Literature summary for 1.1.1.50 extracted from

Steckelbroeck, S.; Jin, Y.; Oyesanmi, B.; Kloosterboer, H.J.; Penning, T.M.
Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: Inversion of stereospecificity with a DELTA5(10)-3-ketosteroid (2004), Mol. Pharmacol., 66, 1702-1711.

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Cloned(Commentary)

Cloned (Comment)	Organism
overexpression of isozymes AKR1C1-AKR1C4 in Escherichia coli C41(DE3)	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
NADPH	strongly inhibits the oxidation of 3-hydroxymetabolites in vivo and in vitro, determining the role of enzymes as 3-ketosteroid reductases in vivo, no inhibition of tibolone reduction in vitro, overview	Homo sapiens
tibolone	strong substrate inhibition of isozyme AKR1C2	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	steady state kinetics, overview	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
additional information	Homo sapiens	due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q04828	4 isozymes AKR1C1-AKR1C4	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant isozymes AKR1C1-AKR1C4 from Escherichia coli by DE52 ion exchange and Blue Sepharose chromatography, to homogeneity	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
liver	specific isozyme AKR1C4	Homo sapiens	-

Specific Activity [micromol/min/mg]

Specific Activity Minimum [µmol/min/mg]	Specific Activity Maximum [µmol/min/mg]	Comment	Organism
0.00002	-	purified recombinant isozymes AKR1C1 and AKR1C3, substrate 3alpha-hydroxytibolone	Homo sapiens
0.00015	-	purified recombinant isozyme AKR1C3, substrate 3beta-hydroxytibolone	Homo sapiens
0.00079	-	purified recombinant isozyme AKR1C1, substrate 3beta-hydroxytibolone	Homo sapiens
0.00653	-	purified recombinant isozyme AKR1C4, substrate 3beta-hydroxytibolone	Homo sapiens
0.0188	-	purified recombinant isozyme AKR1C4, substrate 3alpha-hydroxytibolone	Homo sapiens
0.0253	-	purified recombinant isozyme AKR1C2, substrate 3beta-hydroxytibolone	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
3alpha-hydroxytibolone + NAD+	isozymes AKR1C2 and AKR1C4, no activity with isozyme AKR1C1	Homo sapiens	tibolone + NADH	-	r
3beta-hydroxytibolone + NAD+	isozymes AKR1C2, AKR1C1, and AKR1C4	Homo sapiens	tibolone + NADH	-	r
5alpha-dihydroprogesterone + 2 NADPH + 2 H+	isozyme AKR1C2 acts 3alpha-specific on 5alpha-DHT, preferred substrate	Homo sapiens	pregnan-3alpha,20beta-diol + 2 NADP+	-	r
additional information	due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo	Homo sapiens	?	-	?
additional information	molecular docking experiments using the crystal structures of isozymes AKR1C1 and AKR1C2 reveal the structural basis for stereospecificity of the isozymes	Homo sapiens	?	-	?
tibolone + NADPH + H+	isozyme AKR1C4 acts predominantly 3alpha-specific, isozyme AKR1C3 performs both 3alpha- and 3beta-reduction, tibolone is [7alpha,17alpha]-17-hydroxy-7-methyl-19-nor-pregn-5(10)-en-20-yn-3-one, or livial, a DELTA5(10)-ene-ketosteroid and a hormone replacement therapeutic used in the treatment of climacteric complaints and the prevention of osteoporosis, binding mode	Homo sapiens	3alpha-hydroxytibolone + NADP+	-	r
tibolone + NADPH + H+	isozyme AKR1C1 is stereospecific forming exclusively the beta-isomer, isozyme AKR1C2 is 3beta-specific with substrate tibolone, isozyme AKR1C3 performs both 3alpha- and 3 beta-reduction, tibolbone is [7alpha,17alpha]-17-hydroxy-7-methyl-19-nor-pregn-5(10)-en-20-yn-3-one, or livial, a DELTA5(10)-ene-ketosteroid and a hormone replacement therapeutic used in the treatment of climacteric complaints and the prevention of osteoporosis	Homo sapiens	3beta-hydroxytibolone + NADP+	-	r

Synonyms

Synonyms	Comment	Organism
3alpha/3beta-hydroxysteroid dehydrogenase	-	Homo sapiens
AKR1C	-	Homo sapiens
More	the isozymes belong to the AKR1C subfamily of the aldo-keto-reductase AKR superfamily	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
0.000016	-	3beta-hydroxytibolone	below, pH 7.0, 37°, isozyme AKR1C3	Homo sapiens
0.000016	-	3alpha-hydroxytibolone	below, pH 7.0, 37°, isozymes AKR1C1 and AKR1C3	Homo sapiens
0.0005	-	3beta-hydroxytibolone	pH 7.0, 37°, isozyme AKR1C1	Homo sapiens
0.004	-	3beta-hydroxytibolone	pH 7.0, 37°, isozyme AKR1C4	Homo sapiens
0.012	-	3alpha-hydroxytibolone	pH 7.0, 37°, isozyme AKR1C4	Homo sapiens
0.016	-	3beta-hydroxytibolone	pH 7.0, 37°, isozyme AKR1C1	Homo sapiens

pH Optimum

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

Cofactor

Cofactor	Comment	Organism	Structure
NAD+	-	Homo sapiens
NADH	-	Homo sapiens
NADP+	-	Homo sapiens
NADPH	-	Homo sapiens

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Release 2023.1 (January 2023)