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Information on EC 1.1.1.50 - 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific) and Organism(s) Homo sapiens
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1.1.1.50 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific)IUBMB Comments
The enzyme acts on androsterone and other 3alpha-hydroxysteroids and on 9-, 11- and 15-hydroxyprostaglandin. Si-specific with respect to NAD+ or NADP+. cf. EC 1.1.1.213, 3alpha-hydroxysteroid 3-dehydrogenase (Re-specific).
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Word Map
- 1.1.1.50
-
aldo-keto
- androgen
- testosterone
- reductases
-
beta-hydroxysteroids
-
alpha-reductase
-
beta-diol
- androsterone
- dihydrodiol
- 3alpha-hydroxysteroids
- dihydrotestosterone
- hydroxysteroids
-
alpha-dihydrotestosterone
-
alpha-androstane-3
- 3-ketosteroids
-
alpha-diol
-
trans-dihydrodiols
-
alpha-androstanediol
-
alpha-hsdh
- 15-hydroxyprostaglandin
-
beta-reductase
-
talalay
-
bile-acids
-
pre-receptor
- akr1d1
- 9,10-phenanthrenequinone
- ketosteroid
-
alpha-hydroxy-5
-
20-ketosteroid
-
alpha,17
-
alpha-reduced
- chlordecone
- 17beta-hsd
-
alpha-dht
- environmental protection
- drug development
- biotechnology
- analysis
- medicine
- synthesis
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
Synonyms
3 alpha-hydroxysteroid dehydrogenase, akr1c, hydroxyprostaglandin dehydrogenase, akr1c1-4, type i 3alpha-hsd, bile-acid binding protein, 3alpha-hydroxysteroid dehydrogenase type 3, ps3alphahsd, 3-alpha-hsd, 3alpha-oxidoreductase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-alpha-HSD
-
-
-
-
3alpha-HSD
3alpha-HSD3
3alpha-hydroxysteroid dehydrogenase
AKR1C
HSD28
-
-
-
-
HSD29
-
-
-
-
hydroxyprostaglandin dehydrogenase
-
-
-
-
sterognost 3alpha dehydrogenase, 3alpha-hydroxy steroid
-
-
-
-
type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase
-
-
additional information
3alpha-hydroxysteroid dehydrogenase
-
-
additional information
-
cf. 1.1.1.213, the enzyme belongs to the aldo-keto reductase subfamily AKR1C
additional information
-
cf. EC 1.1.1.213, the enzyme belongs to the aldo-keto reductase subfamily AKR1C
additional information
-
cf. EC 1.1.1.213, the enzyme belongs to the aldo-keto reductase, AKR, superfamily
additional information
-
enzyme belongs to the AKR1C subfamily of the AKR superfamily of enzymes
additional information
-
enzyme belongs to the aldo-keto reductase AKR superfamily
additional information
-
the isozymes belong to the AKR1C subfamily of the aldo-keto-reductase AKR superfamily
additional information
the isozymes belong to the AKR1C subfamily of the aldo-keto-reductase AKR superfamily
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
reaction mechanism
-
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
enzyme isoforms bind substrate in different ways
-
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
isozymes AKR1C1 and AKR1C2 are bifunctional enzymes also showing minor 20alpha-hydroxysteroid dehydrogenase activity, EC 1.1.1.149
-
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
isozymes also performs 17- and 20-ketosteroid reductase and 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidase activities at varying rates
-
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
steroid binding pocket structure of isozyme AKR1C2
-
a 3alpha-hydroxysteroid + NAD(P)+ = a 3-oxosteroid + NAD(P)H + H+
steroid substrate recognition mechanism by isozymes AKR1C1-AKR1C4, Tyr55 is involved in catalysis, ordered bi bi mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
3alpha-hydroxysteroid:NAD(P)+ 3-oxidoreductase (Si-specific)
The enzyme acts on androsterone and other 3alpha-hydroxysteroids and on 9-, 11- and 15-hydroxyprostaglandin. Si-specific with respect to NAD+ or NADP+. cf. EC 1.1.1.213, 3alpha-hydroxysteroid 3-dehydrogenase (Re-specific).
CAS REGISTRY NUMBER
COMMENTARY
9028-56-2
-
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
(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 + NAD+
?
-
-
-
-
r
(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 + NADP+
?
17beta-hydroxy-dihydrotestosterone + NAD+
5alpha-androstan-3,17-dione + NADH
-
-
-
r
3alpha-androstanediol + NAD+
5alpha-dihydrotestosterone + NADH
-
oxidation utilizing NAD+ as a cofactor is the preferred reaction in vitro
-
-
r
3alpha-hydroxytibolone + NAD+
tibolone + NADH
isozymes AKR1C2 and AKR1C4, no activity with isozyme AKR1C1
-
-
r
3alpha-tetrahydroprogesterone + NADH
5alpha-dihydroprogesterone + NAD+
-
-
-
r
3beta-hydroxytibolone + NAD+
tibolone + NADH
isozymes AKR1C2, AKR1C1, and AKR1C4
-
-
r
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
17beta-hydroxy-5alpha-androstan-3-one + NADPH
5alpha-dihydrocortisol + NADPH
3alpha,5alpha-tetrahydrocortisol + NADP+
-
-
-
?
5alpha-dihydroprogesterone + 2 NAD(P)H + 2 H+
pregnan-3alpha,20beta-diol + 2 NAD(P)+
-
-
-
-
?
5alpha-dihydroprogesterone + NADPH + H*
3alpha,5alpha-3-hydroxypregnan-20-one + 5alpha,20alpha-tetrahydroprogesterone + NADP+
-
-
-
-
?
5alpha-dihydroprogesterone + NADPH + H+
(3alpha,5alpha)-3-hydroxypregnan-20-one + NADP+
-
isozymes AKR1C1-AKR1C4
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
5alpha-hydroxy-pregnan-20-one + NADP+
-
isozyme AKR1C2
-
-
?
5alpha-dihydrotestosterone + NAD(P)H + H+
(3beta,5alpha,17beta)-androstane-3,17-diol + NAD(P)+
5alpha-dihydrotestosterone + NADH
3alpha-androstanediol + NAD+
-
reaction direction is regulated by the NAD+:NADPH relation in the cell
-
-
r
5alpha-pregnan-3,20-dione + NAD(P)H
3alpha-hydroxy-5alpha-pregnan-20-one + NAD(P)+
-
-
-
?
5beta-androstan-3,17-dione + NAD(P)H
5beta-androstan-17one-3-ol + NAD(P)+
-
-
-
-
r
5beta-androstan-3alpha,17beta-diol + NADP+
17beta-hydroxy-5beta-androstan-3-one + NADPH
-
-
-
-
r
5beta-dihydrocortisol + NADPH
3alpha,5beta-tetrahydrocortisol + NADP+
-
-
-
?
5beta-dihydroprogesterone + NADPH + H+
3alpha,5beta-3-hydroxypregnan-20-one + NADP+
-
preferred substrate
-
-
?
5beta-dihydrotestosterone + NAD(P)H
5beta-androstan-3alpha,17beta-diol + NAD(P)+
-
-
-
-
?
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADPH
9-[hydroxy(phenyl)methyl]-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADP+
oxidized 8-acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-azabenzo[de]anthracen-10-one + NAD(P)H
reduced 8-acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-azabenzo[de]anthracen-10-one + NAD(P)+
-
synthetic compound with fluorophore core
-
-
r
pregn-4-en-3,20-dione + NADPH + H+
3alpha-hydroxypregn-4-en-20-one + NADP+
-
-
-
r
testosterone + NADP+
4-androstene-3,17-dione + NADPH + H+
-
isozymes AKR1C1-AKR1C4
-
-
r
tibolone + NADPH + H+
3alpha-hydroxytibolone + NADP+
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
-
-
r
tibolone + NADPH + H+
3beta-hydroxytibolone + NADP+
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
-
-
r
(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 + NADP+
?
-
-
-
-
?
(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 + NADP+
?
-
-
-
-
r
4-pregnen-3alpha,20beta-diol + NAD+
(20beta)-20-hydroxypregn-4-en-3-one + NADH + H+
-
-
-
?, ir
4-pregnen-3alpha,20beta-diol + NAD+
(20beta)-20-hydroxypregn-4-en-3-one + NADH + H+
-
-
-
-
ir
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
17beta-hydroxy-5alpha-androstan-3-one + NADPH
-
-
-
r
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
17beta-hydroxy-5alpha-androstan-3-one + NADPH
-
-
-
-
r
5alpha-androstan-3alpha,17beta-diol + NAD(P)H
5alpha-dihydrotestosterone + NAD(P)+
-
-
-
r
5alpha-androstan-3alpha,17beta-diol + NAD(P)H
5alpha-dihydrotestosterone + NAD(P)+
-
-
-
-
r
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
-
-
-
ir
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
-
-
?
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
in the prostate: forward reaction by type 2 isozyme AKR1C3, reverse reaction by type 3 isozyme AKR1C2
-
-
ir
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
inactivation of the potent androgen, 3alpha(beta)-hydroxysteroid oxidoreductase activity
-
-
ir
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
isozyme AKR1C4
-
-
r
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
isozyme AKR1C2 acts 3alpha-specific on 5alpha-DHT, preferred substrate
-
-
r
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
preferred substrate for isozyme AKR1C4, while isozymes AKR1C1-3 show only low activity
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
-
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
in the CNS: both reaction directions by type 3 isozyme AKR1C2
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
last step in neurosteroid allopregnanolone biosynthesis
-
-
?
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
type 2 isozyme AKR1C3 catalyzes the forward reaction, type 3 isozyme AKR1C2 catalyzes the reverse reaction
-
-
ir
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
type 3 isozyme AKR1C2
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
(3beta,5alpha,17beta)-androstane-3,17-diol + NAD(P)+
-
-
-
-
?
5alpha-dihydrotestosterone + NAD(P)H + H+
(3beta,5alpha,17beta)-androstane-3,17-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
(3beta,5alpha,17beta)-androstane-3,17-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
(3beta,5alpha,17beta)-androstane-3,17-diol + NAD(P)+
-
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
-
-
-
-
?
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
-
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstan-3alpha,17beta-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstane-3alpha,17beta-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstane-3alpha,17beta-diol + NAD(P)+
-
discussion of physiological role
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
inactivation of the potent androgen in human prostate
-
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
inactivation of the potent androgen in human prostate, fluorometric activity measurement in intact cells, overview
-
-
?
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
i.e. DHT
-
-
?
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
i.e. DHT
-
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstane-3alpha,17beta-diol + NADP+
-
-
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstane-3alpha,17beta-diol + NADP+
-
-
-
r
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADPH
9-[hydroxy(phenyl)methyl]-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADP+
-
competitive substrate, fluorometric activity measurement in intact cells, overview
-
-
?
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADPH
9-[hydroxy(phenyl)methyl]-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADP+
-
competitive substrate
-
-
?
androsterone + NADP+
androstane-3,17-dione + NADPH
-
isozymes AKR1C2, and AKR1C4
-
-
r
tibolone + NADPH + H+
3-hydroxytibolone + NADP+
-
tibolone is used to treat climacteric symptoms and prevent osteoporosis, it exerts tissue-selective effects via site-specific metabolism into 3alpha- and 3beta-hydroxymetabolites and a DELTA4-isomer
-
-
?
tibolone + NADPH + H+
3-hydroxytibolone + NADP+
-
i.e. [7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, stereoselctive reaction to the 3alpha-hydroxytibolone product
-
-
?
tibolone + NADPH + H+
3-hydroxytibolone + NADP+
-
i.e. [7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, stereoselective reaction to the 3alpha-hydroxytibolone product
-
-
?
additional information
?
-
-
a saturated 4,5 double bound is essential for enzyme activity, 3-ketosteroids are not used as substrates
-
-
?
additional information
?
-
-
can not catalyze conversion of 3alpha-androstanediol to 5alpha-dihydrotestosterone
-
-
?
additional information
?
-
-
type 3 isoform in liver virtually identical with bile acid-binding protein
-
-
?
additional information
?
-
due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo
-
-
?
additional information
?
-
-
due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo
-
-
?
additional information
?
-
-
enzyme inactivates steroid hormones in the liver, regulates 5alpha-dihydrotestosterone levels in the prostate, and forms the neurosteroid allopregnanolone in the CNS, isozymes might be involved in regulation of the levels of active androgens, estrogens, and progestrins
-
-
?
additional information
?
-
in vivo the isozymes act predominantly as 3-ketosteroid reductases due to inhibition by NADPH, but significantly produce 3beta-tetrahydrosteroids physiologically important in steroid metabolim, androgen metabolism, overview
-
-
?
additional information
?
-
-
in vivo the isozymes act predominantly as 3-ketosteroid reductases due to inhibition by NADPH, but significantly produce 3beta-tetrahydrosteroids physiologically important in steroid metabolim, androgen metabolism, overview
-
-
?
additional information
?
-
-
isozyme AKR1C2 is involved in neurosteroid biosynthesis, while isozyme AKE1C1 eliminates the neurosteroid precursor from the pathway and decreases the neurosteroid concentration in the brain, pathway overview
-
-
?
additional information
?
-
-
physiological roles of the isozymes AKR1C1-4, overview, enzyme regulates the occupancy and trans-activation of steroid hormone receptors by interconverting potent hormones with their cognate inactive metabolites
-
-
?
additional information
?
-
-
role of the isozymes in bile acid biosynthesis and steroid metabolism, product profiling, pre-receptor regulation of steroid hormone action, overview
-
-
?
additional information
?
-
-
isozymes AKR1C1, AKR1C4, and AKR1C2 show broad enzyme specificities, overview
-
-
?
additional information
?
-
-
isozymes display 3alpha-, 17beta-, and 20alpha-hydroxysteroid dehydrogenase activities to varying degrees, isozyme AKR1C4 shows the highest 3alpha-hydroxysteroid dehydrogenase activity of all isozymes, overview
-
-
?
additional information
?
-
molecular docking experiments using the crystal structures of isozymes AKR1C1 and AKR1C2 reveal the structural basis for stereospecificity of the isozymes
-
-
?
additional information
?
-
-
molecular docking experiments using the crystal structures of isozymes AKR1C1 and AKR1C2 reveal the structural basis for stereospecificity of the isozymes
-
-
?
additional information
?
-
stereospecificity differs between the isozymes, the enzyme also exhibits in vitro 3alpha[17beta]-hydroxysteroid axidase activity with 3alpha-diol as the substrate
-
-
?
additional information
?
-
-
stereospecificity differs between the isozymes, the enzyme also exhibits in vitro 3alpha[17beta]-hydroxysteroid axidase activity with 3alpha-diol as the substrate
-
-
?
additional information
?
-
-
structure-function study, the isozymes provide 3alpha-, 17beta-, and 20alpha-hydroxysteroid oxidase activity as well as 3-, 17-, and 20-ketosteroid reductase activity in vitro
-
-
?
additional information
?
-
-
AKR1C3 catalyzes androgen, estrogen, and prostaglandin metabolism, AKR1C3 is also involved in cancer development or progression
-
-
?
additional information
?
-
-
type I human hepatic 3alpha-hydroxysteroid dehydrogenase plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism, the enzyme is regulated by expression level of the liver X receptor alpha, i.e. LXRalpha [NR1H3], a nuclear hormone receptor, predictive response element modeling and whole genome analysis of LXRalpha occupancy sites using ChIP/microarray technology, overview
-
-
?
additional information
?
-
-
AKR1C2 and AKR1C3 also possesse prostaglandin 9- and 11-reductase activities, EC 1.1.1.188 and EC 1.1.1.189, respectively, overview
-
-
?
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
4-pregnen-3alpha,20beta-diol + NAD+
(20beta)-20-hydroxypregn-4-en-3-one + NADH + H+
-
-
-
ir
5alpha-dihydroprogesterone + 2 NAD(P)H + 2 H+
pregnan-3alpha,20beta-diol + 2 NAD(P)+
-
-
-
-
?
5alpha-dihydrotestosterone + NADH
3alpha-androstanediol + NAD+
-
reaction direction is regulated by the NAD+:NADPH relation in the cell
-
-
r
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADPH
9-[hydroxy(phenyl)methyl]-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one + NADP+
-
competitive substrate, fluorometric activity measurement in intact cells, overview
-
-
?
tibolone + NADPH + H+
3-hydroxytibolone + NADP+
-
tibolone is used to treat climacteric symptoms and prevent osteoporosis, it exerts tissue-selective effects via site-specific metabolism into 3alpha- and 3beta-hydroxymetabolites and a DELTA4-isomer
-
-
?
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
-
-
?
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
in the prostate: forward reaction by type 2 isozyme AKR1C3, reverse reaction by type 3 isozyme AKR1C2
-
-
ir
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
inactivation of the potent androgen, 3alpha(beta)-hydroxysteroid oxidoreductase activity
-
-
ir
5alpha-dihydroprogesterone + 2 NADPH + 2 H+
pregnan-3alpha,20beta-diol + 2 NADP+
-
isozyme AKR1C4
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
in the CNS: both reaction directions by type 3 isozyme AKR1C2
-
-
r
5alpha-dihydroprogesterone + NADPH + H+
3alpha,5alpha-3-hydroxypregnan-20-one + NADP+
-
last step in neurosteroid allopregnanolone biosynthesis
-
-
?
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstane-3alpha,17beta-diol + NAD(P)+
-
-
-
r
5alpha-dihydrotestosterone + NAD(P)H + H+
5alpha-androstane-3alpha,17beta-diol + NAD(P)+
-
discussion of physiological role
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
inactivation of the potent androgen in human prostate
-
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstan-3alpha,17beta-diol + NADP+
-
inactivation of the potent androgen in human prostate, fluorometric activity measurement in intact cells, overview
-
-
?
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstane-3alpha,17beta-diol + NADP+
-
-
-
r
5alpha-dihydrotestosterone + NADPH + H+
5alpha-androstane-3alpha,17beta-diol + NADP+
-
-
-
r
additional information
?
-
-
type 3 isoform in liver virtually identical with bile acid-binding protein
-
-
?
additional information
?
-
due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo
-
-
?
additional information
?
-
-
due to inhibition by NADPH, the isozymes acts only as 3-ketosteroid reductases in vivo
-
-
?
additional information
?
-
-
enzyme inactivates steroid hormones in the liver, regulates 5alpha-dihydrotestosterone levels in the prostate, and forms the neurosteroid allopregnanolone in the CNS, isozymes might be involved in regulation of the levels of active androgens, estrogens, and progestrins
-
-
?
additional information
?
-
in vivo the isozymes act predominantly as 3-ketosteroid reductases due to inhibition by NADPH, but significantly produce 3beta-tetrahydrosteroids physiologically important in steroid metabolim, androgen metabolism, overview
-
-
?
additional information
?
-
-
in vivo the isozymes act predominantly as 3-ketosteroid reductases due to inhibition by NADPH, but significantly produce 3beta-tetrahydrosteroids physiologically important in steroid metabolim, androgen metabolism, overview
-
-
?
additional information
?
-
-
isozyme AKR1C2 is involved in neurosteroid biosynthesis, while isozyme AKE1C1 eliminates the neurosteroid precursor from the pathway and decreases the neurosteroid concentration in the brain, pathway overview
-
-
?
additional information
?
-
-
physiological roles of the isozymes AKR1C1-4, overview, enzyme regulates the occupancy and trans-activation of steroid hormone receptors by interconverting potent hormones with their cognate inactive metabolites
-
-
?
additional information
?
-
-
role of the isozymes in bile acid biosynthesis and steroid metabolism, product profiling, pre-receptor regulation of steroid hormone action, overview
-
-
?
additional information
?
-
-
AKR1C3 catalyzes androgen, estrogen, and prostaglandin metabolism, AKR1C3 is also involved in cancer development or progression
-
-
?
additional information
?
-
-
type I human hepatic 3alpha-hydroxysteroid dehydrogenase plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism, the enzyme is regulated by expression level of the liver X receptor alpha, i.e. LXRalpha [NR1H3], a nuclear hormone receptor, predictive response element modeling and whole genome analysis of LXRalpha occupancy sites using ChIP/microarray technology, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
cytosolic and microsomal enzymes have different cofactor preferences: cytosolic enzymes prefer NADP+/NADPH, microsomal prefer NAD+/NADH
-
NAD+
-
oxidation utilizing NAD+ as a cofactor is the preferred reaction in vitro
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one
-
competitive
celecoxib
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.050 mM in fluorometric assay, in vitro IC50: 0.050 mM in fluorometric assay
cloxazolam
-
potent and specific, competitive inhibition of isozymes AKR1C1, AKR1C4, and AKR1C2
Ibuprofen
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.017 mM in fluorometric assay, in vitro IC50: 0.009 mM in fluorometric assay
naproxen
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.0094 mM in fluorometric assay, 0.016 mM in radiometric assay, in vitro IC50: 0.0027 mM in fluorometric assay
Phenolphthalein
-
AKR1C4-selective inhibitor, in vitro and in vivo inhibition, IC50: 0.0004 mM
Flufenamic acid
nonsteroidal anti-inflammatory drug, inhibits all 4 isozymes, binding mode
Flufenamic acid
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.0040 mM in fluorometric assay, in vitro IC50: 0.00031 mM in fluorometric assay
NADPH
-
strongly inhibits the oxidation of 3-hydroxymetabolites in vivo and in vitro, determining the role of enzymes as 3-ketosteroid reductases in vivo, overview
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
ursodeoxycholate
-
forward reaction: competitive against 5alpha-dihydroprogesteroneand noncompetitive against NADPH, reverse reaction: competitive against allopregnanolone and noncompetitive against NADP+
ursodeoxycholate
-
natural inhibitor, in vivo IC50: 0.00024 mM in fluorometric assay, 0.00014 mM in radiometric assay, in vitro IC50: 0.000049 mM in fluorometric assay
additional information
-
no inhibition by oxazolam and oxazepam, benzodiazepams inhibit competitive versus the steroid substrates
-
additional information
-
no inhibition by the bile acid 5beta-cholanic acid-3alpha,7alpha-diol
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
fluoxetine
-
activates allopregnanolone formation in vivo, not in vitro at a concentration up to 0.05 mM, therefore in vivo activation is probably not realized by enzyme activation but a different mechanism
additional information
-
no in vitro activation by paroxetine, sertraline, norfluoxetine, carbamazepine, clozapine, flurbiprofen, and sulfobromophthalein at a concentration up to 0.05 mM
-
additional information
-
treatment with 0.002 mM T0901317 induces about 2fold AKR1C4 mRNA expression, liver X receptor alpha mediates transcriptional activation of the AKR1C4 gene, leading to increased AKR1C4 protein expression
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.017 - 0.042
(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
0.003
9-(phenylcarbonyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one
-
recombinant enzyme in intact COS-1 cells
0.0025
oxidized 8-acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-azabenzo[de]anthracen-10-one
-
isozyme AKR1C3
0.017
(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
-
NADP+, detection spectrophotometrically
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
-
NADP+, detection radio- or fluorometrically
0.022
(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
-
pH 7.0, 37°C with NADP+
0.042
(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
-
pH 7.0, 37°C with NAD+
0.022
1-Acenaphthenol
-
pH 7.4, 25°C, recombinant isozyme AKR1C1 and isozyme AKR1C2
0.00218
5alpha-dihydrotestosterone
pH 7.4, 37°C, recombinant wild-type enzyme
0.0035
androsterone
-
pH 7.4, 25°C, recombinant isozyme AKR1C2 and isozyme AKR1C4
additional information
additional information
-
kinetic mechanism, substrate binding mechanism of isozyme AKR1C2
-
additional information
additional information
steady state kinetics, overview
-
additional information
additional information
-
steady state kinetics, overview
-
additional information
additional information
-
steady-state kinetics, ternary complex, sequential, kinetic mechanism of allopregnanolone synthesis with the cofactor binding before the steroid and leaving after it
-
additional information
additional information
-
transient single and multiple turnover kinetics, stopped flow kinetics, isotope kinetics, ligand binding analysis, kinetics with deuterium-substituted cofactor and binary complex of enzyme and cofactor, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.004 - 0.507
(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
0.14
oxidized 8-acetyl-2,3,5,6-tetrahydro-1H,4H-11-oxa-3a-azabenzo[de]anthracen-10-one
-
isozyme AKR1C3
0.004
(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
-
pH 7.0, 37°C with NADP+
0.0167
(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
-
pH 7.0, 37°C with NAD+
0.203
(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
-
detection spectrophotometrically
0.32
(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
-
detection radiometrically
0.507
(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
-
detection fluorometrically
0.000016
3alpha-hydroxytibolone
below, pH 7.0, 37°, isozymes AKR1C1 and AKR1C3
0.0612
5alpha-dihydrotestosterone
pH 7.4, 37°C, recombinant wild-type enzyme
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
28.07
5alpha-dihydrotestosterone
pH 7.4, 37°C, recombinant wild-type enzyme
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
inhibition specificity of benzodiazepams for the 3 isozymes AKR1C1, AKR1C2, and AKR1C4
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.05
celecoxib
Homo sapiens
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.050 mM in fluorometric assay, in vitro IC50: 0.050 mM in fluorometric assay
0.009
Ibuprofen
Homo sapiens
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.017 mM in fluorometric assay, in vitro IC50: 0.009 mM in fluorometric assay
0.0027
naproxen
Homo sapiens
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.0094 mM in fluorometric assay, 0.016 mM in radiometric assay, in vitro IC50: 0.0027 mM in fluorometric assay
0.0004
Phenolphthalein
Homo sapiens
-
AKR1C4-selective inhibitor, in vitro and in vivo inhibition, IC50: 0.0004 mM
0.000049
ursodeoxycholate
Homo sapiens
-
natural inhibitor, in vivo IC50: 0.00024 mM in fluorometric assay, 0.00014 mM in radiometric assay, in vitro IC50: 0.000049 mM in fluorometric assay
0.00031
Flufenamic acid
Homo sapiens
-
synthetic, nonsteroidal anti-inflammatory inhibitor, in vivo IC50: 0.0040 mM in fluorometric assay, in vitro IC50: 0.00031 mM in fluorometric assay
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.00002
purified recombinant isozymes AKR1C1 and AKR1C3, substrate 3alpha-hydroxytibolone
0.00015
purified recombinant isozyme AKR1C3, substrate 3beta-hydroxytibolone
0.00079
purified recombinant isozyme AKR1C1, substrate 3beta-hydroxytibolone
0.0013
-
substrate 5alpha-dihydrotestosterone with cofactor NADP+, detection radiometrically
0.0025
-
substrate 5alpha-dihydrotestosterone with cofactor NADPH, detection spectrophotometrically
0.0037
purified recombinant isozyme AKR1C3, substrate 4-pregnen-3alpha,20beta-diol
0.0039
purified recombinant isozyme AKR1C1, substrate 4-pregnen-3alpha,20beta-diol
0.0042
-
substrate 5alpha-dihydrotestosterone with cofactor NADPH, detection radiometrically
0.0048
-
substrate 3alpha-androstanediol with cofactor NADP+, detection spectrophotometrically
0.00653
purified recombinant isozyme AKR1C4, substrate 3beta-hydroxytibolone
0.0085
-
substrate 3alpha-androstanediol with cofactor NADP+, detection radiometrically
0.0111
-
substrate androstanedione with cofactor NADPH, detection spectrophotometrically
0.0134
-
substrate 3alpha-androstanediol with cofactor NADP+, detection fluorometrically
0.0188
purified recombinant isozyme AKR1C4, substrate 3alpha-hydroxytibolone
0.0253
purified recombinant isozyme AKR1C2, substrate 3beta-hydroxytibolone
0.119
purified recombinant isozyme AKR1C4, substrate 4-pregnen-3alpha,20beta-diol
0.13
-
substrate 4-nitrobenzaldehyde with cofactor NADPH, detection spectrophotometrically
0.538
-
substrate 9,10-phenanthrenequinone with cofactor NADPH, detection spectrophotometrically
76.1
purified recombinant isozyme AKR1C2, substrate 4-pregnen-3alpha,20beta-diol
additional information
additional information
-
development of noninvasive method for visualization and quantification of the reaction, development of selective fluorogenic substrate compounds, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
the urothelial epithelium lining the renal pelvis is strongly immunoreactive, but stromal cells in the underlying supporting connective tissue are negative
-
only a small number of epithelial cells are immunoreactive with both nuclear and cytoplasmic reactivity
-
in Leydig cells, but no or poor activity in germ cells and Sertoli cells
additional information
-
in renal cortex, endothelial cells of the glomeruli lack immunoreactivity for AKR1C3, but the Bowmans capsule and mesangial cells are strongly reactive, as well as larger epithelial cells of the medulla, overview
additional information
-
variations in different tissues concerning number of enzyme isoforms
additional information
-
tissue specificity and substrate specificity of human isozymes, overview
additional information
-
tissue distribution of AKR1C3, immunohistochemic analysis, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
human 3alpha-HSD3 shares 97.8% sequence identity with human 20-alpha hydroxysteroid dehydrogenase (20alpha-HSD) and there is only one amino acid difference (residue 54) that is located in their steroid binding pockets. 20alpha-HSD displays a distinctive ability in transforming progesterone to 20alpha-hydroxy-progesterone
malfunction
physiological function
malfunction
enzyme silencing by specific siRNA suppresses 3alpha-HSD3 expression without interfering with 3alpha-HSD4, which shares a highly homologous active site, the 5alpha-DHT concentration increases, whereas MCF-7 cell growth is suppressed. Downregulation of 3alpha-HSD3 decreases MCF-7 breast cancer cell growth
malfunction
the V54L mutation significantly decreases the 3alpha-HSD activity for the reduction of 5alpha-dihydrotestosterone, while this mutation enhances the 20alpha-HSD activity to convert progesterone
physiological function
3-alpha hydroxysteroid dehydrogenase type 3 has an essential role in the inactivation of 5alpha-dihydrotestosterone preventing binding and activation of androgen receptor from overflowing androgen
physiological function
3alpha-hydroxysteroid dehydrogenase type 3 plays an essential role in the inactivation of the most potent androgen 5alpha-dihydrotestosterone. Role of 3alpha-HSD3 in breast cancer cells
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). PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
43000
-
x * 43000, 3alpha-hydroxysteroid dehydrogenase, x * 65000, 3alpha-hydroxysteroid dehydrogenase-Del1 deposition domain fusion protein, SDS-PAGE
65000
-
x * 43000, 3alpha-hydroxysteroid dehydrogenase, x * 65000, 3alpha-hydroxysteroid dehydrogenase-Del1 deposition domain fusion protein, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 43000, 3alpha-hydroxysteroid dehydrogenase, x * 65000, 3alpha-hydroxysteroid dehydrogenase-Del1 deposition domain fusion protein, SDS-PAGE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
3alpha-HSD3-NADP+-progesterone complex and 3alpha-HSD3 mutant V54L-NADP+-progesterone complex, sitting drop vapor diffusion method, room temperature, the reservoir solution contains 100 mM sodium cacodylate, pH 6.0, 200 mM ammonium sulfate, 24-26% w/v PEG 3350, with 0.8 mM progesterone, 3-14 days, X-ray diffraction structure determination and analysis at 2.0-2.2 A resolution, molecular replacement with search model, PDB ID 1J96. Progesterone adopts two different binding modes to form complexes within the wild-type enzyme, with one binding mode similar to the orientation of a bile acid (ursodeoxycholate) in the reported ternary complex of human 3alpha-HSD3-NADP+-ursodeoxycholate and the other binding mode resembling the orientation of 20alpha-OHProg in the ternary complex of human 20alpha-HSD-NADP+-20alpha-OHProg
alpha/beta-barrel, NADP+ is bound in an extended conformation, type III isoform
-
crystal structure of human 3alpha-HSD3-NADP(+)/5alpha-androstane-3,17-dione/epiandrosterone complex obtained by co-crystallization with 5alpha-androstane-3,17-dione (5alpha-DHT) in the presence of NADP+. Although 5alpha-DHT is introduced during the crystallization, oxidoreduction of 5alpha-DHT occurs. The locations of 5alpha-androstane-3,17-dione and epiandrosterone are identified in the steroid-binding sites of two 3alpha-HSD3 molecules per crystal asymmetric unit. An overlay shows that 5alpha-androstane-3,17-dione and epiandrosterone are oriented upside-down and flipped relative to each other, providing structural clues for 5alpha-DHT reverse binding in the enzyme with the generation of different products
isozyme AKR1C2 in ternary complex with NADP+ and ursodeoxycholate, X-ray diffraction structure determination and analysis at 3.0 A resolution, molecular replacement
-
recombinant type 3 isozyme AKR1C2 in complex with NADP+ and ursodeoxycholate, X-ray structure determination and analysis at 3.0 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
V54L
site-directed mutagenesis, the change renders the sequence identical to that of human 20-alpha hydroxysteroid dehydrogenase. The V54L mutation directly restricts the steroid binding modes to a unique one, which resembles the orientation of 20alpha-OHProg within human 20alpha-HSD. The kinetic study shows that the V54L mutation significantly decreases the 3alpha-HSD activity for the reduction of 5alpha-dihydrotestosterone, while this mutation enhances the 20alpha-HSD activity to convert progesterone
additional information
additional information
-
recombinant AKR1C2 and AKR1C3 mediated prostaglandin D2 metabolism augments the PI3K/Akt proliferative signaling pathway in transfected human prostate cancer cells, overview
additional information
enzyme silencing by specific siRNA suppresses 3alpha-HSD3 expression without interfering with 3alpha-HSD4, which shares a highly homologous active site, the 5alpha-DHT concentration increases, whereas MCF7 cell growth is suppressed
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
stable in phosphate 50 mM plus 10-20% glycerol at 4°C, while freezing and thawing results in a great loss of enzyme activity
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme from Escherichia coli strain C41(DE3) in a successive chromatographic procedure, to homogeneity
-
recombinant enzymes from Escherichia coli by DE52 and Blue Sepharose chromatography
recombinant GST-fusion protein from Escherichia coli by affinity chromatography on a glutathione resin, cleavage of the GST-tag by thrombin
-
recombinant GST-tagged enzyme from Escherichia coli strain BL21(DE3)pLysS by glutathione affinity chromatography, cleavage of the tag by thrombin, and anion exchange chromatography
recombinant isozymes AKR1C1-AKR1C4 from Escherichia coli by DE52 ion exchange and Blue Sepharose chromatography, to homogeneity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
co-expression of the enzyme with the LXR alpha receptor in HuH7 and HepG2 cells
-
from human cDNA library, expression as GST-fusion protein in Escherichia coli strain BL21(DE3)
-
isozymes AKR1C1-AKR1C4, genetic organization, transient expression in COS-1 cells
-
overexpression of GST-tagged enzyme in Escherichia coli strain BL21(DE3)pLysS
stable expression of AKR1C2 and AKR1C3 in androgen insensitive human prostate cancer PC-3 cells
-
transient functional expression in COS-1 cells, stable functional expression in PC-3 cells and in LNCaP cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
biotechnology
-
transfection of cells with plasmids encoding a 3alpha-hydroxysteroid dehydrogenase-Del1 deposition domain fusion protein. The Del1 deposition domain immobilizes the enzyme in the extracellular matrix without interfering with its enzymatic activity. Extracellular matrix conditioned by cells transfected with 3alpha-hydroxysteroid dehydrogenase-Del1 deposition domain fusion significantly suppresses the growth of otherwise untreated LNCaP cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Biswas, M.G.; Russel, D.W.
Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenase from rat and human prostate
J. Biol. Chem.
272
15959-15966
1997
Homo sapiens, Rattus norvegicus
Chetyrkin, S.V.; Belyaeva, O.V.; Gough, W.H.; Kedishvili, N.Y.
Characterization of a novel type of human microsomal 3alpha-hydroxysteroid dehydrogenase
J. Biol. Chem.
276
22278-22286
2001
Homo sapiens
Iyer, R.B.; Binstock, J.M.; Schwartz, I.S.; Gordon, G.G.; Weinstein, B.I.; Southern, A.L.
Purification and properties of human hepatic 3alpha-hydroxysteroid dehydrogenase
J. Steroid Biochem. Mol. Biol.
43
343-349
1992
Homo sapiens
Lin, H.K.; Jez, J.M.; Schlegel, B.P.; Peehl, D.M.; Pachter, J.A.; Penning, T.M.
Expression and characterization of recombinant type 2: 3alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3alpha/17beta-HSD activity and cellular distribution
Mol. Endocrinol.
11
1971-1984
1997
Homo sapiens
Jin, Y.; Stayrook, S.E.; Albert, J.H.; Palackal, N.T.; Penning, T.M.; Lewis, M.
Crystal structure of human type III 3alpha-hydroxysteroid dehydrogenase/bile acid binding protein complexed with NADP(+) and ursodeoxycholate
Biochemistry
40
10161-10168
2001
Homo sapiens
Zhu, D.W.; Cantin, L.; Nahoum, V.; Rehse, P.; Luu-The, V.; Labrie, F.; Breton, R.; Lin S.X.
Crystallization and preliminary X-ray crystallographic analysis of the human type 3 3alpha-hydroxysteroid dehydrogenase at 1.8 A resolution
Acta Crystallogr. Sect. D
57
589-591
2001
Homo sapiens
Trauger, J.W.; Jiang, A.; Stearns, B.A.; LoGrasso, P.V.
Kinetics of allopregnanolone formation catalyzed by human 3alpha-hydroxysteroid dehydrogenase type III (AKR1C2)
Biochemistry
41
13451-13459
2002
Homo sapiens
Usami, N.; Yamamoto, T.; Shintani, S.; Ishikura, S.; Higaki, Y.; Katagiri, Y.; Hara, A.
Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines
Biol. Pharm. Bull.
25
441-445
2002
Homo sapiens
Jin, Y.; Cooper, W.C.; Penning, T.M.
Examination of the differences in structure-function of human and rat 3alpha-hydroxysteroid dehydrogenase
Chem. Biol. Interact.
143-144
383-392
2003
Homo sapiens, Rattus norvegicus
Rizner, T.L.; Lin, H.K.; Peehl, D.M.; Steckelbroeck, S.; Bauman, D.R.; Penning, T.M.
Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells
Endocrinology
144
2922-2932
2003
Homo sapiens
Yee, D.J.; Balsanek, V.; Sames, D.
New tools for molecular imaging of redox metabolism: development of a fluorogenic probe for 3a-hydroxysteroid dehydrogenases
J. Am. Chem. Soc.
126
2282-2283
2004
Comamonas testosteroni, Homo sapiens, Rattus norvegicus
Steckelbroeck, S.; Jin, Y.; Gopishetty, S.; Oyesanmi, B.; Penning, T.M.
Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action
J. Biol. Chem.
279
10784-10795
2004
Homo sapiens (Q04828), Homo sapiens
Penning, T.M.; Jin, Y.; Heredia, V.V.; Lewis, M.
Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms
J. Steroid Biochem. Mol. Biol.
85
247-255
2003
Homo sapiens, Rattus norvegicus
Penning, T.M.; Jin, Y.; Steckelbroeck, S.; Lanisnik Rizner, T.; Lewis, M.
Structure-function of human 3alpha-hydroxysteroid dehydrogenases: genes and proteins
Mol. Cell. Endocrinol.
215
63-72
2004
Homo sapiens
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
Mol. Pharmacol.
66
1702-1711
2004
Homo sapiens (Q04828), Homo sapiens
Jin, Y.; Penning, T.M.
Multiple steps determine the overall rate of the reduction of 5alpha-dihydrotestosterone catalyzed by human type 3 3alpha-hydroxysteroid dehydrogenase: implications for the elimination of androgens
Biochemistry
45
13054-13063
2006
Homo sapiens
Steckelbroeck, S.; Oyesanmi, B.; Jin, Y.; Lee, S.H.; Kloosterboer, H.J.; Penning, T.M.
Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily
J. Pharmacol. Exp. Ther.
316
1300-1309
2006
Homo sapiens
Yee, D.J.; Balsanek, V.; Bauman, D.R.; Penning, T.M.; Sames, D.
Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells
Proc. Natl. Acad. Sci. USA
103
13304-13309
2006
Homo sapiens
Azzarello, J.; Fung, K.M.; Lin, H.K.
Tissue distribution of human AKR1C3 and rat homolog in adult genitourinary system
J. Histochem. Cytochem.
56
853-861
2008
Homo sapiens, Rattus norvegicus
Wang, S.; Yang, Q.; Fung, K.M.; Lin, H.K.
AKR1C2 and AKR1C3 mediated prostaglandin D2 metabolism augments the PI3K/Akt proliferative signaling pathway in human prostate cancer cells
Mol. Cell. Endocrinol.
289
60-66
2008
Homo sapiens
Stayrook, K.R.; Rogers, P.M.; Savkur, R.S.; Wang, Y.; Su, C.; Varga, G.; Bu, X.; Wei, T.; Nagpal, S.; Liu, X.S.; Burris, T.P.
Regulation of human 3 alpha-hydroxysteroid dehydrogenase (AKR1C4) expression by the liver X receptor alpha
Mol. Pharmacol.
73
607-612
2008
Homo sapiens
Hidai, C.; Kitano, H.; Kokubun, S.
The Del1 deposition domain can immobilize 3alpha-hydroxysteroid dehydrogenase in the extracellular matrix without interfering with enzymatic activity
Bioprocess Biosyst. Eng.
32
569-573
2009
Homo sapiens, Mus musculus (Q91WR5)
Zhang, B.; Zhu, D.; Hu, X.; Zhou, M.; Shang, P.; Lin, S.
Human 3-alpha hydroxysteroid dehydrogenase type 3 (3alpha-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20alpha-HSD activity
J. Steroid Biochem. Mol. Biol.
141
135-143
2014
Homo sapiens (Q04828)
Zhang, B.; Hu, X.; Wang, X.; Theriault, J.; Zhu, D.; Shang, P.; Labrie, F.; Lin, S.
Human 3alpha-hydroxysteroid dehydrogenase type 3: structural clues of 5alpha-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth
Biochem. J.
473
1037-1046
2016
Homo sapiens (P52895)
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