Showing papers on "Hydroxysteroid dehydrogenase published in 2020"
16 citations
TL;DR: This review aims to outline the advances in nature-derived steroids outside cardica glycosides with anticancer potential, covering the articles published between Jan. 2015 and Aug. 2020.
15 citations
TL;DR: A method that easily evaluates enzymatic activity of 17β-HSD3 by quantifying the conversion from A4 to T using androgen receptor (AR)-mediated transactivation is adapted and applicable to detect the conversion of 11-ketoandrostenedione to 11- ketotestosterone by HSD17B3.
13 citations
TL;DR: Hypobaric hypoxia causes a state of low circulatory progesterone level in females likely due to the degenerative changes in the female ovarian and adrenal tissues together with low steroidogenic 3ß HSD enzyme activity.
Abstract: The underlying mechanism regulating hypoxia induced alteration in female steroid hormones is first time explored in this study. To understand the mechanistic approach, female Sprague- Dawley rats were exposed to acute and chronic hypobaric hypoxia (282 mm-Hg, ~7620 m, 6 hours, 3 and 7 days). Estrous cycle, body weight, plasma progesterone and estradiol levels, morphology, histology and two key steroidogenic enzymes: 3s hydroxysteroid dehydrogenase (HSD) and 17s HSD activity of ovary and adrenal gland were studied. A persistent diestrous phase and a significant decrease in body weight were found in chronic hypoxia groups. Histological study suggested degenerative changes in ovarian corpus luteum of 7 days chronic hypobaric hypoxia (7CHH) group and a declined percentage of adrenocortical cells in 3 days chronic hypobaric hypoxia (3CHH) and 7CHH groups. Plasma estradiol level was unaltered, but progesterone level was decreased significantly in all hypoxic groups. Ovarian 3s HSD activity was decreased significantly with increasing days of hypoxic treatment along with a significantly low adrenal 3s HSD activity in 7CHH. In conclusion, hypobaric hypoxia causes a state of low circulatory progesterone level in females likely due to the degenerative changes in the female ovarian and adrenal tissues together with low steroidogenic 3s HSD enzyme activity.
13 citations
TL;DR: Findings strongly suggested that Hsd17b12a is one of the enzymes with 17KSR activity responsible for 11KT synthesis in the testis of Japanese eel, and the effects of Gths on the 17K SR activity and the expression of the candidate genes in the immature testis.
9 citations
TL;DR: The laccase/mediator system was investigated as a possible alternative to NOX, employing air as an oxidant and shows higher productivity and scalability than the NOX system.
Abstract: The specific oxidation of 12α-OH group of hydroxysteroids is required for the preparation of cheno-and ursodeoxycholic acid (CDCA and UDCA, respectively) The C12 oxidation of hydroxysteroids into their 12-oxo derivatives can selectively be performed by employing 12α-hydroxysteroid dehydrogenases These enzymes use NAD(P)+ as an electron acceptor, which has to be re-oxidized in a so-called “regeneration system” Recently, the enzyme NAD(P)H oxidase (NOX) was applied for the regeneration of NAD+ in the enzymatic preparation of 12-oxo-CDCA from cholic acid (CA), which allows air to be used as an oxidant However, the NOX system suffers from low activity and low stability Moreover, the substrate loading is limited to 10 mM In this study, the laccase/mediator system was investigated as a possible alternative to NOX, employing air as an oxidant The laccase/mediator system shows higher productivity and scalability than the NOX system This was proven with a preparative biotransformation of 20 g of CA into 12-oxo-CDCA (92% isolated yield) by employing a substrate loading of 120 mM (corresponding to 50 g/L) Additionally, the performance of the laccase/mediator system was compared with a classical ADH/acetone regeneration system and with other regeneration systems reported in literature
8 citations
TL;DR: These findings indicate that the 20 β-HSD type 2 enzymes catalyze the 20β-reduction of a plethora of steroids of the glucocorticoid biosynthesis pathway, implying different physiological roles in different species.
7 citations
TL;DR: It is concluded that H10 could serve as an effective inhibitor of 17β-HSD3, which in turn would inhibit the biosynthesis of androgens and progression of prostate cancer.
Abstract: The 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme is a potential therapeutic target for hormone-dependent prostate cancer, as it is the key enzyme in the last step of testosterone (T) biosynthesis. A curcumin analog, H10, was optimized for inhibiting T production in LC540 cells that stably overexpressed 17β-HSD3 enzyme (LC540 [17β-HSD3]) (P 0.05). This indicated that H10 only inhibited the enzymatic activity of 17β-HSD3 in vitro. Furthermore, H10 inhibited the adione-stimulated growth of xenografts established from LNCaP cells in nude mice in vivo. We conclude that H10 could serve as an effective inhibitor of 17β-HSD3, which in turn would inhibit the biosynthesis of androgens and progression of prostate cancer.
6 citations
TL;DR: In this article, a series of known inhibitors of human 17β-hydroxysteroid dehydrogenase type 7 (HSD17B7) were assayed for potential inhibition against 3-ketosteroid reductase activity.
5 citations
TL;DR: In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11β-HSD1 and results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11 β- HSD1.
Abstract: 11-Beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11β-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11β-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11β-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11β-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11β-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11β-HSD1 better than CLX.
3 citations
TL;DR: Molecular modeling experiments and enzymatic assays with LNCaP prostate cancer cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione, and appear to be in agreement with previous structure-activity relationships.
Abstract:
The last step in the production of androgen testosterone from 4-androstene-
3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3).
Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently,
could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was
developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known.
To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH,
as well as inhibitor RM-532-105.
Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand,
a homology model was prepared followed by molecular docking, and enzymatic assay experiments
were performed.
Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the
transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a
cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest
a competitive action of RM-532-105 with the cofactor and a non-competitive action with the
substrate 4-dione.
These results allow the selection of one inhibitor orientation in the enzyme binding site,
from the two possibilities predicted by the docking experiments, and appear to be in agreement with
previous structure-activity relationships.
TL;DR: In this article, 3-bromo-5-phenylsalicylic acid (5-PBSA) was used to suppress AKR1C18 activity in mouse oocytes.
Abstract: Inhibitors of the enzyme 20α-HSD (AKR1C18) are required to investigate AKR1C18 activity that occurs with meiotic resumption and progression in mouse oocytes. However, currently, no effective inhibitors of AKR1C18 are available. Therefore, we treated mouse oocytes with 3-bromo-5-phenylsalicylic acid (5-PBSA), an inhibitor of human 20α-HSD (AKR1C1), to ascertain whether it suppressed AKR1C18 activity. We also examined the effect of this inhibitor on oocyte maturation and viability.
In the germinal vesicle stage of mouse oocytes treated with 300 and 400 µM 5-PBSA, the number of oocytes showing AKR1C18 activity in the cytoplasm was 0 (0/34 and 0/35); the activity was significantly suppressed as compared with AKR1C18 activity in the control (25/29, 86.2%). In oocytes treated with >200 μM 5-PBSA, the number of degenerated oocytes was significantly increased compared with that in the control, and 17/37 (45.9%) of the oocytes treated with 300 μM were degenerated. In addition, in oocytes treated with 300 and 400 µM 5-PBSA, the number of oocytes that resumed meiosis was 2/20 (10%) and 0/16 (0%), respectively, and the resumption of meiosis was significantly suppressed compared with that in the controls (29/32, 90.6%).
These results revealed that 5-PBSA inhibits not only human AKR1C1 but also mouse AKR1C18 activity. In addition, suppression of meiotic resumption by treatment with 300 μM 5-PBSA suggests that AKR1C18 activity was involved in meiotic resumption. However, because 5-PBSA concentrations as high as 300 µM may also inhibit the activity of the AKR1C subfamily other than AKR1C18, the effects of 5-PBSA on these phylogenetically similar subfamilies must be investigated in the future.
TL;DR: Bile acid 12β-HSDH activity completes the epimerization of DCA by converting 12-oxoLCA to the 12 β-bile acid known as epiDCA, which was more specific for bile acids lacking a 7-hydroxyl group than cholic acid derivatives containing a 7Hydroxyl.
Abstract: Bile acids are detergent molecules that solubilize dietary lipids and lipid-soluble vitamins. Humans synthesize bile acids with α-orientation hydroxyl groups which can be biotransformed by gut microbiota to toxic, hydrophobic bile acids, such as deoxycholic acid (DCA). Gut microbiota are also capable of converting hydroxyl groups from the α-orientation through an oxo-intermediate to the β-orientation, resulting in more hydrophilic and less toxic bile acids. This interconversion is catalyzed by regio- (C-3 vs. C-7) and stereospecific (α vs. β) hydroxysteroid dehydrogenases (HSDHs). Recently, multiple human gut clostridia have been reported to encode 12α-HSDH, which interconverts DCA and 12-oxolithocholic acid (12-oxoLCA). Bile acid 12β-HSDH activity completes the epimerization of DCA by converting 12-oxoLCA to the 12β-bile acid known as epiDCA. While 12β-HSDH activity has been shown in cell extracts of Clostridium paraputrificum, the gene has not yet been reported. In order to identify the first gene encoding this activity, 6 candidate oxidoreductase genes from C. paraputrificum ATCC 25780 were cloned, overexpressed, purified, and screened for activity with 12-oxoLCA and epiDCA. LC-MS analysis was performed on reaction products from the enzyme encoded by DR024_RS09610, confirming the first 12β-HSDH gene discovered. The enzyme was more specific for bile acids lacking a 7-hydroxyl group than cholic acid derivatives containing a 7-hydroxyl. Phylogenetic analysis revealed previously unknown diversity for bile acid 12β-HSDH by experimentally validating two additional 12β-HSDHs within the tree from Eisenbergiella sp. OF01-20 and Olsenella sp. GAM18.
Patent•
09 Jun 2020
TL;DR: In this article, the amino acid sequences of the mutants are shown as SEQ ID NO:2, 3, 4, 5, 6, 7, 8, 9 or 10, and are obtained by changing the 255th amino acid of the 7 alpha-hydroxysteroid dehydrogenase with an amino acid sequence of SEQID NO:1 from Ile to Tyr, Gln, Leu, Th, Gly, Asn,Ser, Ala or Phe.
Abstract: The invention relates to hydroxysteroid dehydrogenase, and in particular to 7alpha-hydroxysteroid dehydrogenase (St-2-2) mutants. The amino acid sequences of the mutants are shown as SEQ ID NO:2, 3, 4, 5, 6, 7, 8, 9 or 10, and are obtained by changing the 255th amino acid of the 7alpha-hydroxysteroid dehydrogenase with an amino acid sequence of SEQ ID NO:1 from Ile to Tyr, Gln, Leu, Thr, Gly, Asn,Ser, Ala or Phe. In the presence of same substrates TCDCA and NADP , enzyme activity of the mutants is respectively 1.49, 1.78, 1.79, 1.79, 1.93, 2.44, 2.58, 2.97 and 3.34 times of enzyme activityof a wild type hydroxysteroid dehydrogenase, and the mutant has a great application potential in a process of obtaining tauroursodeoxycholic acid (TUDCA) through biotransformation of taurochenodeoxycholic acid (TCDCA).
Patent•
05 Jun 2020
TL;DR: In this article, a 3 alpha hydroxysteroid dehydrogenase mutant was characterized in that the 52nd, 76th, 124th, 137th, 169th, and 228th sites of a wild-type 3 alpha-hydroxymethylsteroid-dehydrogenase amino acid sequence were subjected to replacement modification to separately obtain I52V, T76A, K124E, A137S, R169C and F228L.
Abstract: The present invention discloses a 3 alpha hydroxysteroid dehydrogenase mutant and an application thereof in total bile acid cycle enzymatic detection. The 3 alpha hydroxysteroid dehydrogenase mutant is characterized in that the 52nd, 76th, 124th, 137th, 169th and 228th sites of a wild-type 3 alpha hydroxysteroid dehydrogenase amino acid sequence are subjected to replacement modification to separately obtain I52V, T76A, K124E, A137S, R169C and F228L. The mutant has extremely high stability, including pH and temperature stability. A total bile acid cycle enzymatic kit prepared from the mutant enzyme has extremely high stability.