Reviewed, UniProtKB/Swiss-Prot P51857 (AK1D1_HUMAN)

Names and origin

Protein names

Recommended name:
    3-oxo-5-beta-steroid 4-dehydrogenase
    EC=1.3.1.3
Alternative name(s):
    Delta(4)-3-ketosteroid 5-beta-reductase
    Delta(4)-3-oxosteroid 5-beta-reductase
    Aldo-keto reductase family 1 member D1

Gene names

Name:	AKR1D1
Synonyms:	SRD5B1

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	326 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.
Catalytic activity	5-beta-cholestan-3-one + NADP+ = cholest-4-en-3-one + NADPH. 17,21-dihydroxy-5-beta-pregnane-3,11,20-trione + NADP+ = cortisone.
Enzyme regulation	Subject to inhibition by high substrate concentrations. Inhibited by testosterone concentrations above 10 µM. Ref.7
Subcellular location	Cytoplasm.
Tissue specificity	Highly expressed in liver. Expressed in testis and weakly in colon. Ref.2
Involvement in disease	Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:235555]; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine. Ref.8 Ref.9
Sequence similarities	Belongs to the aldo/keto reductase family.
Biophysicochemical properties	Kinetic parameters: KM=2.7 µM for testosterone

Ontologies

Keywords
Biological process	Bile acid catabolism Lipid metabolism Steroid metabolism
Cellular component	Cytoplasm
Disease	Disease mutation Intrahepatic cholestasis
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	C21-steroid hormone metabolic process Ref.1 Inferred from direct assay. Source: UniProtKB androgen metabolic process Ref.1 Inferred from direct assay. Source: UniProtKB bile acid biosynthetic process Ref.1 Inferred from direct assay. Source: UniProtKB bile acid catabolic process Inferred from electronic annotation. Source: UniProtKB-KW cholesterol catabolic process Ref.1 Inferred from direct assay. Source: UniProtKB digestion Ref.1 Inferred from direct assay. Source: UniProtKB oxidation reduction Ref.1 Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	aldo-keto reductase activity Ref.1 Inferred from Experiment. Source: Reactome delta4-3-oxosteroid 5beta-reductase activity Inferred from electronic annotation. Source: EC steroid binding Ref.1 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 – 326

326

3-oxo-5-beta-steroid 4-dehydrogenase

PRO_0000124669

Regions

Nucleotide binding

169 – 170

2

NADP

Nucleotide binding

220 – 224

5

NADP

Nucleotide binding

273 – 283

11

NADP

Sites

Active site

58

1

Proton donor

Binding site

53

1

NADP

Binding site

193

1

NADP

Binding site

230

1

Substrate

Natural variations

Natural variant

106

1

L → F in CBAS2. Ref.8

VAR_033007

Natural variant

133

1

P → R in CBAS2. Ref.9

VAR_044430

Natural variant

198

1

P → L in CBAS2. Ref.8

VAR_033008

Natural variant

261

1

R → C in CBAS2. Ref.9

VAR_044431

Experimental info

Mutagenesis

58

1

Y → A: Loss of activity. Ref.7

Mutagenesis

120

1

E → A: Loss of activity. Ref.7

Sequence conflict

14

1

D → V in BAF82114. Ref.3

Secondary structure

1

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326

Helix Strand Turn

Details...

Beta strand

9 – 11

3

Beta strand

17 – 21

5

Helix

29 – 31

3

Helix

36 – 47

12

Beta strand

51 – 53

3

Helix

56 – 58

3

Helix

61 – 73

13

Helix

79 – 81

3

Beta strand

83 – 88

6

Helix

90 – 92

3

Helix

95 – 97

3

Helix

98 – 109

12

Beta strand

114 – 120

7

Helix

147 – 159

13

Beta strand

162 – 170

9

Helix

173 – 180

8

Beta strand

191 – 195

5

Helix

203 – 211

9

Beta strand

215 – 220

6

Turn

228 – 230

3

Helix

238 – 240

3

Helix

242 – 251

10

Helix

255 – 265

11

Helix

277 – 284

8

Helix

293 – 300

8

Helix

312 – 314

3

Beta strand

321 – 324

4

Sequences

	Sequence		Length	Mass (Da)
	P51857-1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 1FE02B95398A0A6F	FASTA	326	37,377
	10 20 30 40 50 60 MDLSAASHRI PLSDGNSIPI IGLGTYSEPK STPKGACATS VKVAIDTGYR HIDGAYIYQN 70 80 90 100 110 120 EHEVGEAIRE KIAEGKVRRE DIFYCGKLWA TNHVPEMVRP TLERTLRVLQ LDYVDLYIIE 130 140 150 160 170 180 VPMAFKPGDE IYPRDENGKW LYHKSNLCAT WEAMEACKDA GLVKSLGVSN FNRRQLELIL 190 200 210 220 230 240 NKPGLKHKPV SNQVECHPYF TQPKLLKFCQ QHDIVITAYS PLGTSRNPIW VNVSSPPLLK 250 260 270 280 290 300 DALLNSLGKR YNKTAAQIVL RFNIQRGVVV IPKSFNLERI KENFQIFDFS LTEEEMKDIE 310 320 ALNKNVRFVE LLMWRDHPEY PFHDEY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of cDNA of human delta 4-3-oxosteroid 5 beta-reductase and substrate specificity of the expressed enzyme." Kondo K.-H., Kai M.-H., Setoguchi Y., Eggertsen G., Sjoeblom P., Setoguchi T., Okuda K., Bjoerkhem I. Eur. J. Biochem. 219:357-363(1994) [PubMed: 7508385] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"Genomic organization of a human 5beta-reductase and its pseudogene and substrate selectivity of the expressed enzyme." Charbonneau A., The V.L. Biochim. Biophys. Acta 1517:228-235(2001) [PubMed: 11342103] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], CHARACTERIZATION, TISSUE SPECIFICITY.
[3]	"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: Mammary gland.
[4]	"Human chromosome 7: DNA sequence and biology." Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C. Science 300:767-772(2003) [PubMed: 12690205] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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].
[7]	"Crystal structure of human liver delta(4)-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis." Di Costanzo L., Drury J.E., Penning T.M., Christianson D.W. J. Biol. Chem. 283:16830-16839(2008) [PubMed: 18407998] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEXES WITH NADP; TESTOSTRONE; PROGESTERONE AND CORTISONE, MUTAGENESIS OF TYR-58 AND GLU-120, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[8]	"Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy." Lemonde H.A., Custard E.J., Bouquet J., Duran M., Overmars H., Scambler P.J., Clayton P.T. Gut 52:1494-1499(2003) [PubMed: 12970144] [Abstract] Cited for: VARIANTS CBAS2 PHE-106 AND LEU-198.
[9]	"SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect." Gonzales E., Cresteil D., Baussan C., Dabadie A., Gerhardt M.F., Jacquemin E. J. Hepatol. 40:716-718(2004) [PubMed: 15030995] [Abstract] Cited for: VARIANTS CBAS2 ARG-133 AND CYS-261.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

Z28339 mRNA. Translation: CAA82193.1.
AF283659 , AF283651, AF283652, AF283653, AF283654, AF283655, AF283656, AF283657, AF283658 Genomic DNA. Translation: AAG39381.1.
AK289425 mRNA. Translation: BAF82114.1.
CH236950 Genomic DNA. Translation: EAL24049.1.
CH471070 Genomic DNA. Translation: EAW83881.1.
BC130625 mRNA. Translation: AAI30626.1.
BC130627 mRNA. Translation: AAI30628.1.

IPI

IPI00020955.

PIR

S41120.

RefSeq

NP_005980.1.

UniGene

Hs.201667

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3BUR	X-ray	1.62	A/B	1-326	[»]
3BUV	X-ray	1.35	A/B	1-326	[»]
3BV7	X-ray	1.79	A/B	1-326	[»]
3CAQ	X-ray	2.20	A/B	1-326	[»]
3CAS	X-ray	2.00	A/B	1-326	[»]
3CAV	X-ray	1.90	A/B	1-326	[»]
3CMF	X-ray	1.90	A/B	1-326	[»]
3COT	X-ray	2.03	A/B	1-326	[»]
3DOP	X-ray	2.00	A/B	1-326	[»]
3G1R	X-ray	1.70	A/B	1-326	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P51857.

Proteomic databases

PRIDE

P51857.

Genome annotation databases

Ensembl

ENST00000242375; ENSP00000242375; ENSG00000122787; Homo sapiens. [Genome view]
ENST00000297463; ENSP00000297463; ENSG00000122787; Homo sapiens. [Genome view]
ENST00000411726; ENSP00000402374; ENSG00000122787; Homo sapiens. [Genome view]
ENST00000432161; ENSP00000389197; ENSG00000122787; Homo sapiens. [Genome view]
ENST00000438242; ENSP00000397042; ENSG00000122787; Homo sapiens. [Genome view]

GeneID

6718.

KEGG

hsa:6718.

UCSC

uc003vtz.1. human.

Organism-specific databases

CTD

6718.

GeneCards

GC07P137411.

H-InvDB

HIX0018220.

HGNC

HGNC:388. AKR1D1.

MIM

235555. phenotype.
604741. gene.

Orphanet

163631. Bile acid synthesis defect with cholestasis and malabsorption.
79303. Bile acid synthesis defect, congenital, type 2.

PharmGKB

PA24681.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P51857.

HOVERGEN

P51857.

OMA

ITHRIAM.

Enzyme and pathway databases

BRENDA

1.3.1.3. 247.

Reactome

REACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P51857.

Bgee

P51857.

CleanEx

HS_AKR1D1.

Genevestigator

P51857.

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.

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

NextBio

26206.

SOURCE

Search...

Entry information

Entry name

AK1D1_HUMAN

Accession

Primary (citable) accession number: P51857
Secondary accession number(s): A1L4P6, A8K060

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	November 3, 2009
This is version 80 of the entry and version 1 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.