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Information on EC 1.1.1.149 - 20alpha-hydroxysteroid dehydrogenase and Organism(s) Homo sapiens and UniProt Accession Q04828
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1.1.1.149 20alpha-hydroxysteroid dehydrogenaseIUBMB Comments
Re-specific with respect to NAD(P)+ (cf. EC 1.1.1.62 17beta-estradiol 17-dehydrogenase).
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Word Map
- 1.1.1.149
- progesterone
- androgen
- prostate
- reductases
- testosterone
- prostaglandin
- akr1cs
-
steroidogenic
- luteal
-
castration-resistant
- srd5a1
- androstenedione
-
5alpha-reductase
- cyp17a1
- dihydrotestosterone
- progestin
- akr1b10
-
17beta-hydroxysteroid
- 3alpha-hsds
- abiraterone
-
neurosteroids
-
luteolysis
- hsd3b1
- 5alpha-dihydrotestosterone
- 17beta-hsds
-
enzalutamide
-
flufenamic
-
17beta
- ketosteroid
- allopregnanolone
- 3beta-hsd
-
17alpha
- 17alpha-hydroxyprogesterone
-
hydrogenans
-
pgf2alpha
- hsd17b3
-
pre-receptor
-
intracrine
- 3-ketosteroids
- dihydrodiol
-
scarb1
- analysis
- biotechnology
- food industry
- medicine
- environmental protection
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Synonyms
akr1c3, akr1c1, 20alpha-hsd, 20alpha-hydroxysteroid dehydrogenase, 20beta-hydroxysteroid dehydrogenase, akr1c9, akr1c14, 3alpha-hsor, 3alpha-hydroxysteroid oxidoreductase, aldo-keto reductase family 1 member c1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
AKR1C1
20-alpha-HSD
20alpha-HSD
20alpha-HSDH
-
-
-
-
20alpha-hydroxy steroid dehydrogenase
-
-
-
-
20alpha-hydroxysteroid dehydrogenase
20alpha-hydroxysteroid oxidoreductase
-
-
-
-
20alpha-OH-SDH
-
-
-
-
HSD1
-
-
-
-
20-alpha-HSD
-
-
-
-
20alpha-HSD
-
-
-
-
20alpha-hydroxysteroid dehydrogenase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
17alpha,20alpha-dihydroxypregn-4-en-3-one + NAD(P)+ = 17alpha-hydroxyprogesterone + NAD(P)H + H+
aldoketo reductase superfamily
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
20alpha-hydroxysteroid:NAD(P)+ 20-oxidoreductase
Re-specific with respect to NAD(P)+ (cf. EC 1.1.1.62 17beta-estradiol 17-dehydrogenase).
CAS REGISTRY NUMBER
COMMENTARY
9040-08-8
-
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
(S)-tetralol + NAD(P)+
3,4-dihydronaphthalen-1(2H)-one + NAD(P)H + H+
-
-
-
?
5alpha-dihydroprogesterone + NADPH + H+
5alpha,20alpha-tetrahydroprogesterone + NADP+
-
-
-
r
5alpha-pregnane-3alpha,20alpha-diol + NAD(P)+
3alpha-hydroxy-5alpha-pregnan-20-one + NAD(P)H + H+
-
-
-
?
5beta-pregnan-3alpha-ol-20-one + NAD(P)H + H+
5alpha-pregnan-3alpha,20alpha-diol + NAD(P)+
-
-
-
?
dihydrotestosterone + NADPH + H+
4-androsten-3alpha,17beta-diol + NADP+
reaction of EC 1.1.1.357
-
-
r
17alpha-hydroxyprogesterone + NAD(P)H + H+
17alpha,20alpha-dihydroxy-pregn-4-en-3-one + NAD(P)+
-
-
-
-
?
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one + NADP+
?
-
-
-
-
r
4-pregnen-20alpha-ol-3-one + NAD(P)+
4-pregnen-3,20-dione + NAD(P)H + H+
-
-
-
-
r
5alpha-pregnan-20alpha-ol-3-one + NAD(P)+
5alpha-pregnan-3,20-dione + NAD(P)H
-
-
-
-
r
5alpha-pregnan-20alpha-ol-3-one + NAD(P)+
5alpha-pregnane-3,20-dione + NAD(P)H
-
-
-
-
r
5alpha-pregnan-3alpha-ol-20-one + NAD(P)H
5alpha-pregnan-3alpha,20alpha-diol + NAD(P)+
-
-
-
-
r
5alpha-pregnan-3alpha-ol-20-one + NAD(P)H + H+
5alpha-pregnan-3alpha,20alpha-diol + NAD(P)+
-
-
-
-
r
5alpha-pregnane-21-ol-3,20-dione + NAD(P)H
5alpha-pregnane-20alpha,21-diol-3-one + NAD(P)+
-
-
-
-
r
5alpha-pregnane-3,20-dione + NAD(P)H
5alpha-pregnan-20alpha-ol-3-one + NAD(P)+
-
-
-
-
r
5alpha-pregnane-3alpha,20alpha-diol + NAD(P)+
3alpha-hydroxy-5alpha-pregnan-20-one + NAD(P)H + H+
-
-
-
-
r
5alpha-pregnane-3alpha,21-diol-20-one + NAD(P)H + H+
5alpha-pregnane-3alpha,20alpha,21-triol + NAD(P)+
-
-
-
-
r
5beta-pregnan-20alpha-ol-3-one + NAD(P)+
5beta-pregnan-3,20-dione + NAD(P)H
-
-
-
-
r
5beta-pregnan-3alpha-ol-20-one + NAD(P)H
5beta-pregnan-3alpha,20alpha-diol + NAD(P)+
-
-
-
-
r
5beta-pregnan-3alpha-ol-20-one + NAD(P)H
5beta-pregnane-3alpha,20alpha-diol + NAD(P)+
-
-
-
-
r
5beta-pregnane-3,20-dione + NAD(P)H + H+
5alpha-pregnan-20alpha-ol-3-one + NAD(P)+
-
-
-
-
r
5beta-pregnane-3alpha,20alpha-diol + NAD(P)+
5beta-pregnan-20alpha-ol-3-one + NAD(P)H + H+
additional information
?
-
-
negligible activity with dehydroepiandrosterone, estrone estradiol, 4-androstenendione, testosterone and diydrotestosterone as substrates
-
-
?
daunorubicin + NADPH + H+
daunorubicinol + NADP+
inactivation of the anticancer drug
-
-
r
daunorubicin + NADPH + H+
daunorubicinol + NADP+
the enzyme reduces daunorubicin to its corresponding alcohol daunorubicinol using NADPH as the coenzyme
-
-
r
17alpha-hydroxyprogesterone + NAD(P)H
17alpha,20alpha-dihydroxypregn-4-en-3-one + NAD(P)+
-
-
-
-
r
17alpha-hydroxyprogesterone + NAD(P)H
17alpha,20alpha-dihydroxypregn-4-en-3-one + NAD(P)+
-
the enzyme activity is highest in women with visceral obesity
-
-
r
5beta-pregnane-3alpha,20alpha-diol + NAD(P)+
5beta-pregnan-20alpha-ol-3-one + NAD(P)H + H+
-
-
-
-
?
5beta-pregnane-3alpha,20alpha-diol + NAD(P)+
5beta-pregnan-20alpha-ol-3-one + NAD(P)H + H+
-
-
-
-
r
progesterone + NAD(P)H
20alpha-hydroxyprogesterone + NAD(P)+
-
NADPH much more efficient, 4-fold lower Km
-
?
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
5alpha-dihydroprogesterone + NADPH + H+
5alpha,20alpha-tetrahydroprogesterone + NADP+
-
-
-
r
daunorubicin + NADPH + H+
daunorubicinol + NADP+
inactivation of the anticancer drug
-
-
r
dihydrotestosterone + NADPH + H+
4-androsten-3alpha,17beta-diol + NADP+
reaction of EC 1.1.1.357
-
-
r
17alpha-hydroxyprogesterone + NAD(P)H
17alpha,20alpha-dihydroxypregn-4-en-3-one + NAD(P)+
-
-
-
-
r
17alpha-hydroxyprogesterone + NAD(P)H
17alpha,20alpha-dihydroxypregn-4-en-3-one + NAD(P)+
-
the enzyme activity is highest in women with visceral obesity
-
-
r
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4'-butyl-5-chloro-4-hydroxybiphenyl-3-carboxylic acid
7fold selectivity relative to 3alpha-hydroxysteroid dehydrogenase AKR1C2
5-chloro-4-hydroxy-3'-methylbiphenyl-3-carboxylic acid
13fold selectivity relative to 3alpha-hydroxysteroid dehydrogenase AKR1C2
5-chloro-4-hydroxy-4'-methylbiphenyl-3-carboxylic acid
24fold selectivity relative to 3alpha-hydroxysteroid dehydrogenase AKR1C2
5-chloro-4-hydroxybiphenyl-3-carboxylic acid
24fold selectivity relative to 3alpha-hydroxysteroid dehydrogenase AKR1C2
5-fluoro-4-hydroxybiphenyl-3-carboxylic acid
1.2fold selectivity relative to 3alpha-hydroxysteroid dehydrogenase AKR1C2
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0026
2-amino-8-((2-fluoro-4-methoxybenzyl)thio)-1,9-dihydro-6H-purin-6-one
-
pH 7.0, 25°C
additional information
additional information
-
rapid activity decrease upon homogenization
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0358
1-phenylcyclopentanecarboxylic acid
pH 6.5, temperature not specified in the publication
0.0172
2-(4-chlorobenzylidene)cyclopentanone
pH 6.5, temperature not specified in the publication
0.0305
2-(4-chlorobenzylidene)cyclopentyl ethyl ether
pH 6.5, temperature not specified in the publication
0.0485
3-phenylcyclopentanecarboxylic acid
pH 6.5, temperature not specified in the publication
0.0000021
4'-butyl-5-chloro-4-hydroxybiphenyl-3-carboxylic acid
wild-type, 25°C, pH not specified in the publication
0.0000013
5-chloro-4-hydroxy-3'-methylbiphenyl-3-carboxylic acid
wild-type, 25°C, pH not specified in the publication
0.0000026
5-chloro-4-hydroxy-4'-methylbiphenyl-3-carboxylic acid
wild-type, 25°C, pH not specified in the publication
0.00000086
5-chloro-4-hydroxybiphenyl-3-carboxylic acid
wild-type, 25°C, pH not specified in the publication
0.0000013
5-fluoro-4-hydroxybiphenyl-3-carboxylic acid
wild-type, 25°C, pH not specified in the publication
0.0000007
3',3'',5',5''-tetrabromophenolphthalein
-
binding to NADPH-enzyme complex via ordered bi-bi-mechanism
0.0000059
3,5-dichlorosalicylic acid
wild type enzyme, in 0.1 M potassium phosphate buffer, pH 7.4
0.0000059
3,5-dichlorosalicylic acid
wild-type, 25°C, pH not specified in the publication
0.000078
3,5-dichlorosalicylic acid
mutant L308V, 25°C, pH not specified in the publication
0.00027
3,5-dichlorosalicylic acid
mutant enzyme L306A, in 0.1 M potassium phosphate buffer, pH 7.4
0.00058
3,5-dichlorosalicylic acid
mutant enzyme H222S, in 0.1 M potassium phosphate buffer, pH 7.4
0.00085
3,5-dichlorosalicylic acid
mutant enzyme L54V, in 0.1 M potassium phosphate buffer, pH 7.4
0.00279
3,5-dichlorosalicylic acid
mutant L308A, 25°C, pH not specified in the publication
0.0028
3,5-dichlorosalicylic acid
mutant enzyme L308A, in 0.1 M potassium phosphate buffer, pH 7.4
0.0000041
3-bromo-5-phenylsalicylic acid
wild-type, 25°C, pH not specified in the publication
0.000014
3-bromo-5-phenylsalicylic acid
mutant L308V, 25°C, pH not specified in the publication
0.000113
3-bromo-5-phenylsalicylic acid
mutant L308A, 25°C, pH not specified in the publication
0.0000059
3,5-dichlorosalicylic acid
-
wild-type, pH and temperature not specified in the publication
0.0000066
3,5-dichlorosalicylic acid
-
mutant F311A, pH and temperature not specified in the publication
0.000007
3,5-dichlorosalicylic acid
-
mutant F311L, pH and temperature not specified in the publication
0.000078
3,5-dichlorosalicylic acid
-
mutant L308V, pH and temperature not specified in the publication
0.000085
3,5-dichlorosalicylic acid
-
mutant L54V, pH and temperature not specified in the publication
0.000273
3,5-dichlorosalicylic acid
-
mutant L306A, pH and temperature not specified in the publication
0.00279
3,5-dichlorosalicylic acid
-
mutant L308V, pH and temperature not specified in the publication
0.00000085
3-chloro-5-phenylsalicylic acid
-
mutant F311L, pH and temperature not specified in the publication
0.00000086
3-chloro-5-phenylsalicylic acid
-
wild-type, pH and temperature not specified in the publication
0.0000012
3-chloro-5-phenylsalicylic acid
-
mutant L308V, pH and temperature not specified in the publication
0.0000015
3-chloro-5-phenylsalicylic acid
-
mutant F311A, pH and temperature not specified in the publication
0.0000017
3-chloro-5-phenylsalicylic acid
-
mutant L308V, pH and temperature not specified in the publication
0.0000048
3-chloro-5-phenylsalicylic acid
-
mutant L54V, pH and temperature not specified in the publication
0.00007
3-chloro-5-phenylsalicylic acid
-
mutant L306A, pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0729
1-phenylcyclopentanecarboxylic acid
Homo sapiens
pH 6.5, temperature not specified in the publication
0.035
2-(4-chlorobenzylidene)cyclopentanone
Homo sapiens
pH 6.5, temperature not specified in the publication
0.0621
2-(4-chlorobenzylidene)cyclopentyl ethyl ether
Homo sapiens
pH 6.5, temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
enzyme activity is 8-14fold higher in nontumorgenic strain MCF-10A than in tumorgenic strains MCF-7, MDA-MB-231, T-47D
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
-
abdominal subcutaneous and omental adipose tissue, the enzyme activity is highest in women with visceral obesity, expression analysis
-
breast cancer cells: tumorgenic strains MCF-7, MDA-MB-231, T-47D, nontumorgenic strain MCF-10A
additional information
additional information
the expression of AKR1C1 is elevated in lung, uterine cervix, and colon cancers
additional information
-
the expression of AKR1C1 is elevated in lung, uterine cervix, and colon cancers
additional information
in addition to neurons, 3alpha-HSOR activity appears to be highly localized in glial cells, such as type 1 astrocytes in culture and oligodendrocytes, although, 3alpa-HSOR activity has not been detected in myelin membranes of the CNS
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
the expression of 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR) and the levels of progesterone and testosterone reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. In other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5alpha-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. Low plasma testosterone levels are significantly associated with increased risk of Alzheimer's disease in elderly men, while higher free testosterone levels in women are associated with lower cerebral Abeta positivity
metabolism
the enzymatic complex 5alpha-reductase (5alpha-R) and 3alpha/3beta-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone and testosterone into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5alpha-R and 3alpha-HSOR and the levels of progesterone and testosterone reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. Biosynthesis of progesterone and testosterone metabolites and their mechanism of action, overview
physiological function
evolution
the enzyme is a member of the aldo-keto reductase (AKR) superfamily that metabolizes endogenous substrates, such as carbohydrates, prostaglandins and steroids, and xenobiotics in a NAD(P)(H)-dependent manner
physiological function
crucial role of AKR1C1 in the acquisition of daunorubicin resistance of leukemic cells by metabolizing both daunorubicin and cytotoxic aldehydes derived from ROS-linked lipid peroxidation. Daunorubicin, at its sublethal doses, induces the expression of AKR1C1 and AKR1C3, EC 1.1.1.239, both of which reduce the daunorubicin sensitivity of the cells, AKR1C3 is more inducible than AKR1C1 by the daunorubicin treatment
physiological function
the enzymatic complex 5alpha-R and 3alpha-HSOR colocalizes in glutamatergic and GABAergic neurons of the cerebral cortex, hippocampus, amygdala and thalamus, suggesting that metabolites so formed are relevant for neurotransmitter synthesis and the modulation of their activity in these cells. The metabolites of progesterone and testosterone formed by the action of the enzymatic complex 5alpha-R and 3alpha- or 3beta-HSOR have a profound physiological impact in the nervous system, because they are also ligands for a variety of neuronal and glial receptors that are not directly modulated by progesterone and testosterone. The reduced metabolites of progesterone are also involved in mood regulation. Actions of progesterone and testosterone metabolites in physiological conditions, overview. The enzyme is involed in regulation of the levels of progesterone and testosterone reduced metabolites in the nervous system. Metabolite of dihydrotestosterone (DHT), 4-androsten-3alpha,17beta-diol, exerts europrotective effects in SH-SY5Y neuronal cells and in primary cortical neurons, inhibiting the phosphorylation of extracellular signal-regulated kinase induced by amyloid beta peptide 1-42. Interestingly, this effect is mediated by both GABA-A receptor-dependent and independent mechanisms
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). AK1C1_HUMAN
323
0
36788
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
35000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
docking model with substrates 5alpha-pregnane-3alpha,20alpha-diol and 5beta-pregnan-3alpha-ol-20-one. In the docked model of 5alpha-pregnane-3alpha,20alpha-diol the conformation of the steroid molecule is similar to that of 20alpha-hydroxyprogesterone in the crystal structure of the AKR1C1 complex where the steroid does not interact with the catalytic residues Tyr55 and His117. In the case of 5beta-pregnan-3alpha-ol-20-one the steroid interacts with the catalytic residue His117 and forms close contacts with Leu308
in ternary complex with NADP+ and 3,5-dichlorosalicylic acid, hanging drop vapour diffusion method, using 25% (v/v) polyethylene glycol monomethyl ether 550, 0.02 M zinc sulfate in 0.1 M MES buffer (pH 6.5)
mutant L308V in complex with the inhibitor 3,5-dichlorosalicylic acid, to 1.9 A resolution. The inhibitor molecule is anchored from its carboxylate group that forms hydrogen bonds with the catalytic residues His117 and Tyr55, while the hydroxyl group is hydrogen bonded to His222. Van der Waals contacts are present between the inhibitor and residues Leu54, Leu306, and Phe311. Unlike the WT enzyme, the side-chain of the mutated Val308 makes long contacts with the inhibitor, the closest point of contact being 3.9 A
crystal structure of AKR1C1 complexed with the first structure-based designed inhibitor 3-chloro-5-phenylsalicylic acid bound in the active site is reported. The binding of 3-chloro-5-phenylsalicylic acid to AKR1C1 results in a conformational change in the side chain of Phe311 to accommodate the bulky phenyl ring substituent at the 5-position of the inhibitor
-
purified recombinant enzyme in complex with cofactor and several substrates, hanging drop vapour diffusion method, 4°C, HEPES or sodium acetate buffer, CaCl2, precipitant is PEG 4000, X-ray diffraction structure determination and analysis at 2.4-2.5 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H222S
the mutation in AKR1C1 results in a 10fold reduction in the potency of the inhibitor 3,5-dicholorosalicylic acid
L306
the mutation in AKR1C1 results in a 46fold reduction in the potency of the inhibitor 3,5-dicholorosalicylic acid
L308A
L308V
L54V
the mutation in AKR1C1 results in a 14fold reduction in the potency of the inhibitor 3,5-dicholorosalicylic acid
F311A
-
mutation results in increased Ki values for 3-chloro-5-phenylsalicylic acid and 3,5-dichlorosalicylic acid compared to the wild-type enzyme
F311L
-
mutation results in equal Ki value for 3-chloro-5-phenylsalicylic acid and increased Ki value for 3,5-dichlorosalicylic acid compared to the wild-type enzyme
L306A
-
mutation results in 81fold increase Ki values for 3-chloro-5-phenylsalicylic acid compared to the wild-type enzyme
L308A
-
mutation results in increased Ki values for 3-chloro-5-phenylsalicylic acid and 3,5-dichlorosalicylic acid compared to the wild-type enzyme
L308V
-
mutation results in increased Ki values for 3-chloro-5-phenylsalicylic acid and 3,5-dichlorosalicylic acid compared to the wild-type enzyme
L54V
-
mutation results in increased Ki values for 3-chloro-5-phenylsalicylic acid and 3,5-dichlorosalicylic acid compared to the wild-type enzyme
L308A
the mutation in AKR1C1 results in a 470fold reduction in the potency of the inhibitor 3,5-dicholorosalicylic acid
L308A
mutation renders the enzyme inactive towards the two substrates 5alpha-pregnane-3alpha,20alpha-diol and 5beta-pregnan-3alpha-ol-20-one
L308A
mutation results in 473-fold and 27fold reductions in the inhibitory potencies of 3,5-dichlorosalicylic acid and 3-bromo-5-phenylsalicylic acid, respectively
L308V
crystallization data. Mutation results in 13-fold and 3fold reductions in the inhibitory potencies of 3,5-dichlorosalicylic acid and 3-bromo-5-phenylsalicylic acid, respectively
L308V
mutation improves the catalytic efficiency towards the two substrates 5alpha-pregnane-3alpha,20alpha-diol and 5beta-pregnan-3alpha-ol-20-one
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
co-purification with 17beta-estradiol dehydrogenase, EC 1.1.1.62, affinity chromatography
-
recombinant GST-fusion enzyme by glutahione affinity chromatography and cleavage of the GST-tag by Factor Xa, followed by ion exchange chromatography, and gel filtration, to homogeneity
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNA of skin fibroblast cDNA library inserted into pCMV expression vector, transiently transfected into and expressed in HEK-293 cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
human immunodeficiency virus-infected pregnant women receiving protease inhibitor-based combination antiretroviral therapy show an elevation in placental expression of the 20-alpha-hydroxysteroid dehydrogenase
-
placental enzyme expression is significantly elevated in human immunodeficiency virus-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
biotechnology
medicine
-
enzyme activity is 8-14fold higher in nontumorgenic strain MCF-10A than in tumorgenic strains MCF-7, MDA-MB-231, T-47D
biotechnology
-
a process is developed that that allows the production of 20alpha- dihydrodydrogesterone at technical scale (several grams of 20a-DHD per week and fermenter). Genetic improvement of the production strain, an increase of substrate solubility by addition of ß-cyclodextrin, and the development of a sophisticated high-cell density fermentation at pilot scale are employed. By usage of the exemplary substrate progesterone, it is hsown that this innovative fission yeast-based whole cell biotransformation process is transferable to the conversion of other AKR1C1 substrates without special adaptation
biotechnology
-
an aldo-keto reductases-dependent whole-cell biotransformation process is established that can be used for production of human aldo-keto reductases metabolites on a large scale
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Strickler, R.C.; Tobias, B.; Covey, D.F.
Human placental 17beta-estradiol dehydrogenase and 20alpha-hydroxysteroid dehydrogenase. Two activities at a single enzyme active site
J. Biol. Chem.
256
316-321
1981
Homo sapiens
Blomquist, C.H.; Lindemann, N.J.; Hakanson, E.Y.
17beta-Hydroxysteroid and 20alpha-hydroxysteroid dehydrogenase activities of human placental microsomes: kinetic evidence for two enzymes differing in substrate specificity
Arch. Biochem. Biophys.
239
206-215
1985
Homo sapiens
Hatono-Sato, F.; Shikita, M.
20alpha-hydroxy steroid dehydrogenase of cultured mammalian (HeLa S3) cells
Endocrinol. Jpn.
20
385-390
1973
Homo sapiens
Zhang, Y.; Dufort, I.; Rheault, P.; Luu-The, V.
Characterization of a human 20alpha-hydroxysteroid dehydrogenase
J. Mol. Endocrinol.
25
221-228
2000
Homo sapiens, Mammalia
Couture, J.F.; Cantin, L.; Legrand, P.; Luu-The, V.; Labrie, F.; Breton, R.
Expression, crystallization and preliminary X-ray analysis of human and rabbit 20alpha-hydroxysteroid dehydrogenases in complex with NADP(H) and various steroid substrates
Acta Crystallogr. Sect. D
58
135-139
2002
Oryctolagus cuniculus, Homo sapiens
Wiebe, J.P.; Lewis, M.J.
Activity and expression of progesterone metabolizing 5alpha-reductase, 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells
BMC Cancer
3
9
2003
Homo sapiens
Higaki, Y.; Usami, N.; Shintani, S.; Ishikura, S.; El-Kabbani, O.; Hara, A.
Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone
Chem. Biol. Interact.
143-144
503-513
2003
Homo sapiens
Couture, J.F.; Legrand, P.; Cantin, L.; Luu-The, V.; Labrie, F.; Breton, R.
Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids
J. Mol. Biol.
331
593-604
2003
Homo sapiens
Blanchette, S.; Blouin, K.; Richard, C.; Dupont, P.; Luu-The, V.; Tchernof, A.
Expression and activity of 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in abdominal subcutaneous and omental adipose tissue in women
J. Clin. Endocrinol. Metab.
90
264-270
2005
Homo sapiens
Dhagat, U.; Carbone, V.; Chung, R.P.; Matsunaga, T.; Endo, S.; Hara, A.; El-Kabbani, O.
A salicylic acid-based analogue discovered from virtual screening as a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase
Med. Chem.
3
546-550
2007
Homo sapiens
Dhagat, U.; Endo, S.; Sumii, R.; Hara, A.; El-Kabbani, O.
Selectivity determinants of inhibitor binding to human 20alpha-hydroxysteroid dehydrogenase: crystal structure of the enzyme in ternary complex with coenzyme and the potent inhibitor 3,5-dichlorosalicylic acid
J. Med. Chem.
51
4844-4848
2008
Homo sapiens (Q04828), Homo sapiens
El-Kabbani, O.; Scammells, P.J.; Gosling, J.; Dhagat, U.; Endo, S.; Matsunaga, T.; Soda, M.; Hara, A.
Structure-guided design, synthesis, and evaluation of salicylic acid-based inhibitors targeting a selectivity pocket in the active site of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1)
J. Med. Chem.
52
3259-3264
2009
Homo sapiens
Smuc, T.; Rizner, T.L.
Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer
Mol. Cell. Endocrinol.
301
74-82
2009
Homo sapiens
Dhagat, U.; Endo, S.; Soda, M.; Hara, A.; El-Kabbani, O.
Factorizing the role of a critical leucine residue in the binding of substrate to human 20alpha-hydroxysteroid dehydrogenase (AKR1C1): molecular modeling and kinetic studies of the Leu308Val mutant enzyme
Bioorg. Med. Chem. Lett.
20
5274-5276
2010
Homo sapiens (Q04828), Homo sapiens
Stefane, B.; Brozic, P.; Vehovc, M.; Rizner, T.L.; Gobec, S.
New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3
Eur. J. Med. Chem.
44
2563-2571
2009
Homo sapiens (Q04828)
El-Kabbani, O.; Scammells, P.J.; Day, T.; Dhagat, U.; Endo, S.; Matsunaga, T.; Soda, M.; Hara, A.
Structure-based optimization and biological evaluation of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors
Eur. J. Med. Chem.
45
5309-5317
2010
Homo sapiens (Q04828), Homo sapiens
Naumann, J.M.; Zoellner, A.; Dragan, C.A.; Messinger, J.; Adam, J.; Bureik, M.
Biotechnological production of 20-alpha-dihydrodydrogesterone at pilot scale
Appl. Biochem. Biotechnol.
165
190-203
2011
Homo sapiens
El-Kabbani, O.; Dhagat, U.; Soda, M.; Endo, S.; Matsunaga, T.; Hara, A.
Probing the inhibitor selectivity pocket of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) with X-ray crystallography and site-directed mutagenesis
Bioorg. Med. Chem. Lett.
21
2564-2567
2011
Homo sapiens
Naumann, J.M.; Messinger, J.; Bureik, M.
Human 20alpha-hydroxysteroid dehydrogenase (AKR1C1)-dependent biotransformation with recombinant fission yeast Schizosaccharomyces pombe
J. Biotechnol.
150
161-170
2010
Homo sapiens
Papp, E.; Balogun, K.; Banko, N.; Mohammadi, H.; Loutfy, M.; Yudin, M.; Shah, R.; Macgillivray, J.; Murphy, K.; Walmsley, S.; Silverman, M.; Serghides, L.
Low prolactin and high 20-alpha-hydroxysteroid dehydrogenase levels contribute to lower progesterone levels in hiv-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy
J. Infect. Dis.
213
1532-1540
2016
Homo sapiens
Matsunaga, T.; Yamaguchi, A.; Morikawa, Y.; Kezuka, C.; Takazawa, H.; Endo, S.; El-Kabbani, O.; Tajima, K.; Ikari, A.; Hara, A.
Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells
Anticancer Drugs
25
868-877
2014
Homo sapiens (Q04828), Homo sapiens
Giatti, S.; Diviccaro, S.; Falvo, E.; Garcia-Segura, L.; Melcangi, R.
Physiopathological role of the enzymatic complex 5alpha-reductase and 3alpha/beta-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites
Front. Neuroendocrinol.
57
100836
2020
Rattus norvegicus, Homo sapiens (Q04828), Mus musculus (Q91WT7)
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