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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
evolution
the enzyme belongs to the AKR1C subfamily, the members of which catalyze the reduction of ketosteroids and ketoprostaglandins
evolution
enzyme 3alpha-HSD/CR belongs to the short chain dehydrogenase/ reductase (SDR) superfamily
evolution
3alpha-HSOR is a member of the aldo-keto reductase superfamily
evolution
3alpha-HSOR is a member of the aldo-keto reductase superfamily
evolution
3alpha-HSOR is a member of the aldo-keto reductase superfamily
evolution
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enzyme AKR1C14 belongs to the aldo-keto reductase family
malfunction
downregulation of 3alpha-HSD3 decreases MCF-7 breast cancer cell growth
malfunction
mutation at P185 in the hinge region and T188 in the loop causes a significant increase in the Kd value for NADH. Mutants P185A, P185G, T188A, and T188S show an increase the dissociation of the nucleotide cofactor, thereby increasing the rate of release of the product and producing the rate-limiting step in the hydride transfer
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
malfunction
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loss of hydrogen bonding with NADH upon the Y153F mutation results in increased enthalpy change, partially compensated by increased entropy change. The NADH binding affinity of K157A mutant is much lower than that of the wild-type, mainly due to loss of a hydrogen bond. The decreased affinity results in decreased kcat. Compared to the wild-type, the mutants S114A and Y153F show higher Km and lower kcat values in both oxidation and reduction reactions. Simultaneous mutation of S114A and Y153F results in a significant decrease in kcat relative to the single mutant
malfunction
the expression of 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR) and the levels of progesterone (PROG) and testosterone (T) 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. Changes in brain levels of PROG metabolites have been detected in Alzheimer's disease (AD) mouse models, such as the 3xTg-AD mouse
malfunction
the expression of 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR) and the levels of progesterone (PROG) and testosterone (T) 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
enzyme is involved in inactivation of steroid hormones
metabolism
enzyme is involved in inactivation of steroid hormones
metabolism
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3alpha-hydroxysteroid dehydrogenase isoform AKR1C4 plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism
metabolism
enzyme is involved in the inactivation of steroid hormones
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
metabolism
the enzymatic complex 5alpha-reductase (5alpha-R) and 3alpha/3beta-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) 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 PROG and T 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
metabolism
the enzymatic complex 5alpha-reductase (5alpha-R) and 3alpha/3beta-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) 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 PROG and T 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
metabolism
the enzymatic complex 5alpha-reductase (5alpha-R) and 3alpha/3beta-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) 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 PROG and T 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
metabolism
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the homeostasis of neurosteroids, such as allopregnanolone and 5alpha-androstane-3alpha,17beta-diol (DIOL), depends on the catalysis of AKR1C14 and RDH2. These two enzymes are present in the different subcellular regions, with AKR1C14 in the cytoplasm and RDH2 in the smooth endoplasmic reticulum (microsome), and they use different cofactors, with AKR1C14 of NADPH and RDH2 of NAD+, and the cofactor availability determines the catalytic direction
metabolism
the synthesis of allopregnanolone (ALLO) and 5alpha-androstane-3alpha,17beta-diol (DIOL) needs 5alpha-reductase 1 (SRD5A1) and 3alpha-hydroxysteroid dehydrogenase (AKR1C9). SRD5A1 is a microsomal NADPH-dependent enzyme, which metabolizes progesterone into dihydroprogesterone or testosterone into dihydrotestosterone (DHT). Subsequently, cytosolic NADPH-dependent AKR1C9 metabolizes the above steroid intermediates into ALLO and DIOL, respectively. Another microsomal NAD+-dependent retinol dehydrogenase 2 (RoDH2, EC 1.1.1.53) catalyzes the opposite direction of AKR1C9. Thus, the levels of ALLO and DIOL also depend on the activity of RoDH2. These three enzymes have been shown to be present in the brain
metabolism
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enzyme is involved in inactivation of steroid hormones
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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 catalyzes the oxidation of the 3-hydroxyl group of steroids. The enzymatic conversion is a critical step in the enzymatic assay of urinary sulfated bile acids
physiological function
3alpha-hydroxysteroid dehydrogenase type 3 plays an essential role in the inactivation of the most potent androgen 5alpha-dihydrotestosterone
physiological function
the steroidogenic enzyme AKR1C3 regulates stability of the ubiquitin ligase Siah2 in prostate cancer cells. AKR1C3 binds and stabilizes Siah2 by blocking Siah2 self-ubiquitination and degradation. It has a catalytic independent role on androgen receptor activity via Siah2 that promotes activity of androgen receptor in prostate cancer cells. AKR1C3 is a downstream effector of Siah2 in Rv1 cells
physiological function
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enzyme AKR1C14 adds a hydrogen to the 3alpha-position of many steroids, including neurosteroids. It is a cytosolic NADPH-dependent enzyme, which primarily catalyzes the formation of allopregnanolone or 5alpha-androstane-3alpha,17beta-diol (DIOL) from dihydroprogesterone and dihydrotestosterone (DHT), respectively
physiological function
the cytosolic NADPH-dependent AKR1C9 metabolizes the steroid intermediates dihydroprogesterone and dihydrotestosterone into allopregnanolone (ALLO) and 5alpha-androstane-3alpha,17beta-diol (DIOL), respectively
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 (PROG) and testosterone (T) 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 PROG and T. The reduced metabolites of PROG 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
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 (PROG) and testosterone (T) 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 PROG and T. The reduced metabolites of PROG 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
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 (PROG) and testosterone (T) 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 PROG and T. The reduced metabolites of PROG 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. Tetrahydroprogesterone (THP) treatment reduces seizures, prevents cell apoptosis in the spinal cord of STZ diabetic and protects against stroke, oxygen-glucose deprivation
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
additional information
catalytic tetrad N86-S114-Y155-K159, catalytic roles of P185 and T188 and substrate-binding loop flexibility in 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase. Structurally the substrate-binding loop of the residues, T188-K208, is unresolved, while binding with NAD+ causes the appearance of T188-P191 in the binary complex, functional roles of the flexible substrate-binding loop in conformational changes and enzyme catalysis, overview. Simulated molecular modeling gives results that are consistent with the conformational change in the substrate-binding loop after NAD+ binding. These results indicate that P185, T188 and the flexible substrate-binding loop are involved in binding with the nucleotide cofactor and with androsterone and are also involved in catalysis. Homology structure modeling, overview
additional information
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AKR1C14 has two substrate binding sites, the steroid binding and the cofactor binding site
additional information
AKR1C9 has two substrate binding sites, the steroid binding site and the cofactor binding site
additional information
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residues Ser114, Tyr153, and Lys157 form the catalytic triad. Tyr153 is a catalytic base and Ser114 is a substitute