEMILNKP 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]	"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: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"Genomic organization and chromosomal localization of a novel human hepatic dihydrodiol dehydrogenase with high affinity bile acid binding." Lou H., Hammond L., Sharma V., Sparkes R.S., Lusis A.J., Stolz A. J. Biol. Chem. 269:8416-8422(1994) [PubMed: 8132567] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Blood.
[3]	"Regulation of human dihydrodiol dehydrogenase by Michael acceptor xenobiotics." Ciaccio P.J., Jaiswal A.K., Tew K.D. J. Biol. Chem. 269:15558-15562(1994) [PubMed: 7515059] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Colon.
[4]	"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]. 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]	"Characterization of a human 20alpha-hydroxysteroid dehydrogenase." Zhang Y., Dufort I., Rheault P., Luu-The V. J. Mol. Endocrinol. 25:221-228(2000) [PubMed: 11013348] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY. Tissue: Skin fibroblast.
[7]	"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].
[8]	"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].
[9]	"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 Testis.
[10]	"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] OF 4-323. Tissue: Liver.
[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 10-31; 40-61; 69-126; 137-153; 162-206; 209-230; 250-267; 271-289 AND 295-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[12]	"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 18-323, PROTEIN SEQUENCE OF 18-31; 105-131; 176-193 AND 271-294. Tissue: Liver.
[13]	"Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids." Couture J.-F., Legrand P., Cantin L., Luu-The V., Labrie F., Breton R. J. Mol. Biol. 331:593-604(2003) [PubMed: 12899831] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH NADP AND 20ALPHA-HYDROXY-PROGESTERONE, MUTAGENESIS OF GLU-127; HIS-222; ARG-304; TYR-305; THR-307 AND ASP-309.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	M86609 mRNA. Translation: AAB02880.1. U05861