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Literature summary for 1.1.1.357 extracted from

  • Wan, R.; Kong, X.; Yang, Y.; Tao, S.; Chen, Y.; Teichmann, A.T.; Wieland, F.H.
    Role of human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C3) in the extrahepatic metabolism of the steroidal aromatase inactivator Formestane (2020), J. Steroid Biochem. Mol. Biol., 198, 105527 .
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
-
Homo sapiens
AKR1C1, transient expression in COS-1 cells, and recombinant overexpression in Escherichia coli strain BL21(DE3), quantitative real-time PCR analysis Homo sapiens
AKR1C2, transient expression in COS-1 cells, and recombinant overexpression in Escherichia coli strain BL21(DE3), quantitative real-time PCR analysis Homo sapiens
AKR1C3, transient expression in COS-1 cells, and recombinant overexpression in Escherichia coli strain BL21(DE3), quantitative real-time PCR analysis Homo sapiens
AKR1C4, transient expression in COS-1 cells, and recombinant overexpression in Escherichia coli strain BL21(DE3), quantitative real-time PCR analysis Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
additional information flufenamic acid inhibits the isozyme's 17beta-oxosteroid reductase activity Homo sapiens
Phenolphthalein strong inhibition Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
additional information AKR1C isozymes kinetics analysis, steady-state Michaelis-Menten kinetics Homo sapiens
0.00212
-
4-androstenedione pH 7.4, 37°C Homo sapiens
0.0023
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.00603
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.00622
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.00843
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.00884
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.00977
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.01029
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.0117
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.016
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.02687
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.03362
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol
-
Homo sapiens 5829
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
4-hydroxyandrostenedione + NADPH + H+ Homo sapiens
-
3alpha,4beta-dihydroxy-5alpha-androstan-17-one + NADP+
-
?
dihydrotestosterone + NADPH + H+ Homo sapiens low activity 4-androsten-3alpha,17beta-diol + NADP+
-
?
dihydrotestosterone + NADPH + H+ Homo sapiens high activity 4-androsten-3alpha,17beta-diol + NADP+
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P17516
-
-
Homo sapiens P42330
-
-
Homo sapiens P52895
-
-
Homo sapiens Q04828
-
-

Purification (Commentary)

Purification (Comment) Organism
-
Homo sapiens
recombinant enzyme from Escherichia coli strain BL21(DE3) Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
4-androstenedione + NADPH the enzyme act as reductase for 4-hydroxyandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
4-hydroxyandrostenedione + NADPH the enzyme act as reductase for 4-hydroxandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
4-hydroxyandrostenedione + NADPH the enzyme act as reductase for 4-hydroxyandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
4-hydroxyandrostenedione + NADPH + H+
-
Homo sapiens 3alpha,4beta-dihydroxy-5alpha-androstan-17-one + NADP+
-
?
4-hydroxytestosterone + NADPH the enzyme act as reductase for 4-hydroxandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
4-hydroxytestosterone + NADPH the enzyme act as reductase for 4-hydroxyandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
4-hydroxytestosterone + NADPH + H+
-
Homo sapiens 3alpha,4beta-dihydroxy-5alpha-androstan-17-ol + NADP+
-
?
dihydrotestosterone + NADPH the enzyme act as reductase for 4-hydroxandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
dihydrotestosterone + NADPH the enzyme act as reductase for 4-hydroxyandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?
dihydrotestosterone + NADPH + H+ low activity Homo sapiens 4-androsten-3alpha,17beta-diol + NADP+
-
?
dihydrotestosterone + NADPH + H+ high activity Homo sapiens 4-androsten-3alpha,17beta-diol + NADP+
-
?
additional information identification of metabolites by GC-MSMS in feeding experiments of recombinant COS-1 cells. Substrate specificity of recombinant AKR1C isozymes, overview. The isozymes also have 17beta-hydroxysteroid dehydrogenase activity. No activity with 4-androstenedione and testosterone, and poor activity with 4-hydroxytestosterone (4-OHT) Homo sapiens ?
-
-
additional information identification of metabolites by GC-MSMS in feeding experiments of recombinant COS-1 cells. Substrate specificity of recombinant AKR1C isozymes, overview. The isozymes also have 17beta-hydroxysteroid dehydrogenase activity. No activity with 4-androstenedione, testosterone and poor activity with 4-hydroxytestosterone (4-OHT) Homo sapiens ?
-
-
additional information identification of metabolites by GC-MSMS in feeding experiments of recombinant COS-1 cells. Substrate specificity of recombinant AKR1C isozymes, overview. The isozymes also have 17beta-hydroxysteroid dehydrogenase activity. No activity with 4-androstenedione, testosterone, and 4-hydroxytestosterone (4-OHT) Homo sapiens ?
-
-
additional information identification of metabolites by GC-MSMS in feeding experiments of recombinant COS-1 cells. Substrate specificity of recombinant AKR1C isozymes, overview. The isozymes also have 17beta-hydroxysteroid dehydrogenase activity. No activity with testosterone and 4-androstenedione Homo sapiens ?
-
-
testosterone + NADPH + H+ the enzyme act as reductase for 4-hydroxyandrostenedione in both COS-1 cells and in reaction systems with purified enzymes. It exerts 3alpha-, 3beta-, and 17beta-hydroxysteroid dehydrogenase activities Homo sapiens ?
-
?

Subunits

Subunits Comment Organism
? x * 37000, recombinant AKR1C1, SDS-PAGE Homo sapiens

Synonyms

Synonyms Comment Organism
3-alpha-HSD type 2 UniProt Homo sapiens
3-alpha-HSD1 UniProt Homo sapiens
3-alpha-hydroxysteroid dehydrogenase type 2 UniProt Homo sapiens
3-alpha-hydroxysteroid dehydrogenase type I UniProt Homo sapiens
3alpha-HSD
-
Homo sapiens
3alpha-hydroxysteroid dehydrogenase
-
Homo sapiens
AKR1C1
-
Homo sapiens
AKR1C2
-
Homo sapiens
AKR1C3
-
Homo sapiens
AKR1C4
-
Homo sapiens
aldo-keto reductase family 1 member C1 UniProt Homo sapiens
aldo-keto reductase family 1 member C2 UniProt Homo sapiens
aldo-keto reductase family 1 member C3 UniProt Homo sapiens
type III 3-alpha-hydroxysteroid dehydrogenase UniProt Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.00075
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.0038
-
4-androstenedione pH 7.4, 37°C Homo sapiens
0.0052
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.0078
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.01
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.017
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.0175
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.023
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.0245
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.025
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.026
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.032
-
testosterone pH 7.4, 37°C Homo sapiens
0.032
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
NADPH usage of NADPH-Na4 to NADP-Na2 in enzyme activity assays Homo sapiens

General Information

General Information Comment Organism
metabolism human aldo-keto reductases (AKR1C1-AKR1C4, AKR1Cs) play an important role in the intracellular metabolism of steroids. All AKR1Cs have both 3alpha- and 3beta-HSD activities, AKR1C2 and AKR1C4 have a higher 3alpha-HSD activity, whereas AKR1C1 and AKR1C3 have a higher 3beta-HSD activity Homo sapiens
physiological function the enzyme metabolizes the aromatase inhibitor formestane (4-hydroxandrostenedione, 4-OHA), which binds with high affinity to the androgen receptor, molecular docking and binding kinetics. All recombinant AKR1C isozymes reduce 4-androstenedione to testosterone presenting 17-oxo reductase activity. AKR1C3 is most active as a 17-oxosteroid reductase followed by AKR1C1 and then AKR1C2, whereas AKR1C4 only weakly reduces 4-androstenedione to testosterone. For dihydrotestosterone (DHT), all four enzymes exhibit both 3alpha/beta-oxoreductase activities to various degrees. The major sources of 3beta-diol are AKR1C1, AKR1C3, and AKR1C4, and that of 3alpha-diol is AKR1C2. In this set-up, isolated AKR1C4 preferentially catalysed the 3beta-reduction of DHT. Inhibition by phenolphthalein changes the stereoselectivity back to the normal 3alpha-reduction. For testosterone, the AKR1C isozymes have no catalytic function and even no oxidative 17beta-HSD activity. For 4-hydroxyandrostenedione (4-OHA), some AKR1Cs behave as 17beta-HSD or as 3beta-HSD, but all AKR1Cs convert 4-OHA to 3alpha,4beta-dihydroxy-5alpha-androstan-17-one, possibly reducing the oxo-group at C4, thereby eliminating the double bond to varying extent. AKR1C3 is most active as a 17-oxosteroid reductase. AKR1C4 shows higher activities of 4-oxo-reductase, 3alpha-HSD, and 3beta-HSD, producing the largest amount of 3alpha,4beta-dihydroxy-5alpha-androstan-17-one and 3beta,4beta-dihydroxy-5alpha-androstan-17-one. Like testosterone, 4-hydroxytestosterone (4-OHT) is not a good substrate for isozymes AKR1C1 and AKR1C2. In contrast to testosterone, 4-OHT undergoes some AKR1C catalysed metabolism. Both AKR1C3 and AKR1C4 have some oxidative 17beta-HSD activity, and AKR1C4 has additional obvious 4-5 double bond reductase and 3-oxoreductase activities, making a good production of to 3alpha,4beta-dihydroxy-5alpha-androstan-17-one. AKR1C3 predominantly catalyzes the reduction at C17 of 4-andostenedione as a first step, whereas it catalyzes the first step in the metabolism of 4-OHT as oxidative 17beta-HSD. Apparently, AKR1C4 also catalyses the way of 4-OHT via a special 17beta-hydroxy pathway to 3alpha-adiol, a pathway whereby the 17beta-OH-group is preserved Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.75
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
0.943
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
0.959
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
0.96
-
testosterone pH 7.4, 37°C Homo sapiens
1.29
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
1.43
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
1.63
-
4-hydroxytestosterone pH 7.4, 37°C Homo sapiens
1.7
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens
1.8
-
4-androstenedione pH 7.4, 37°C Homo sapiens
2.25
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
2.9
-
4-hydroxyandrostenedione pH 7.4, 37°C Homo sapiens
2.98
-
dihydrotestosterone pH 7.4, 37°C Homo sapiens