Reviewed, UniProtKB/Swiss-Prot P42330 (AK1C3_HUMAN)

Names and origin

Protein names

Recommended name:
    Aldo-keto reductase family 1 member C3
    EC=1.-.-.-
Alternative name(s):
    Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
    EC=1.3.1.20
    3-alpha-hydroxysteroid dehydrogenase type 2
      Short name=3-alpha-HSD type 2
    EC=1.1.1.213
    3-alpha-HSD type II, brain
    Testosterone 17-beta-dehydrogenase 5
    EC=1.1.1.63
    EC=1.1.1.64
    17-beta-hydroxysteroid dehydrogenase type 5
      Short name=17-beta-HSD 5
    Prostaglandin F synthase
      Short name=PGFS
    EC=1.1.1.188
    Dihydrodiol dehydrogenase type I
    Dihydrodiol dehydrogenase 3
      Short name=DD-3
      Short name=DD3
    Chlordecone reductase homolog HAKRb
    HA1753

Gene names

Name:	AKR1C3
Synonyms:	DDH1, HSD17B5, KIAA0119, PGFS

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	Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.
Catalytic activity	Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) = catechol + NADPH. Androsterone + NAD(P)(+) = 5-alpha-androstane-3,17-dione + NAD(P)H. (5Z,13E)-(15S)-9-alpha,11-alpha,15-trihydroxyprosta-5,13-dienoate + NADP(+) = (5Z,13E)-(15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate + NADPH. Testosterone + NAD(+) = androst-4-ene-3,17-dione + NADH. Testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH.
Enzyme regulation	Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs).
Subcellular location	Cytoplasm.
Tissue specificity	Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. The dominant HSD in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.
Sequence similarities	Belongs to the aldo/keto reductase family.
Biophysicochemical properties	Kinetic parameters: KM=142.1 µM for progesterone KM=2.37 µM for 5-alpha-dihydrotestosterone KM=1.0 µM for androstanediol Vmax=20.1 nmol/min/mg enzyme with progesterone as substrate Vmax=1.8 nmol/min/mg enzyme with 5-alpha-dihydrotestosterone as substrate Vmax=4.4 nmol/min/mg enzyme with androstanediol as substrate

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	NAD NADP
Molecular function	Oxidoreductase
Technical term	3D-structure
Gene Ontology (GO)
Biological process	oxidation reduction Traceable author statement. Source: UniProtKB prostaglandin metabolic process Traceable author statement. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	3-alpha-hydroxysteroid dehydrogenase (A-specific) activity Inferred from electronic annotation. Source: EC aldo-keto reductase activity Traceable author statement. Source: UniProtKB prostaglandin-F synthase activity Inferred from electronic annotation. Source: EC testosterone 17-beta-dehydrogenase (NADP+) activity Inferred from electronic annotation. Source: EC testosterone 17-beta-dehydrogenase activity Inferred from electronic annotation. Source: EC trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity Inferred from electronic annotation. Source: EC
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 C3

PRO_0000124638

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

Site

54

1

Important for substrate specificity By similarity

Site

84

1

Lowers pKa of active site Tyr By similarity

Site

227

1

Involved in ligand recognition and product release

Site

306

1

Involved in ligand recognition and product release

Natural variations

Natural variant

5

1

Q → H: dbSNP rs12529.

VAR_013288

Natural variant

66

1

R → Q: dbSNP rs35961894.

VAR_032767

Natural variant

170

1

R → C: dbSNP rs35575889.

VAR_032768

Natural variant

175

1

M → I No effect on 17beta-HSD activity. dbSNP rs1131132.

VAR_013289

Natural variant

180

1

P → S: dbSNP rs34186955.

VAR_032769

Experimental info

Mutagenesis

75

1

K → E: No effect on 17beta-HSD activity

Sequence conflict

3

1

S → P Ref.3

Sequence conflict

6

1

Q → K Ref.3

Sequence conflict

38

1

T → S in AAF07272. Ref.6

Sequence conflict

75

1

K → E in AAD14011. Ref.1

Sequence conflict

75

1

K → E Ref.3

Sequence conflict

75

1

K → M in AAB41916. Ref.2

Sequence conflict

89

1

F → S in AAF07272. Ref.6

Sequence conflict

270

1

K → R in AAF07272. Ref.6

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 – 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 – 312

4

Sequences

	Sequence		Length	Mass (Da)
	P42330-1 [UniParc]. Last modified May 10, 2002. Version 3. Checksum: A152E37F6990C5CB	FASTA	323	36,844
	10 20 30 40 50 60 MDSKQQCVKL NDGHFMPVLG FGTYAPPEVP RSKALEVTKL AIEAGFRHID SAHLYNNEEQ 70 80 90 100 110 120 VGLAIRSKIA DGSVKREDIF YTSKLWSTFH RPELVRPALE NSLKKAQLDY VDLYLIHSPM 130 140 150 160 170 180 SLKPGEELSP TDENGKVIFD IVDLCTTWEA MEKCKDAGLA KSIGVSNFNR RQLEMILNKP 190 200 210 220 230 240 GLKYKPVCNQ VECHPYFNRS KLLDFCKSKD IVLVAYSALG SQRDKRWVDP NSPVLLEDPV 250 260 270 280 290 300 LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTA EDMKAIDGLD 310 320 RNLHYFNSDS FASHPNYPYS 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], VARIANT ILE-175. 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], CHARACTERIZATION, TISSUE SPECIFICITY, VARIANT ILE-175.
[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], VARIANT HIS-5. Tissue: Liver.
[4]	"Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution." Lin H.-K., Jez J.M., Schlegel B.P., Peehl D.M., Pachter J.A., Penning T.M. Mol. Endocrinol. 11:1971-1984(1997) [PubMed: 9415401] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, TISSUE SPECIFICITY. Tissue: Prostate.
[5]	"cDNA cloning, expression and characterization of human prostaglandin F synthase." Suzuki-Yamamoto T., Nishizawa M., Fukui M., Okuda-Ashitaka E., Nakajima T., Ito S., Watanabe K. FEBS Lett. 462:335-340(1999) [PubMed: 10622721] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], CHARACTERIZATION, TISSUE SPECIFICITY. Tissue: Lung.
[6]	"Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes." Griffin L.D., Mellon S.H. Proc. Natl. Acad. Sci. U.S.A. 96:13512-13517(1999) [PubMed: 10557352] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY. Tissue: Brain.
[7]	"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]. Tissue: Liver.
[8]	"Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3)." Penning T.M., Burczynski M.E., Jez J.M., Lin H.-K., Ma H., Moore M., Ratnam K., Palackal N. Mol. Cell. Endocrinol. 171:137-149(2001) [PubMed: 11165022] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, TISSUE SPECIFICITY. Tissue: Prostate.
[9]	"Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1." Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S., Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N. DNA Res. 2:37-43(1995) [PubMed: 7788527] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow.
[10]	"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], VARIANT HIS-5.
[11]	"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 HIS-5.
[12]	"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 HIS-5. Tissue: Colon and Urinary bladder.
[13]	"Characteristics of a highly labile human type 5 17beta-hydroxysteroid dehydrogenase." Dufort I., Rheault P., Huang X.-F., Soucy P., Luu-The V. Endocrinology 140:568-574(1999) [PubMed: 9927279] [Abstract] Cited for: CHARACTERIZATION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANT ILE-175, MUTAGENESIS OF LYS-75.
[14]	"Crystal structure of human prostaglandin F synthase (AKR1C3)." Komoto J., Yamada T., Watanabe K., Takusagawa F. Biochemistry 43:2188-2198(2004) [PubMed: 14979715] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH PROSTAGLANDIN H(2); NADPH AND RUTIN.
[15]	"Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin." Lovering A.L., Ride J.P., Bunce C.M., Desmond J.C., Cummings S.M., White S.A. Cancer Res. 64:1802-1810(2004) [PubMed: 14996743] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH FLUFENAMIC ACID AND INDOMETHACIN.
[16]	"Crystal structures of the multispecific 17beta-hydroxysteroid dehydrogenase type 5: critical androgen regulation in human peripheral tissues." Qiu W., Zhou M., Labrie F., Lin S.-X.