Showing papers on "Hydroxysteroid dehydrogenase published in 2019"
TL;DR: The association of variants in HSD17B13 with specific features of NAFLD histology is demonstrated and the enzyme is identified as a lipid droplet–associated RDH; the data suggest that HSD 17B13 plays a role inNAFLD through its enzymatic activity.
184 citations
TL;DR: AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases and produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase.
63 citations
TL;DR: Dehydrogenases are widely employed as biocatalysts for the production of optically pure chemicals under mild conditions.
Abstract: Dehydrogenases are widely employed as biocatalysts for the production of optically pure chemicals under mild conditions. Most dehydrogenases are nicotinamide cofactor (NADPH or NADH)-dependent oxid...
37 citations
15 citations
TL;DR: In this paper, the development of a reliable gram-scale synthesis of 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methylbenzamide (PBRM) was reported.
9 citations
TL;DR: The acidophilic nature of 7α‐HSDH expands its application environment and the natural enzyme bank of HSDHs, providing a promising candidate enzyme for the biosynthesis of TUDCA or other related chemical entities.
Abstract: 7α-Hydroxysteroid dehydrogenase (7α-HSDH) is an NAD(P)H-dependent oxidoreductase belonging to the short-chain dehydrogenases/reductases. In vitro, 7α-HSDH is involved in the efficient biotransformation of taurochenodeoxycholic acid (TCDCA) to tauroursodeoxycholic acid (TUDCA). In this study, a gene encoding novel 7α-HSDH (named as St-2-1) from fecal samples of black bear was cloned and heterologously expressed in Escherichia coli. The protein has subunits of 28.3 kDa and a native size of 56.6 kDa, which suggested a homodimer. We studied the relevant properties of the enzyme, including the optimum pH, optimum temperature, thermal stability, activators, and inhibitors. Interestingly, the data showed that St-2-1 differs from the 7α-HSDHs reported in the literature, as it functions under acidic conditions. The enzyme displayed its optimal activity at pH 5.5 (TCDCA). The acidophilic nature of 7α-HSDH expands its application environment and the natural enzyme bank of HSDHs, providing a promising candidate enzyme for the biosynthesis of TUDCA or other related chemical entities.
9 citations
TL;DR: Structural analysis showed that His221 is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead‐end complex, which exists widely in NADP(H)‐preferred enzymes for the regulation of their enzymatic activity.
Abstract: Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17β-HSD members, 17β-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β-HSD1 in complex with estrone (E1) and cofactor analog NADP+ , demonstrating critical enzyme-substrate-cofactor interactions. These complexes revealed a reversely bound E1 in 17β-HSD1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His221 is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead-end complex, which exists widely in NADP(H)-preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17β-HSD1 through the formation of a dead-end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17β-HSD1 based on the dead-end inhibition model for efficiently targeting EDDs. DATABASES: Coordinates and structure factors of 17β-HSD1-E1 and 17β-HSD1-E1-NADP+ have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively. ENZYMES: 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) EC 1.1.1.62.
7 citations
TL;DR: The chemical synthesis and characterization of two series of analogs are described to address the impact of A- and D-ring modifications on 17β-HSD3 inhibitory activity, androgenic effect, and metabolic stability.
Abstract: Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivati...
7 citations
TL;DR: The recombinant expression and biochemical characterization of the nicotinamide adenine dinucleotide (NAD + )-dependent HSDH from Eggerthella lenta (El12α-HSDH) are reported and it is shown that this enzyme shows comparable properties with the well-known nicotinamide adenin din nucleotide phosphate (NadP)-dependent enzyme from Clostridium sp.
Abstract: The C12 specific oxidation of hydroxysteroids is an essential reaction required for the preparation of pharmaceutical ingredients like ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA), which can be synthesized by Wolff-Kishner reduction of the obtained 12-oxo-hydroxysteroids. 12α-hydroxysteroid dehydrogenases (12α-HSDHs) have been shown to perform this reaction with high yields, under mild conditions and without the need of protection and deprotection steps, required in chemical synthesis. Here, the recombinant expression and biochemical characterization of the nicotinamide adenine dinucleotide (NAD + )-dependent HSDH from Eggerthella lenta (El12α-HSDH) are reported. This enzyme shows comparable properties with the well-known nicotinamide adenine dinucleotide phosphate (NADP + )-dependent enzyme from Clostridium sp. 48–50. In order to perform a viable and atom efficient enzymatic hydroxysteroid oxidation, NAD(P)H oxidase (NOX) was employed as cofactor regeneration system: NOX uses oxygen (O 2 ) as sacrificial substrate and produces only water as side product. 10 mM of cholic acid was fully and selectively converted to 12-oxo-CDCA in 24 h. The possibility to employ this system on UCA and 7-oxo-deoxycholic acid (7-oxo-DCA) as substrates was additionally investigated. The performance of the El12α-HSDH was evaluated also in combination with a “classical” regeneration system (oxaloacetate/malate dehydrogenase) showing full conversion in 4 h. Finally, the feasibility of a catalytic aerobic-NAD + -dependent enzymatic oxidation was shown on a preparative scale (oxidation of CA to 12-oxo-CDCA) employing the El12α-HSDH-NOX system in a segmented-flow-reactor. (Figure presented.).
7 citations
TL;DR: The kinetic and binding results strongly support that the inhibition of 17β-HSD7 constitutes the basis of breast cancer cell proliferation decreasing that led to the shrinkage of xenograft ER + breast tumor mice model.
6 citations
TL;DR: Results indicated that 17β-HSD2 plays both hormone-dependent and hormone-independent enzymatic roles, and in-depth investigations of this enzyme on the genomic level will help clarify its related molecular mechanisms.
01 Jan 2019
Patent•
29 Oct 2019
TL;DR: In this article, a 12-α-hydroxysteroid dehydrogenase derived from rhodococcus ruber and a mutant thereof was used to synthesize an ursodeoxycholic acid precursor.
Abstract: The present invention relates to a hydroxysteroid dehydrogenase and an application thereof in synthesis of an ursodeoxycholic acid precursor, and specifically discloses a 12-alpha-hydroxysteroid dehydrogenase derived from rhodococcus ruber and a mutant thereof, encoding gene and amino acid sequences, a recombinant expression vector containing the gene, a recombinant expression transformant, and anapplication of the hydroxysteroid dehydrogenase catalyzing oxidation of 12-alpha-hydroxysteroids to form 12-carbonyl steroids. Compared with the prior art, a used recombinant steroid dehydrogenase-catalyzed oxidation reaction is NAD+coenzyme-dependent type. The hydroxysteroid dehydrogenase has advantages of low application cost, simple operation, mild reaction conditions, environmental friendliness, high yield, etc., and thus has a very good prospect in an application of cholic acid as a raw material for production and preparation of the ursodeoxycholic acid precursor.
Patent•
31 Oct 2019
TL;DR: In this paper, a 7B-hydroxysteroid dehydrogenase with co-substrate specificity of NAD+ instead of NADP+ was proposed, which can be used to convert cholic acid and/or chenodeoxycholic acid (CDCA) into URSOCHolic acid.
Abstract: The present invention relates to a NAD+ dependent 7B— hydroxysteroid dehydrogenases and to methods of providing a 7B— hydroxysteroid dehydrogenase with a co-substrate specificity of NAD+ instead of NADP+. The invention further relates to methods for converting cholic acid (CA) and/or chenodeoxycholic acid (CDCA) into ursocholic acid (UCA) and/or ursodeoxycholic acid (UDCA) respectively, and more specifically methods for converting 7-oxo-deoxycholic acid (7-oxo-DCA) and/or 7-oxo-lithocholic acid (7-oxo LCA) into ursocholic acid (UCA) and/or ursodeoxycholic acid (UDCA) respectively, by using an NAD+ dependent 7B— hydroxysteroid dehydrogenase.
Patent•
20 Mar 2019
TL;DR: In this article, a nucleic acid molecule comprising a nucleotide sequence encoding a 7β-hydroxysteroid dehydrogenase (7β-HSDH) mutant was described.
Abstract: In various aspects and embodiments, the invention provides a nucleic acid molecule comprising a nucleotide sequence encoding a 7β-hydroxysteroid dehydrogenase (7β-HSDH) mutant that catalyzes at least the stereospecific enzymatic reduction of a 7-ketosteroid to the corresponding 7-hydroxysteroid, wherein the mutant has, compared to the wildtype 7β-HSDH of SEQ ID NO:2, a decreased substrate inhibition and/or an altered cofactor usage, and the mutant has, in comparison with the wildtype 7β-HSDH of SEQ ID NO:2, 1 to 15 amino acid additions, substitutions, deletions and/or inversions in the sequence motif VMVGRRE corresponding to positions 36 to 42 of SEQ ID NO:2.
01 Jan 2019
TL;DR: The 17β-hydroxysteroid dehydrogenases are a group of enzymes with the role of activating and inactivating steroid hormones by reduction and oxidation of the oxygen moiety at C17 of the steroid molecule.
Abstract: The 17β-hydroxysteroid dehydrogenases are a group of enzymes with the role of activating and inactivating steroid hormones by reduction and oxidation of the oxygen moiety at C17 of the steroid molecule. Deficiency of the type 3 enzyme leads to a disorder of sex development through failure of testicular androgen production - a similar phenotype to androgen insensitivity and 5α-reductase deficiency. Biochemical diagnosis can be made by measurement of serum steroids prior to gonadectomy; otherwise genetic testing is essential.