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Information on EC 1.1.1.209 - 3(or 17)alpha-hydroxysteroid dehydrogenase and Organism(s) Mus musculus and UniProt Accession Q91WR5
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1.1.1.209 3(or 17)alpha-hydroxysteroid dehydrogenaseIUBMB Comments
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).
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Word Map
- 1.1.1.209
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17beta-hydroxysteroids
- testosterone
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aldo-keto
- 3beta-hsd
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neurosteroids
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steroidogenesis
- epitestosterone
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17-ketosteroids
- leydig
- corticosterone
- 17alpha-hydroxysteroids
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3alpha-hydroxysteroid
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3beta-hydroxysteroid
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5alpha-reductase
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lh-stimulated
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17alpha
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
akr1c21, 3beta- and 17beta-hydroxysteroid dehydrogenase, 3(17)alpha-hydroxysteroid dehydrogenase, 3(or 17)alpha-hydroxysteroid dehydrogenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3(17)alpha-hydroxysteroid dehydrogenase
dehydrogenase, 3(17)alpha-hydroxy steroid
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additional information
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AKR1C21 is a member of the aldo-keto reductase superfamily
3(17)alpha-hydroxysteroid dehydrogenase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
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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
83294-77-3
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
21-hydroxy-5beta-pregnane-3,20-dione + NADPH
21-hydroxy-5beta-pregnane-20alpha-ol-3-one + NADP+
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r
5-androstene-3beta,17beta-diol + NADP+
? + NADPH
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+
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?
5alpha-androstan-3alpha-ol-17-one + NADPH + H+
5alpha-androstan-3alpha-ol-17beta-ol + NADP+
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?
5beta-pregnane-20alpha-ol-3-one + NADP+
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
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r
5beta-pregnane-3,20-dione + NADPH + H+
5beta-pregnane-3alpha-ol-20-one + NADP+
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r
testosterone + NADP+
androst-4-en-3,17-dione + NADPH + H+
mutant G225P/G226P, wild-type shows no activity with testosterone
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?
(R)-1-indanol + NADP+
1-indanone + NADPH
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37% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
(S)-1-indanole + NADP+
1-indanone + NADPH
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7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
1-acenaphthenol + NADP+
1-acenaphthenone + NADPH
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
4-nitrobenzaldehyde + NADPH
4-nitrobenzyl alcohol + NADP+
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58% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-androstane-3alpha,17beta-diol + NADP+
5alpha-androstane-17beta-ol-3-one + NADPH
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7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-pregnan-3alpha,20alpha-diol + NADP+
5alpha-pregnan-20alpha-ol-3-one + NADPH
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6% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-pregnan-3alpha,21-diol-20-one + NADP+
5alpha-pregnan-21alpha-ol-3,20-dione + NADPH
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7% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-pregnane-21-ol-3,20-dione + NADPH
5beta-pregnane-3alpha,21-diol-20-one + NADP+
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75% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-pregnane-3,20-dione + NADPH
5alpha-pregnane-3alpha-ol-20-one + NADP+
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-androstan-17beta-ol-3-one + NADPH
5beta-androstan-17beta,3alpha-diol + NADP+
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-androstane-3,17-dione + NADPH
5beta-androstan-3alpha-ol-17-one + NADP+
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-androstane-3alpha,17beta-diol + NADP+
5beta-androstane-17beta-ol-3-one + NADPH
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11% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-androstane-3alpha-ol-17-one + NADP+
5beta-androstane-3,17-dione + NADPH
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9% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-pregnan-3alpha,20alpha-diol + NADP+
5beta-pregnan-3-one-20alpha-ol + NADPH
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26% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-pregnan-3alpha-ol-20-one + NADP+
5beta-pregnan-3,20-dione + NADPH
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19% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5beta-pregnane-3,20-dione + NADPH + H+
5beta-pregnane-3alpha-ol-20-one + NADP+
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21% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
acenaphthenequinone + NADPH
acenaphthenehydroquinone + NADP+
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44% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
androst-4-ene-3,17-dione + NADPH
androst-4-ene-3alpha-ol-17-one + NADP+
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10% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
camphorquinone + NADPH + H+
camphorhydroquinone + NADP+
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52% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
cis-1,2-dihydroxy-3,5-cyclohexadiene + NADP+
catechol + NADPH
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60% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
cyclohex-2-ene-1-ol + NADP+
cyclohex-2-en-1-one + NADPH
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9% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
cyclohexanone + NADPH
cyclohexanol + NADP+
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16% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
epitestosterone + NADP+
testosterone + NADPH + H+
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11% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
glycolithocholic acid + NADP+
N-[(5beta)-3,24-dioxocholan-24-yl]glycine + NADPH
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56% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
naphthalene dihydrodiol + NADP+
naphthacatechol + NADPH
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49% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
pyridine-4-ol + NADP+
3H-pyridine-4-one + NADPH
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75% of activity with trans-1,2-dihydroxy-3,5-cyclohexadiene
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?
5alpha-androstan-17beta-ol-3-one + NADP+
5alpha-androstan-3,17-dione + NADPH + H+
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no substrate for wild-type, but substrate for mutants Y224F, Y224D, Q222D
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?
5alpha-androstan-17beta-ol-3-one + NADP+
5alpha-androstan-3,17-dione + NADPH + H+
wild-type shows no activity with 5alpha-androstan-17beta-ol-3-one
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?
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
5beta-pregnane-20alpha-ol-3-one + NADP+
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r
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
5beta-pregnane-20alpha-ol-3-one + NADP+
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r
additional information
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a bifunctional enzyme that catalyses the oxidoreduction of the 3- and 17-hydroxy/keto groups of steroid substrates such as oestrogens, androgens and neurosteroids, 5beta-pregnane-3alpha,20alpha-diol, 21-hydroxy-5beta-pregnane-3,20-dione, and androstenedione are docked into the substrate-binding cavity and structure analysis, Lys31, Gly225 and Gly226 are important for ligand recognition and orientation in the active site, molecular-docking simulations, overview
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additional information
?
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a bifunctional enzyme that catalyses the oxidoreduction of the 3- and 17-hydroxy/keto groups of steroid substrates such as oestrogens, androgens and neurosteroids, 5beta-pregnane-3alpha,20alpha-diol, 21-hydroxy-5beta-pregnane-3,20-dione, and androstenedione are docked into the substrate-binding cavity and structure analysis, Lys31, Gly225 and Gly226 are important for ligand recognition and orientation in the active site, molecular-docking simulations, overview
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additional information
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wild-type shows no activity with testosterone and 5alpha-androstan-17beta-ol-3-one
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additional information
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wild-type shows no activity with testosterone and 5alpha-androstan-17beta-ol-3-one
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?
additional information
?
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the enzyme catalyses the oxidoreduction of steroid hormones such as estrogens, androgens and neurosteroids
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
21-hydroxy-5beta-pregnane-3,20-dione + NADPH
21-hydroxy-5beta-pregnane-20alpha-ol-3-one + NADP+
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r
5beta-pregnane-3alpha,20alpha-diol + NADPH + H+
5beta-pregnane-20alpha-ol-3-one + NADP+
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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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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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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
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). AK1CL_MOUSE
323
0
36877
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
39000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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+
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
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
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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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
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
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
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type and mutant enzymes expressed in Escherichia coli JM109
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Nakagawa, M.; Tsukuda, F.; Nakayama, T.; Matsuura, K.; Hara, A.; Sawada, H.
Identification of two dihydrodiol dehydrogenases associated with 3(17)alpha-hydoxysteroid dehydrogenase activity in mouse kidney
J. Biochem.
106
633-638
1989
Mus musculus
El-Kabbani, O.; Ishikura, S.; Wagner, A.; Schulze-Briese, C.; Hara, A.
Crystallization and preliminary X-ray diffraction analysis of mouse 3(17)alpha-hydroxysteroid dehydrogenase
Acta crystallogr. Sect. F
61
688-690
2005
Mus musculus
Dhagat, U.; Carbone, V.; Chung, R.P.; Schulze-Briese, C.; Endo, S.; Hara, A.; El-Kabbani, O.
Structure of 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) holoenzyme from an orthorhombic crystal form: an insight into the bifunctionality of the enzyme
Acta Crystallogr. Sect. F
63
825-830
2007
Mus musculus (Q91WR5), Mus musculus
Dhagat, U.; Endo, S.; Hara, A.; El-Kabbani, O.
Inhibition of 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) by aldose reductase inhibitors
Bioorg. Med. Chem.
16
3245-3254
2008
Mus musculus
Dhagat, U.; Endo, S.; Mamiya, H.; Hara, A.; El-Kabbani, O.
Structure of the G225P/G226P mutant of mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) ternary complex: implications for the binding of inhibitor and substrate
Acta Crystallogr. Sect. D
65
257-265
2009
Mus musculus (Q91WR5), Mus musculus
Dhagat, U.; Endo, S.; Mamiya, H.; Hara, A.; El-Kabbani, O.
Studies on a Tyr residue critical for the binding of coenzyme and substrate in mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21): structure of the Y224D mutant enzyme
Acta Crystallogr. Sect. D
66
198-204
2010
Mus musculus (Q91WR5), Mus musculus
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