Information on EC 1.1.1.209 - 3(or 17)alpha-hydroxysteroid dehydrogenase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.1.1.209
-
RECOMMENDED NAME
GeneOntology No.
3(or 17)alpha-hydroxysteroid dehydrogenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
androsterone + NAD(P)+ = 5alpha-androstane-3,17-dione + NAD(P)H + H+
show the reaction diagram
random binding pattern of substrate, ordered release of product, pro-R-hydrogen atom of NAD(P)H is transferred to the carbonyl site
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
testosterone and androsterone degradation to androstendione
-
-
SYSTEMATIC NAME
IUBMB Comments
3(or 17)alpha-hydroxysteroid:NAD(P)+ oxidoreductase
Acts on the 3alpha-hydroxy group of androgens of the 5alpha-androstane series; and also, more slowly, on the 17alpha-hydroxy group of both androgenic and estrogenic substrates (cf. EC 1.1.1.51 3(or 17)beta-hydroxysteroid dehydrogenase).
CAS REGISTRY NUMBER
COMMENTARY hide
83294-77-3
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(R)-1-indanol + NADP+
1-indanone + NADPH
show the reaction diagram
-
37% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
(S)-1-indanole + NADP+
1-indanone + NADPH
show the reaction diagram
-
7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
1-acenaphthenol + NADP+
1-acenaphthenone + NADPH
show the reaction diagram
-
10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
17alpha-estradiol + NAD(P)+
estrone + NAD(P)H
show the reaction diagram
17alpha-estradiol 3-glucuronide + NAD(P)+
estrone 3-glucuronide + NAD(P)H
show the reaction diagram
21-hydroxy-5beta-pregnane-3,20-dione + NADPH
21-hydroxy-5beta-pregnane-20alpha-ol-3-one + NADP+
show the reaction diagram
-
-
-
r
3alpha-androstanediol + NAD(P)+
androsterone + NAD(P)H
show the reaction diagram
-
-
-
r
3alpha-hydroxy-5alpha-androstan-17-one + NAD(P)+
5alpha-androstan-3,17-dione + NAD(P)H
show the reaction diagram
4-androstene-3,17-dione + NADPH
? + NADP+
show the reaction diagram
-
-
-
-
?
4-androstene-3,17-dione + NADPH + H+
? + NADP+
show the reaction diagram
-
-
-
-
r
4-nitrobenzaldehyde + NADPH
4-nitrobenzyl alcohol + NADP+
show the reaction diagram
-
58% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5-androstene-3beta,17beta-diol + NADP+
? + NADPH
show the reaction diagram
-
no substrate for wild-type, but substrate for mutants Y224F, Y224D, Q222D
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-
?
5alpha-androstan-17alpha-ol-3-one + NADP+
5alpha-androstan-3,17-dione + NADPH + H+
show the reaction diagram
-
-
-
-
?
5alpha-androstan-17alpha-ol-3-one + NADP+
? + NADPH
show the reaction diagram
-
-
-
-
?
5alpha-androstan-17beta-ol-3-one + NADP+
5alpha-androstan-3,17-dione + NADPH + H+
show the reaction diagram
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
17beta-hydroxy-5alpha-androstan-3-one + NAD(P)H
show the reaction diagram
5alpha-androstan-3alpha-ol-17-one + NADPH
? + NADP+
show the reaction diagram
-
-
-
-
?
5alpha-androstan-3alpha-ol-17-one + NADPH + H+
5alpha-androstan-3alpha-ol-17beta-ol + NADP+
show the reaction diagram
-
-
-
-
?
5alpha-androstan-3beta,17beta-diol + NADP+
? + NADPH
show the reaction diagram
-
-
-
-
?
5alpha-androstan-3beta,17beta-diol + NADP+
? + NADPH + H+
show the reaction diagram
-
-
-
-
?
5alpha-androstane-3alpha,17beta-diol + NADP+
5alpha-androstane-17beta-ol-3-one + NADPH
show the reaction diagram
-
7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5alpha-dihydrotestosterone + NAD(P)H
androstanedione + NAD(P)+
show the reaction diagram
-
-
-
r
5alpha-pregnan-3alpha,20alpha-diol + NADP+
5alpha-pregnan-20alpha-ol-3-one + NADPH
show the reaction diagram
-
6% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5alpha-pregnan-3alpha,21-diol-20-one + NADP+
5alpha-pregnan-21alpha-ol-3,20-dione + NADPH
show the reaction diagram
-
7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5alpha-pregnane-21-ol-3,20-dione + NADPH
5beta-pregnane-3alpha,21-diol-20-one + NADP+
show the reaction diagram
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75% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5alpha-pregnane-3,20-dione + NADPH
5alpha-pregnane-3alpha-ol-20-one + NADP+
show the reaction diagram
-
10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5alpha-pregnane-3alpha,20alpha-diol + NADP+
? + NADPH
show the reaction diagram
-
-
-
-
?
5beta-androstan-17alpha-ol-3-one + NADP+
? + NADPH
show the reaction diagram
-
-
-
-
?
5beta-androstan-17beta-ol-3-one + NADPH
5beta-androstan-17beta,3alpha-diol + NADP+
show the reaction diagram
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-androstane-3,17-dione + NADPH
5beta-androstan-3alpha-ol-17-one + NADP+
show the reaction diagram
-
10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-androstane-3alpha,17beta-diol + NADP+
5beta-androstane-17beta-ol-3-one + NADPH
show the reaction diagram
-
11% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-androstane-3alpha-ol-17-one + NADP+
5beta-androstane-3,17-dione + NADPH
show the reaction diagram
-
9% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-pregnan-3alpha,20alpha-diol + NADP+
5beta-pregnan-3-one-20alpha-ol + NADPH
show the reaction diagram
-
26% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-pregnan-3alpha-ol-20-one + NADP+
5beta-pregnan-3,20-dione + NADPH
show the reaction diagram
-
19% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
5beta-pregnane-20alpha-ol-3-one + NADP+
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
show the reaction diagram
-
-
-
-
r
5beta-pregnane-3,20-dione + NADPH + H+
5beta-pregnane-3alpha-ol-20-one + NADP+
show the reaction diagram
5beta-pregnane-3alpha,20alpha-diol + NADP+
? + NADPH
show the reaction diagram
-
-
-
-
?
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
5beta-pregnane-20alpha-ol-3-one + NADP+
show the reaction diagram
acenaphthenequinone + NADPH
acenaphthenehydroquinone + NADP+
show the reaction diagram
-
44% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
androst-4-ene-3,17-dione + NADPH
androst-4-ene-3alpha-ol-17-one + NADP+
show the reaction diagram
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
androstenedione + NADPH + H+
androsterone + NADP+
show the reaction diagram
-
-
-
r
camphorquinone + NADPH + H+
camphorhydroquinone + NADP+
show the reaction diagram
-
52% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
cis-1,2-dihydroxy-3,5-cyclohexadiene + NADP+
catechol + NADPH
show the reaction diagram
-
60% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
cyclohex-2-ene-1-ol + NADP+
cyclohex-2-en-1-one + NADPH
show the reaction diagram
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9% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
cyclohexanone + NADPH
cyclohexanol + NADP+
show the reaction diagram
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16% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
epitestosterone
? + NADPH
show the reaction diagram
-
-
-
-
?
epitestosterone + NAD(P)+
androst-4-en-3,17-dione + NAD(P)H + H+
show the reaction diagram
epitestosterone + NADP+
testosterone + NADPH + H+
show the reaction diagram
estrone 3-sulfate + NAD(P)H
17alpha-estradiol 3-sulfate + NAD(P)+
show the reaction diagram
-
-
-
?
glycolithocholic acid + NADP+
dehydroglycolithocholic acid + NADPH
show the reaction diagram
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56% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
lithocholic acid + NADP+
? + NADPH + H+
show the reaction diagram
-
-
-
-
r
naphthalene dihydrodiol + NADP+
naphthacatechol + NADPH
show the reaction diagram
-
49% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
pyridine-4-ol + NADP+
3H-pyridine-4-one + NADPH
show the reaction diagram
-
75% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
-
?
testosterone + NAD(P)+
androstenedione + NAD(P)H + H+
show the reaction diagram
-
-
-
?
testosterone + NADP+
androst-4-en-3,17-dione + NADPH + H+
show the reaction diagram
-
mutant G225P/G226P, wild-type shows no activity with testosterone
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-
?
trans-1,2-dihydroxy-3,5-cyclohexadiene + NADP+
catechol + NADPH
show the reaction diagram
-
-
-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
21-hydroxy-5beta-pregnane-3,20-dione + NADPH
21-hydroxy-5beta-pregnane-20alpha-ol-3-one + NADP+
show the reaction diagram
Q91WR5
-
-
-
r
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
5beta-pregnane-20alpha-ol-3-one + NADP+
show the reaction diagram
Q91WR5
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-
-
r
androstenedione + NADPH + H+
androsterone + NADP+
show the reaction diagram
Q91WR5
-
-
-
r
additional information
?
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-
the enzyme catalyses the oxidoreduction of steroid hormones such as estrogens, androgens and neurosteroids
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-
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
low activity
NADP+
NADPH
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
17beta-estradiol
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5 mM, 77% inhibition
5alpha-Androstan-3beta-ol-17-one
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1 mM, 80% inhibition
5alpha-pregnan-3beta-ol-21-one
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1 mM, 66% inhibition
5beta-androstan-3beta-ol-17-one
-
1 mM, 91% inhibition
5beta-Pregnan-3beta-ol-20-one
-
1 mM, 80% inhibition
androsterone
-
competitive vs. epitestosterone
Barbital
-
100 mM, 11% inhibition
chrysin
-
-
Dienstrol
-
1 mM, 22% inhibition
fidarestat
-
-
Hexestrol
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1 mM, 77% inhibition
Hexoestrol
-
-
minalrestat
-
inhibition pattern for AKR1C21, overview
myricetin
-
-
quercetin
-
inhibition pattern for AKR1C21, overview
quercitrin
-
-
sorbinil
-
-
Stilbestrol
-
10 mM, 75% inhibition
testosterone
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1 mM, 48% inhibition
Tolrestat
-
inhibition pattern for AKR1C21, overview
zopolrestat
-
-
additional information
-
enzyme-inhibitor complexe modelling, Tyr118 and Phe311 are important residues for inhibitor recognition and orientation in the active site of AKR1C21, overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.019
(2Z)-2-(5-hydroxy-4,6-dimethyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N,N-di(prop-2-en-1-yl)hydrazinecarbothioamide
-
-
0.16
(R)-1-indanol
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cofactor NADP+
0.0002 - 0.0078
4-androstene-3,17-dione
0.0004 - 0.014
5alpha-Androstan-17alpha-ol-3-one
0.0047 - 0.096
5alpha-androstan-17beta-ol-3-one
0.0006 - 0.015
5alpha-Androstan-3alpha-ol-17-one
0.013 - 0.1
5alpha-androstan-3beta,17beta-diol
0.026
5alpha-dihydrotestosterone
-
-
0.0005 - 0.08
5alpha-pregnane-3alpha,20alpha-diol
0.0004 - 0.0013
5beta-androstan-17alpha-ol-3-one
0.0001 - 0.0003
5beta-androstane-3alpha,17beta-diol
0.0002 - 0.015
5beta-pregnane-20alpha-ol-3-one
0.0004 - 0.0059
5beta-pregnane-3,20-dione
0.0005 - 0.018
5beta-pregnane-3alpha,20alpha-diol
0.0007
5beta-pregnane-3alpha-ol-20-one
-
cofactor NADP+
0.0012 - 0.048
androsterone
1.99
cis-benzene dihydrodiol
-
cofactor NADP+
2.23
cyclohex-2-ene-1-ol
-
cofactor NADP+
0.0001 - 0.02
Epitestosterone
0.0004
glycolithocholic acid
-
cofactor NADP+
0.0001 - 0.0067
lithocholic acid
0.26
NAD+
-
-
0.004
NADP+
-
-
2.67
Naphthalene dihydrodiol
-
cofactor NADP+
0.012 - 0.023
testosterone
0.77
trans-benzene dihydrodiol
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cofactor NADP+
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00617
(2Z)-2-(5-hydroxy-4,6-dimethyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N,N-di(prop-2-en-1-yl)hydrazinecarbothioamide
Homo sapiens
-
-
0.0217 - 0.617
4-androstene-3,17-dione
0.145 - 0.867
5alpha-Androstan-17alpha-ol-3-one
0.0025 - 0.383
5alpha-androstan-17beta-ol-3-one
0.0217 - 0.233
5alpha-Androstan-3alpha-ol-17-one
0.00167 - 0.167
5alpha-androstan-3beta,17beta-diol
0.003
5alpha-dihydrotestosterone
Homo sapiens
-
-
0.105 - 0.15
5alpha-pregnane-3alpha,20alpha-diol
0.055 - 0.14
5beta-androstan-17alpha-ol-3-one
0.383 - 4.83
5beta-pregnane-20alpha-ol-3-one
0.35 - 4.83
5beta-pregnane-3,20-dione
0.00367 - 0.4
5beta-pregnane-3alpha,20alpha-diol
0.000367
androsterone
Homo sapiens
-
-
0.23 - 0.57
Epitestosterone
0.0073 - 0.105
lithocholic acid
0.0009 - 0.04
testosterone
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3.3 - 833
4-androstene-3,17-dione
1186
20 - 417
5alpha-Androstan-17alpha-ol-3-one
5116
0.03 - 4.5
5alpha-androstan-17beta-ol-3-one
2393
1.5 - 122
5alpha-Androstan-3alpha-ol-17-one
2394
0.05 - 0.65
5alpha-androstan-3beta,17beta-diol
5504
83 - 8000
5beta-pregnane-20alpha-ol-3-one
6309
60 - 8000
5beta-pregnane-3,20-dione
2074
1 - 366
5beta-pregnane-3alpha,20alpha-diol
3128
11.67 - 500
Epitestosterone
2140
1 - 467
lithocholic acid
1325
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0085
chrysin
Mus musculus
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pH 7.4, 25°C
0.000009
fidarestat
Mus musculus
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pH 7.4, 25°C
0.00026 - 0.0006
Hexoestrol
0.00007
minalrestat
Mus musculus
-
pH 7.4, 25°C
0.029
myricetin
Mus musculus
-
pH 7.4, 25°C
0.0022
quercetin
Mus musculus
-
pH 7.4, 25°C
0.00015
quercitrin
Mus musculus
-
pH 7.4, 25°C
0.00091
sorbinil
Mus musculus
-
pH 7.4, 25°C
0.00004
Tolrestat
Mus musculus
-
pH 7.4, 25°C
0.00003
zopolrestat
Mus musculus
-
pH 7.4, 25°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0035
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reduction of 5alpha-dihydrotestosteerone, cofactor NADPH, pH 6.0
0.0063
-
oxidation of 3alpha-androstanediol, cofactor NADP+, pH 9.0
0.0253
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reduction of 5alpha-androstanedione, cofactor NADPH, pH 6.0
0.27
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 6.8
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5beta-pregnane-3,20-dione as substrate, cofactor NADPH
7.4
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
34000
-
gel filtration
40000
-
female rabbit, form IB, gel filtration
41000
-
female rabbit, forms II and III, gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
-
x * 39000, recombinant isozyme AKR1C21, SDS-PAGE
monomer
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
double mutant G225P/G226P of AKR1C21 in complex with the coenzyme NADP+ and the inhibitor hexoestrol, by hanging-drop vapour-diffusion method, at 2.1 A resolution. Overall fold of the mutant is similar to that of wild-type, apart from the loop region lining the active-site pocket, in which the two glycines at positions 225 and 226 are mutated to prolines which have a more rigid structure, resulting in a larger substrate-binding pocket. The mutation affects the conformation of the adjoining residues Tyr224 and Trp227, resulting in a further opening up of the active-site pocket while the catalytic residues remain unaffected. The inhibitor molecule is bound to the active site with one hydroxyl group pointing towards the catalytic residues, the bulky phenyl rings and the methyl groups of hexoestrol form van der Waals contacts with Trp227, Tyr224, Tyr55 and the nicotinamide ring of NADP+
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purified recombinant enzyme, in a AKR1C21-NADPH binary complex, hanging drop vapour diffusion method, 22°C, 18 mg/ml of protein in 0.1 M HEPES, pH 7.5, 10% PEG 6000, and 5% 2-methyl-2,4-pentanediol, mixing with an equal volume of the crystallization buffer, and equilibration against 1 ml reservoir solution, X-ray diffraction structure determination and analysis at 1.8 A resolution
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purified recombinant isozyme AKR1C21, hanging drop vapour diffusion method, 16 mg/ml enzyme in 10 mM Tris-HCl, pH 7.5, and 2 mM 2-mercaptoethanol, mixed with an equal volume of 0.003 ml of reservoir solution containing 0.1 M HEPES, pH 7.5, 10% PEG 6000, 5% 2-methyl-2,4-pentanediol, equilibration against 1 ml reservoir solution, 22°C, 1 week, X-ray diffraction structure determination and analysis at 1.8 A resolution, molecular replacement
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Y224D mutant at 2.3 A resolution. Mutation results in a change in the conformation of the flexible loop B, including the V-shaped groove
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
female, 4 forms of enzyme
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Q-Sepharose, Matrex Red A, HA-Ultrogel, Sephadex G-100, two enzyme preparations DD1 and DD2 with almost identical properties, products of post-translational or post-mortem modification rather than isoenzymes
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recombinant isozyme AKR1C21 from Escherichia coli strain JM109 to homogeneity
-
recombinant wild-type and mutant enzymes purified to homogeneity
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
-
expression of isozyme AKR1C21 in Escherichia coli strain JM109
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recombinant wild-type and mutant enzymes expressed in Escherichia coli JM109
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
G225P/G226P
-
reduced affinity (Km) for both 3alpha- and 17alpha-hydroxysteroid substrates by up to 160fold, shows high selectivity for 5beta-pregnane-3alpha,20alpha-diol in the oxidation of the 3alpha-hydroxy group and, conversely, broad specificity for both 17alpha- and 17beta-hydroxysteroids
Q222N
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mutation of residue involved in forming the safety belt for binding of the coenzyme. Kinetic constants for 3-hydroxy/3-ketosteroids and 17-hydroxy/ketosteroids similar to wild type
Y224D
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mutation reduces the Km value for NADP(H) by up to 80fold and completely reverses the 17alpha stereospecificity of the enzyme
Y224F
-
mutation of residue involved in forming the safety belt for binding of the coenzyme. Kinetic constants for 3-hydroxy/3-ketosteroids and 17-hydroxy/ketosteroids similar to wild type