show all | hide all No of entries

Information on EC 1.3.1.3 - DELTA4-3-oxosteroid 5beta-reductase and Organism(s) Homo sapiens and UniProt Accession P51857

for references in articles please use BRENDA:EC1.3.1.3
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
IUBMB Comments
The enzyme from human efficiently catalyses the reduction of progesterone, androstenedione, 17alpha-hydroxyprogesterone and testosterone to 5beta-reduced metabolites; it can also act on aldosterone, corticosterone and cortisol, but to a lesser extent . The bile acid intermediates 7alpha,12alpha-dihydroxy-4-cholesten-3-one and 7alpha-hydroxy-4-cholesten-3-one can also act as substrates .
Specify your search results
Select one or more organisms in this record:
This record set is specific for:
Homo sapiens
UNIPROT: P51857
Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
3-oxo-DELTA4-steroid 5beta-reductase, 4,5beta-dihydrocortisone:NADP+ DELTA4-oxidoreductase, 5-beta-reductase, 5beta-POR, 5beta-red, AKR1D1, aldo-keto reductase, aldo-keto reductase 1D1, aldoketo reductase 1D1, androstenedione 5beta-reductase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3-oxo-DELTA4-steroid 5beta-reductase
289906
-
4,5beta-dihydrocortisone:NADP+ DELTA4-oxidoreductase
-
-
-
-
5-beta-reductase
-
-
-
-
5beta-red
247
-
AKR1D1
aldo-keto reductase 1D1
247
-
aldoketo reductase 1D1
289906
-
androstenedione 5beta-reductase
-
-
-
-
cortisone 5beta-reductase
-
-
-
-
cortisone beta-reductase
-
-
-
-
DELTA 4-5beta-reductase
-
-
-
-
DELTA4-3-ketosteroid 5beta-reductase
DELTA4-3-oxosteroid 5beta-reductase
289906
-
DELTA4-hydrogenase
-
-
-
-
h5beta-red
247
-
h5beta-reductase
247
-
reductase, cholestenone 5beta.-
-
-
-
-
reductase, cortisone DELTA4-5beta-
-
-
-
-
steroid 5beta-reductase
steroid 5beta.-reductase
-
-
-
-
testosterone 5-beta-reductase
-
-
-
-
testosterone 5beta-reductase
-
-
-
-
additional information
247
human 5beta-red belongs to the aldo-keto reductase, AKR, superfamily and is the first member of the 1D subfamily, AKR1D1
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
17,21-dihydroxy-5beta-pregnane-3,11,20-trione + NADP+ = cortisone + NADPH + H+
show the reaction diagram
reaction mechanism, overview
-
5beta-cholestan-3-one + NADP+ = cholest-4-en-3-one + NADPH + H+
show the reaction diagram
reaction mechanism, overview
-
17,21-dihydroxy-5beta-pregnane-3,11,20-trione + NADP+ = cortisone + NADPH + H+
show the reaction diagram
catalyzes the reduction of the DELTA4 double bond of DELTA4-3-ketosteroids, converting those steroids into 5beta-dihydro-3-ketosteroids
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
reduction
SYSTEMATIC NAME
IUBMB Comments
5beta-cholestan-3-one:NADP+ 4,5-oxidoreductase
The enzyme from human efficiently catalyses the reduction of progesterone, androstenedione, 17alpha-hydroxyprogesterone and testosterone to 5beta-reduced metabolites; it can also act on aldosterone, corticosterone and cortisol, but to a lesser extent [8]. The bile acid intermediates 7alpha,12alpha-dihydroxy-4-cholesten-3-one and 7alpha-hydroxy-4-cholesten-3-one can also act as substrates [9].
CAS REGISTRY NUMBER
COMMENTARY hide
37255-35-9
-
9029-08-7
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
cholest-4-en-3-one + NADPH + H+
5beta-cholestan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
11beta,21dihydroxy-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
17,21-dihydroxy-5beta-pregnane-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
progesterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH + H+
(5beta,17beta)-17-hydroxyandrostan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
1,4-androstadien-17beta-ol-3-one + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
17alpha-hydroxyprogesterone + NADPH
?
show the reaction diagram
-
-
-
-
?
4-androstene-3,17-dione + NADPH
5beta-androstan-3,17-dione + NADP+
show the reaction diagram
-
-
-
-
?
4-androstene-3,17-dione + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
4-cholesten-7alpha-ol-3-one + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
4-estren-17beta-ol-3-one + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
7alpha,12alpha-dihydroxy-4-cholesten-3-one + NADPH + H+
?
show the reaction diagram
-
-
-
-
-
7alpha,12beta-dihydroxy-4-cholesten-3-one + NADPH
(5beta,7alpha,12beta)-7,12-dihydroxycholestan-3-one + NADPH
show the reaction diagram
-
-
-
?
7alpha-hydroxy-4-cholesten-3-one + NADPH
(5beta,7alpha)-7-hydroxycholestan-3-one + NADP+
show the reaction diagram
-
-
-
?
7alpha-hydroxy-4-cholesten-3-one + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
aldosterone + NADPH
?
show the reaction diagram
-
low activity
-
-
?
aldosterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
androstenedione + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
cholestenone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
corticosterone + NADPH
?
show the reaction diagram
-
low activity
-
-
?
corticosterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
cortisol + NADPH
?
show the reaction diagram
-
very low activity
-
-
?
cortisol + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
cortisone + NADPH
5beta-17,21dihydroxy-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
11beta,21dihydroxy-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
DELTA 4-cholestene-7alpha,12alpha-diol-3-one + NADPH + H+
5beta-cholestane-7alpha,12alpha-diol-3-one + NADP+
show the reaction diagram
-
a bile acid intermediate
-
-
?
DELTA4-cholesten-7alpha-ol-3-one + NADPH + H+
5beta-cholestan-7alpha-ol-3-one + NADP+
show the reaction diagram
-
a bile acid intermediate
-
-
?
epitestosterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
progesterone + NADPH
5beta-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
?
progesterone + NADPH
?
show the reaction diagram
-
-
-
-
?
progesterone + NADPH + H+
5beta-pregnane-3,20-dione + NADP+
show the reaction diagram
-
-
-
-
?
progesterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH + H+
(5beta,17beta)-17-hydroxyandrostan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
testosterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
cholest-4-en-3-one + NADPH + H+
5beta-cholestan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
11beta,21dihydroxy-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
cortisone + NADPH + H+
17,21-dihydroxy-5beta-pregnane-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
progesterone + NADPH + H+
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH + H+
(5beta,17beta)-17-hydroxyandrostan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
17alpha-hydroxyprogesterone + NADPH
?
show the reaction diagram
-
-
-
-
?
aldosterone + NADPH
?
show the reaction diagram
-
low activity
-
-
?
corticosterone + NADPH
?
show the reaction diagram
-
low activity
-
-
?
cortisol + NADPH
?
show the reaction diagram
-
very low activity
-
-
?
cortisone + NADPH + H+
11beta,21dihydroxy-pregnan-3,11,20-trione + NADP+
show the reaction diagram
-
-
-
-
?
DELTA 4-cholestene-7alpha,12alpha-diol-3-one + NADPH + H+
5beta-cholestane-7alpha,12alpha-diol-3-one + NADP+
show the reaction diagram
-
a bile acid intermediate
-
-
?
DELTA4-cholesten-7alpha-ol-3-one + NADPH + H+
5beta-cholestan-7alpha-ol-3-one + NADP+
show the reaction diagram
-
a bile acid intermediate
-
-
?
progesterone + NADPH
?
show the reaction diagram
-
-
-
-
?
testosterone + NADPH + H+
(5beta,17beta)-17-hydroxyandrostan-3-one + NADP+
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
AKR1D1 catalyzes the central 5beta-reduction step and reduces bile acid precursors such as DELTA4-cholesten-7alpha-ol-3-one and DELTA 4-cholestene-7alpha,12alpha-diol-3-one to 5beta-cholestan-7alpha-ol-3-one and 5beta-cholestane-7alpha,12alpha-diol-3-one, respectively
-
-
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
-
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
testosterone
-
substrate inhibition
4-benzoylbenzoic acid
-
-
androstenedione
-
the enzyme is rapidly inhibited by the substrate once its concentration reaches 2times the Km value. Androstenedione completely impedes the passage of another substrate molecule toward the catalytic site
chenodeoxycholic acid
-
-
indomethacin
-
-
Mefenamic acid
-
-
progesterone
-
the enzyme is rapidly inhibited by the substrate once its concentration reaches 2times the Km value
testosterone
Ursodeoxycholic acid
-
-
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0013 - 0.0151
cortisone
0.0027 - 0.0127
testosterone
0.0032
1,4-androstadien-17beta-ol-3-one
-
pH 6.0, 37C
0.0009
4-androstene-3,17-dione
-
pH 6.0, 37C
0.0008
4-cholesten-7alpha-ol-3-one
-
pH 6.0, 37C
0.003
4-estren-17beta-ol-3-one
-
pH 6.0, 37C
0.0025
aldosterone
-
pH 6.0, 37C
0.00037 - 0.01629
androstenedione
0.0003
cholestenone
-
pH 6.0, 37C
0.0022
corticosterone
-
pH 6.0, 37C
0.0131
cortisol
-
pH 6.0, 37C
0.0013 - 0.0151
cortisone
0.0029
Epitestosterone
-
pH 6.0, 37C
0.0027 - 0.0127
testosterone
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01 - 0.17
cortisone
0.05 - 0.12
testosterone
0.035
1,4-androstadien-17beta-ol-3-one
-
pH 6.0, 37C
0.1
4-androstene-3,17-dione
-
pH 6.0, 37C
0.033
4-cholesten-7alpha-ol-3-one
-
pH 6.0, 37C
0.045
4-estren-17beta-ol-3-one
-
pH 6.0, 37C
0.15
aldosterone
-
pH 6.0, 37C
0.013 - 0.0425
androstenedione
0.01
cholestenone
-
pH 6.0, 37C
0.032
corticosterone
-
pH 6.0, 37C
0.045
cortisol
-
pH 6.0, 37C
0.01 - 0.195
cortisone
0.1
Epitestosterone
-
pH 6.0, 37C
0.012 - 0.14
testosterone
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7.7 - 11
cortisone
3.5 - 43.8
testosterone
10.94
1,4-androstadien-17beta-ol-3-one
-
pH 6.0, 37C
2.77
4-androstene-3,17-dione
-
pH 6.0, 37C
41.25
4-cholesten-7alpha-ol-3-one
-
pH 6.0, 37C
15
4-estren-17beta-ol-3-one
-
pH 6.0, 37C
60
aldosterone
-
pH 6.0, 37C
2.609 - 43.08
androstenedione
33.33
cholestenone
-
pH 6.0, 37C
14.54
corticosterone
-
pH 6.0, 37C
3.44
cortisol
-
pH 6.0, 37C
7.69 - 12.91
cortisone
34.48
Epitestosterone
-
pH 6.0, 37C
3.54 - 51.85
testosterone
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0145
testosterone
-
wild-type, pH not specified in the publication, temperature not specified in the publication
0.0145
testosterone
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.3
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
-
the enzyme is responsible for steroid hormone 5beta-reduction, as well as for cholic acid and chenodeoxycholic bile-acid synthesis
evolution
-
the enzyme is a member of the aldo-keto reductase (AKR) family
malfunction
-
deficient 5beta-reductase activity can lead to cholestasis and neo-natal liver failure and is often lethal if it remains untreated
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
AK1D1_HUMAN
326
0
37377
Swiss-Prot
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
65000
-
recombinant GST-5beta-reductase fusion protein, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
CRYSTALLIZATION/commentary
ORGANISM
UNIPROT
LITERATURE
enzyme in binary complex with product NADP+, containing two monomers of AKR1D1, each of which consists of a 325-residue polypeptide chain that adopts an (alpha/beta)8-barrel fold, the AKR1D1-NADP+ complex adopts an extended anti-conformation, X-ray diffraction structure determination and analysis at 1.79 A resolution, comparison with other enzyme binary and tertiary ligand complex structures, overview
-
hanging drop vapour diffusion method in 20% (w/v) PEG-4K, 0.1 M sodium cacodylate (pH 6.5), 0.2 M sodium citrate, 0.5 M (NH4)2SO4
-
hanging drop vapour diffusion method, in 0.1 M Tris/HEPES (pH 7.5), 10-20% (w/v) polyethylene glycol 4000, and 10% isopropyl alcohol
-
purifed recombinant h5beta-red in ternary complex with NADPH and androstenedione, hanging-drop vapor diffusion technique, 2:1 v/v ratio of protein and well solution, about 5 days, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
G223E
the naturally occuring mutation of gene SRD5B1 are involved in hyper-3-oxo-DELTA4 bile aciduria from primary 3-oxo-DELTA4-steroid 5beta-reductase deficiency, phenotypes, overview
L106F
-
mutant identified in patient with reduced enzymic activity
P133R
-
mutant identified in patient with reduced enzymic activity; mutant identified in patient with reduced enzymic activity. Mutant displays a highly reduced Km and Vmax reminiscent of uncompetitive kinetics with 4-cholesten-7alpha-ol-3-one as substrate. Mutant displays no change in cofactor affinity but is more thermolabile in the absence of NADPH
P198L
R217stop
the naturally occuring mutation of gene SRD5B1 are involved in hyper-3-oxo-DELTA4 bile aciduria from primary 3-oxo-DELTA4-steroid 5beta-reductase deficiency, phenotypes, overview
R261C
-
mutant identified in patient with reduced enzymic activity
E120A
-
mutant is devoid of activity
G223E
L106F
P133R
P198L
R261C
V309F
-
replacement of one of the residues delineating this site by a phenylalanine completely abolishes the enzyme's substrate inhibition, but the catalytic efficiency of the mutated enzyme is similar to that of the wild-type h5beta-red enzyme
Y132F
-
replacement of one of the residues delineating this site by a phenylalanine completely abolishes the enzyme's substrate inhibition, but the catalytic efficiency of the mutated enzyme is similar to that of the wild-type h5beta-red enzyme
Y58F
-
mutant is devoid of activity
additional information
-
determination of AKR1D1 reaction mechanism by mutational analysis revealing that the 4-pro-R hydride is transferred from the re-face of the nicotinamide ring to C5 of the steroid substrate. E120, a unique substitution in the AKR catalytic tetrad, permits a deeper penetration of the steroid substrate into the active site to promote optimal reactant positioning. It participates with Y58 to create a superacidic oxyanion hole for polarization of the C3 ketone, no role for K87 in the proton relay, overview
PURIFICATION/commentary
ORGANISM
UNIPROT
LITERATURE
glutathione-Sepharose column chromatography and Sephacryl-S100 gel filtration
-
Ni2+-Sepharose column chromatography
-
recombinant AKR1D1 enzyme mutant P133R from HEK-293 cells, the other expressed mutants cannot be purified
-
recombinant GST-tagged enzyme from Escherichia coli by glutathione affinity and anion exchange chromatography, and gel filtration
-
CLONED/commentary
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli and HEK-293 cell
-
gene SRD5B1, DNA and amino acid sequence determination and analysis of wild-type and mutant enzymes
expressed in Escherichia coli
-
expressed in Escherichia coli strain C41(DE3)
-
expression in human HEK-293 cells; pseudogene found
-
expression of GST-tagged enzyme in Escherichia coli
-
recombinant expression of AKR1D1 enzyme mutants in HEK-293 cells
-
recombinant expression of AKR1D1 enzyme mutants in HEK-293 cells only at low levels possible and with low activities
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Charbonneau, A.; The, V.L.
Genomic organization of a human 5beta-reductase and its pseudogene and substrate selectivity of the expressed enzyme
Biochim. Biophys. Acta
1517
228-235
2001
Homo sapiens
Manually annotated by BRENDA team
Faucher, F.; Cantin, L.; Luu-The, V.; Labrie, F.; Breton, R.
The crystal structure of human DELTA4-3-ketosteroid 5beta-reductase defines the functional role of the residues of the catalytic tetrad in the steroid double bond reduction mechanism
Biochemistry
47
8261-8270
2008
Homo sapiens, Homo sapiens (P51857)
Manually annotated by BRENDA team
Di Costanzo, L.; Drury, J.E.; Penning, T.M.; Christianson, D.W.
Crystal structure of human liver DELTA4-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis
J. Biol. Chem.
283
16830-16839
2008
Homo sapiens
Manually annotated by BRENDA team
Faucher, F.; Cantin, L.; Luu-The, V.; Labrie, F.; Breton, R.
Crystal structures of human Delta4-3-ketosteroid 5beta-reductase (AKR1D1) reveal the presence of an alternative binding site responsible for substrate inhibition
Biochemistry
47
13537-13546
2008
Homo sapiens, Homo sapiens (P51857)
Manually annotated by BRENDA team
Ueki, I.; Kimura, A.; Chen, H.L.; Yorifuji, T.; Mori, J.; Itoh, S.; Maruyama, K.; Ishige, T.; Takei, H.; Nittono, H.; Kurosawa, T.; Kage, M.; Matsuishi, T.
SRD5B1 gene analysis needed for the accurate diagnosis of primary 3-oxo-Delta4-steroid 5beta-reductase deficiency
J. Gastroenterol. Hepatol.
24
776-785
2009
Homo sapiens (P51857)
Manually annotated by BRENDA team
Di Costanzo, L.; Drury, J.E.; Christianson, D.W.; Penning, T.M.
Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1)
Mol. Cell. Endocrinol.
301
191-198
2009
Homo sapiens, Homo sapiens (P51857)
Manually annotated by BRENDA team
Palermo, M.; Marazzi, M.G.; Hughes, B.A.; Stewart, P.M.; Clayton, P.T.; Shackleton, C.H.
Human Delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism
Steroids
73
417-423
2008
Homo sapiens, Homo sapiens (P51857)
Manually annotated by BRENDA team
Mindnich, R.; Drury, J.E.; Penning, T.M.
The effect of disease associated point mutations on 5beta-reductase (AKR1D1) enzyme function
Chem. Biol. Interact.
191
250-254
2011
Homo sapiens
Manually annotated by BRENDA team
Drury, J.E.; Mindnich, R.; Penning, T.M.
Characterization of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency
J. Biol. Chem.
285
24529-24537
2010
Homo sapiens, Homo sapiens (P51857)
Manually annotated by BRENDA team
Chen, M.; Drury, J.E.; Penning, T.M.
Substrate specificity and inhibitor analyses of human steroid 5beta-reductase (AKR1D1)
Steroids
76
484-490
2011
Homo sapiens
Manually annotated by BRENDA team
Select items on the left to see more content.