An Overview of 7α- and 7β-Hydroxysteroid Dehydrogenases: Structure, Specificity and Practical Application

2021 ◽  
Vol 28 ◽  
Author(s):  
Deshuai Lou ◽  
Xi Liu ◽  
Jun Tan
Keyword(s):  
Bile Acid ◽  
Structural Characteristics ◽  
Basic Research ◽  
Hydroxysteroid Dehydrogenase ◽  
Biochemical Properties ◽  
Molecular Engineering ◽  
Hydroxyl Group ◽  
Bile Acid Metabolism ◽  
In Vitro Biosynthesis

: 7α-Hydroxysteroid dehydrogenase and 7β-hydroxysteroid dehydrogenase are key enzymes involved in bile acid metabolism. They catalyze the epimerization of a hydroxyl group through 7-keto bile acid intermediates. Basic research of the two enzymes has focused on exploring new enzymes and the structure-function relationship. The application research focused on the in vitro biosynthesis of bile acid drugs and the exploration and improvement of their catalytic ability based on molecular engineering. This article summarized the primary and advanced structural characteristics, specificities, biochemical properties, and applications of the two enzymes. The emphasis is also given to obtaining of novel 7α-hydroxysteroid dehydrogenase and 7β-hydroxysteroid dehydrogenase that are thermally stable and active in the presence of organic solvents, high substrate concentration, and extreme pH values. To achieve these goals, enzyme redesigning based on protein engineering and genomics may be the most useful approaches.

Effects of different digestible carbohydrates on bile acid metabolism and SCFA production by human gut micro-flora grown in an in vitro semi-continuous culture

Anaerobe ◽  
2004 ◽  
Vol 10 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Andrea Zampa ◽  
Stefania Silvi ◽  
Roberto Fabiani ◽  
Guido Morozzi ◽  
Carla Orpianesi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Continuous Culture ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Human Gut

scholarly journals Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

2019 ◽  
Author(s):  
Pavan Bhargava ◽  
Leah Mische ◽  
Matthew D. Smith ◽  
Emily Harrington ◽  
Kathryn C Fitzgerald ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
White Matter Lesions ◽  
The Body ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
Microglial Polarization

AbstractMultiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Lactiplantibacillus plantarum H-87 prevents high-fat diet-induced obesity by regulating bile acid metabolism in C57BL/6J mice

2021 ◽  
Author(s):  
Cong Liang ◽  
Xiao-Hong Zhou ◽  
Pi-Min Gong ◽  
Hai-Yue Niu ◽  
Lin-Zheng Lyu ◽  
...  
Keyword(s):  
Bile Acid ◽  
High Fat Diet ◽  
Acid Metabolism ◽  
Liver Fat ◽  
Bile Acid Metabolism ◽  
Bile Salt Hydrolase ◽  
Lipid Digestion ◽  
Diet Induced Obesity ◽  
Bile Salt Hydrolase Activity

Lactiplantibacillus plantarum H-87 shows excellent bile salt hydrolase activity in vitro and effectively prevents obesity by regulating bile acid metabolism to inhibit liver fat accumulation, insulin resistance and lipid digestion in C57BL/6J mice.

Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1

2011 ◽  
Vol 436 (3) ◽  
pp. 621-629 ◽  
Author(s):  
Alex Odermatt ◽  
Thierry Da Cunha ◽  
Carlos A. Penno ◽  
Charlie Chandsawangbhuwana ◽  
Christian Reichert ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Human Liver ◽  
Liver Microsomes ◽  
Three Dimensional ◽  
Hydroxysteroid Dehydrogenase ◽  
Binding Mode ◽  
Bile Acid Metabolism ◽  
Secondary Bile Acid ◽  
Micro Organisms

The oxidized bile acid 7-oxoLCA (7-oxolithocholic acid), formed primarily by gut micro-organisms, is reduced in human liver to CDCA (chenodeoxycholic acid) and, to a lesser extent, UDCA (ursodeoxycholic acid). The enzyme(s) responsible remained unknown. Using human liver microsomes, we observed enhanced 7-oxoLCA reduction in the presence of detergent. The reaction was dependent on NADPH and stimulated by glucose 6-phosphate, suggesting localization of the enzyme in the ER (endoplasmic reticulum) and dependence on NADPH-generating H6PDH (hexose-6-phosphate dehydrogenase). Using recombinant human 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), we demonstrate efficient conversion of 7-oxoLCA into CDCA and, to a lesser extent, UDCA. Unlike the reversible metabolism of glucocorticoids, 11β-HSD1 mediated solely 7-oxo reduction of 7-oxoLCA and its taurine and glycine conjugates. Furthermore, we investigated the interference of bile acids with 11β-HSD1-dependent interconversion of glucocorticoids. 7-OxoLCA and its conjugates preferentially inhibited cortisone reduction, and CDCA and its conjugates inhibited cortisol oxidation. Three-dimensional modelling provided an explanation for the binding mode and selectivity of the bile acids studied. The results reveal that 11β-HSD1 is responsible for 7-oxoLCA reduction in humans, providing a further link between hepatic glucocorticoid activation and bile acid metabolism. These findings also suggest the need for animal and clinical studies to explore whether inhibition of 11β-HSD1 to reduce cortisol levels would also lead to an accumulation of 7-oxoLCA, thereby potentially affecting bile acid-mediated functions.

scholarly journals Coordinated Recruitment of Histone Methyltransferase G9a and Other Chromatin-Modifying Enzymes in SHP-Mediated Regulation of Hepatic Bile Acid Metabolism

2006 ◽  
Vol 27 (4) ◽  
pp. 1407-1424 ◽  
Author(s):  
Sungsoon Fang ◽  
Ji Miao ◽  
Lingjin Xiang ◽  
Bhaskar Ponugoti ◽  
Eckardt Treuter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Critical Role ◽  
Histone Methyltransferase ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
H3k9 Methylation ◽  
Hepatic Bile

ABSTRACT SHP has been implicated as a pleiotropic regulator of diverse biological functions by its ability to inhibit numerous nuclear receptors. Recently, we reported that SHP inhibits transcription of CYP7A1, a key gene in bile acid biosynthesis, by recruiting histone deacetylases (HDACs) and a Swi/Snf-Brm complex. To further delineate the mechanism of this inhibition, we have examined whether methylation of histones is also involved and whether a functional interplay between chromatin-modifying enzymes occurs. The histone methyltransferase G9a, but not SUV39, was colocalized with SHP in the nucleus and directly interacted with SHP in vitro. G9a, which was coimmunoprecipitated with hepatic SHP, methylated Lys-9 of histone 3 (H3K9) in vitro. Expression of G9a enhanced inhibition of CYP7A1 transcription by SHP, while a catalytically inactive G9a dominant negative (DN) mutant reversed the SHP inhibition. G9a was recruited to and H3K9 was methylated at the CYP7A1 promoter in a SHP-dependent manner in bile acid-treated HepG2 cells. Expression of the G9a-DN mutant inhibited H3K9 methylation, blocked the recruitment of the Brm complex, and partially reversed CYP7A1 inhibition by bile acids. Inhibition of HDAC activity with trichostatin A blocked deacetylation and methylation of H3K9 at the promoter, and, conversely, inhibition of H3K9 methylation by G9a-DN partially blocked deacetylation. Hepatic expression of G9a-DN in mice fed cholic acid disrupted bile acid homeostasis, resulting in increased bile acid pools and partial de-repression of Cyp7a1 and Cyp8b1. Our studies establish a critical role for G9a methyltransferase, histone deacetylases, and the Swi/Snf-Brm complex in the SHP-mediated inhibition of hepatic bile acid synthesis via coordinated chromatin modification at target genes.

scholarly journals Biochemical and Genetic Studies of the Initiation of Human Rhinovirus 2 RNA Replication: Purification and Enzymatic Analysis of the RNA-Dependent RNA Polymerase 3Dpol

2001 ◽  
Vol 75 (22) ◽  
pp. 10969-10978 ◽  
Author(s):  
Kinga Gerber ◽  
Eckard Wimmer ◽  
Aniko V. Paul
Keyword(s):  
Rna Polymerase ◽  
Rna Virus ◽  
Biochemical Properties ◽  
Human Rhinovirus ◽  
Hydroxyl Group ◽  
Genetic Studies ◽  
Vitro Assay ◽  
Enzyme Preparations ◽  
Synthetic Reactions

ABSTRACT The replication of human rhinovirus 2 (HRV2), a positive-stranded RNA virus belonging to the Picornaviridae, requires a virus-encoded RNA polymerase. We have expressed in Escherichia coli and purified both a glutathioneS-transferase fusion polypeptide and an untagged form of the HRV2 RNA polymerase 3Dpol. Using in vitro assay systems previously described for poliovirus RNA polymerase 3Dpol(J. B. Flanegan and D. Baltimore, Proc. Natl. Acad. Sci. USA 74:3677–3680, 1977; A. V. Paul, J. H. van Boom, D. Filippov, and E. Wimmer, Nature 393:280–284, 1998), we have analyzed the biochemical properties of the two different enzyme preparations. HRV2 3Dpol is both template and primer dependent, and it catalyzes two types of synthetic reactions in the presence of UTP, Mn2+, and a poly(A) template. The first consists of an elongation reaction of an oligo(dT)15 primer into poly(U). The second is a protein-priming reaction in which the enzyme covalently links UMP to the hydroxyl group of tyrosine in the terminal protein VPg, yielding VPgpU. This precursor is elongated first into VPgpUpU and then into VPg-linked poly(U), which is identical to the 5′ end of picornavirus minus strands. The two forms of the enzyme are about equally active both in the oligonucleotide elongation and in the VPg-primed reaction. Various synthetic mutant VPgs were tested as substrates in the VPg uridylylation reaction.

Molecular Mechanism of Bushen Jianpi Inhibition of Postoperative Recurrence and Metastasis of Hepatocellular Carcinoma

2021 ◽  
Vol 17 (1) ◽  
pp. 53-63
Author(s):  
Zhangjie Zhou ◽  
Shujuan Fu ◽  
Yun Li ◽  
Zujun Que ◽  
Xinhua Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Bile Acid ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Liver Cancer ◽  
Immune Cell ◽  
Cancer Recurrence ◽  
Bile Acid Metabolism

Compared with western medicine, traditional Chinese medicine can better regulate the internal environment and inhibit liver cancer recurrence and metastasis. Bushen Jianpi Recipe (BSJPR) is a traditional Chinese medicine for tonifying the kidney and invigorating the spleen. It has also been used to treat tumors and other related diseases. Here we explore the efficacy of BSJPR inhibition of hepatocellular carcinoma (HCC) in vivo and in vitro . We hypothesize that BSJPR reduces intrahepatic cholestasis and inflammation and increases expression of the bile acid receptor and downstream targets. This study aims to test this hypothesis and determine whether the inhibitory effect of BSJPR on liver cancer recurrence and metastasis is related to bile acid metabolism. We also observed changes in immune cell expression, suggesting that regulation of the immune microenvironment could inhibit the recurrence and metastasis of HCC. These findings provide a basis for the treatment of HCC and new ideas for follow-up studies of BSJPR.

scholarly journals Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges

2012 ◽  
Vol 2012 ◽  
pp. 1-22 ◽  
Author(s):  
Jan Víteček ◽  
Antonín Lojek ◽  
Giuseppe Valacchi ◽  
Lukáš Kubala
Keyword(s):  
Nitric Oxide ◽  
Drug Design ◽  
Therapeutic Potential ◽  
Structural Characteristics ◽  
Biochemical Properties ◽  
Modern Drug ◽  
Nos Inhibitors ◽  
Specific Inhibitors

In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects bothin vitroandin vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted.

scholarly journals Mechanisms of Interactions between Bile Acids and Plant Compounds—A Review

2020 ◽  
Vol 21 (18) ◽  
pp. 6495
Author(s):  
Susanne Naumann ◽  
Dirk Haller ◽  
Peter Eisner ◽  
Ute Schweiggert-Weisz
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
Future Research ◽  
Bile Acid Metabolism ◽  
Dietary Fibres ◽  
Research Activities ◽  
Plant Compounds

Plant compounds are described to interact with bile acids during small intestinal digestion. This review will summarise mechanisms of interaction between bile acids and plant compounds, challenges in in vivo and in vitro analyses, and possible consequences on health. The main mechanisms of interaction assume that increased viscosity during digestion results in reduced micellar mobility of bile acids, or that bile acids and plant compounds are associated or complexed at the molecular level. Increasing viscosity during digestion due to specific dietary fibres is considered a central reason for bile acid retention. Furthermore, hydrophobic interactions are proposed to contribute to bile acid retention in the small intestine. Although frequently hypothesised, no mechanism of permanent binding of bile acids by dietary fibres or indigestible protein fractions has yet been demonstrated. Otherwise, various polyphenolic structures were recently associated with reduced micellar solubility and modification of steroid and bile acid excretion but underlying molecular mechanisms of interaction are not yet fully understood. Therefore, future research activities need to consider the complex composition and cell-wall structures as influenced by processing when investigating bile acid interactions. Furthermore, influences of bile acid interactions on gut microbiota need to be addressed to clarify their role in bile acid metabolism.

scholarly journals Metabolic Soft Spot and Pharmacokinetics: Functionalization of C-3 Position of an Eph–Ephrin Antagonist Featuring a Bile Acid Core as an Effective Strategy to Obtain Oral Bioavailability in Mice

2021 ◽  
Vol 15 (1) ◽  
pp. 41
Author(s):  
Francesca Ferlenghi ◽  
Carmine Giorgio ◽  
Matteo Incerti ◽  
Lorenzo Guidetti ◽  
Paola Chiodelli ◽  
...  
Keyword(s):  
Bile Acid ◽  
Oral Bioavailability ◽  
Mouse Liver ◽  
Hydroxyl Group ◽  
Effective Strategy ◽  
Secondary Bile Acid ◽  
Hydroxylated Metabolites ◽  
Soft Spot ◽  
Hydroxylated Metabolite

UniPR129, an L-β-homotryptophan conjugate of the secondary bile acid lithocholic acid (LCA), acts as an effective protein-protein interaction (PPI) inhibitor of the Eph–ephrin system but suffers from a poor oral bioavailability in mice. To improve UniPR129 bioavailability, a metabolic soft spot, i.e., the 3α-hydroxyl group on the LCA steroidal ring, was functionalized to 3-hydroxyimine. In vitro metabolism of UniPR129 and 3-hydroxyimine derivative UniPR500 was compared in mouse liver subcellular fractions, and main metabolites were profiled by high resolution (HR-MS) and tandem (MS/MS) mass spectrometry. In mouse liver microsomes (MLM), UniPR129 was converted into several metabolites: M1 derived from the oxidation of the 3-hydroxy group to 3-oxo, M2–M7, mono-hydroxylated metabolites, M8–M10, di-hydroxylated metabolites, and M11, a mono-hydroxylated metabolite of M1. Phase II reactions were only minor routes of in vitro biotransformation. UniPR500 shared several metabolic pathways with parent UniPR129, but it showed higher stability in MLM, with a half-life (t1/2) of 60.4 min, if compared to a t1/2 = 16.8 min for UniPR129. When orally administered to mice at the same dose, UniPR500 showed an increased systemic exposure, maintaining an in vitro valuable pharmacological profile as an EphA2 receptor antagonist and an overall improvement in its physico-chemical profile (solubility, lipophilicity), if compared to UniPR129. The present work highlights an effective strategy for the pharmacokinetic optimization of aminoacid conjugates of bile acids as small molecule Eph–ephrin antagonists.

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