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Sean M Mythen, Saravanan Devendran, Celia Méndez-García, Isaac Cann, Jason M Ridlon
Gut metagenomic sequences provide a rich source of microbial genes, the majority of which are annotated by homology or unknown. Genes and gene pathways that encode enzymes catalyzing biotransformation of host bile acids are important to identify in gut metagenomic sequences due to the importance of bile acids on gut microbiome structure and host physiology. Hydroxysteroid dehydrogenases (HSDH) are pyridine nucleotide-dependent enzymes with stereo-specificity and regio-specificity for bile acid and steroid hydroxyl groups...
January 12, 2018: Applied and Environmental Microbiology
Jiaoping Zhang, Xianzhi Wang, Yaming Lu, Siddhi J Bhusal, Qijian Song, Perry B Cregan, Yang Yen, Michael Brown, Guo-Liang Jiang
The complex genetic architecture of quality traits has hindered efforts to modify seed nutrients in soybean (Glycine max). Genome-wide association studies were conducted for the seed composition including protein, oil, fatty acids and amino acids using 313 diverse soybean germplasm accessions genotyped with a high-density SNP array. A total of 87 chromosomal regions were identified to be associated with seed composition, explaining 8-89% of genetic variances. The candidate genes GmSAT1, AK-HSDH, SACPD-C and FAD3A of known function, and putative MtN21 nodulin, FATB and steroid-5-α-reductase involved in N2 fixation, amino acid biosynthesis and fatty acid metabolism were found at the major-effect loci...
January 2, 2018: Molecular Plant
Deshuai Lou, Jun Tan, Liancai Zhu, Shunlin Ji, Shijin Tang, Kaiyi Yao, Jingxuan Han, Bochu Wang
Enhancing thermostability of the 7α-Hydroxysteroid dehydrogenases (7α-HSDHs) is beneficial to its industrial application broadly. Based on unfolding free energy changes (ΔΔG) prediction seven mutations of Clostridium absonum (CA) 7α-HSDH were selected and experimentally verified, and these mutants fitted three-state denaturation model well, among which S22L located in the αA possessed the greatest TmN→I increase (>8 °C). Mutants P124L, L197E, N171L and Y259E also became more stable than wild type CA 7α-HSDH with different ranges...
November 12, 2017: Protein and Peptide Letters
Ming-Min Zheng, Fei-Fei Chen, Hao Li, Chun-Xiu Li, Jian-He Xu
Ursodeoxycholic acid (UDCA) is an effective drug for the treatment of hepatitis. In this study, 7α-hydroxysteroid dehydrogenase (7α-HSDH) and lactate dehydrogenase (LDH), as well as 7β-HSDH and glucose dehydrogenase (GDH), were co-immobilized onto an epoxy-functionalized resin (ES-103) for catalyzing the synthesis of UDCA from chenodeoxycholic acid (CDCA). Through optimizing the immobilization pH, time and the loading ratio of enzymes to resin, the specific activities of immobilized LDH-7αHSDH@ES-103 and 7βHSDH-GDH@ES-103 were 43...
September 19, 2017: Chembiochem: a European Journal of Chemical Biology
Rui Wang, Jiaquan Wu, David Kin Jin, Yali Chen, Zhijia Lv, Qian Chen, Qiwei Miao, Xiaoyu Huo, Feng Wang
In mammals, bile acids/salts and their glycine and taurine conjugates are effectively recycled through enterohepatic circulation. 7β-Hydroxysteroid dehydrogenases (7β-HSDHs; EC, including that from the intestinal microbe Collinsella aerofaciens, catalyse the NADPH-dependent reversible oxidation of secondary bile-acid products to avoid potential toxicity. Here, the first structure of NADP(+) bound to dimeric 7β-HSDH is presented. In one active site, NADP(+) adopts a conventional binding mode similar to that displayed in related enzyme structures...
May 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
Can Song, Bochu Wang, Jun Tan, Liancai Zhu, Deshuai Lou
Tauroursodeoxycholic acid (TUDCA) has been used to treat many diseases effectively. 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 7β-hydroxysteroid dehydrogenase (7β-HSDH) are two key enzymes that drive the efficient biosynthesis of TUDCA from taurochenodeoxycholic acid (TCDCA) in vitro. In this study, a metagenomic approach was used to isolate 7α- and 7β-HSDHs from fecal samples of black bears. Five new 7α-HSDHs and one new 7β-HSDH enzyme were discovered and identified from the gut microbiota of black bears, and four of them presented good enzymatic properties...
April 24, 2017: Scientific Reports
Jie Shi, Jie Wang, Lu Yu, Li Yang, Shujuan Zhao, Zhengtao Wang
Bear bile powder is a precious medicinal material. It is characterized by high content of tauroursodeoxycholic acid (TUDCA) at a ratio of 1.0-1.5 to taurochenodeoxycholic acid (TCDCA). Here, we reported the biotransformation of tauroursodeoxycholic acid (TUDCA) through Escherichia coli engineered with a two-step mimic biosynthetic pathway of TUDCA from taurochenodeoxycholic acid (TCDCA). Two 7α-hydroxysteroid dehydrogenase (7α-HSDH) and two 7β-hydroxysteroid dehydrogenase (7β-HSDH) genes (named as α1, α2, β1, and β2) were selected and synthesized to create four pathway variants using ePathBrick...
July 2017: Journal of Industrial Microbiology & Biotechnology
Saravanan Devendran, Celia Méndez-García, Jason M Ridlon
Members of the gastrointestinal microbiota are known to convert glucocorticoids to androstanes, which are subsequently converted to potent androgens by other members of the gut microbiota or host tissues. Butyricicoccus desmolans and Clostridium cadaveris have previously been reported for steroid-17,20-desmolase and 20β-hydroxysteroid dehydrogenase (HSDH) activities that are responsible for androstane formation from cortisol; however, the genes encoding these enzymes have yet to be reported. In this work, we identified and located a gene encoding 20β-HSDH in both B...
May 2017: Journal of Lipid Research
Daniel Bakonyi, Werner Hummel
A gene encoding a novel 7α-specific NADP(+)-dependent hydroxysteroid dehydrogenase from Clostridium difficile was cloned and heterologously expressed in Escherichia coli. The enzyme was purified using an N-terminal hexa-his-tag and biochemically characterized. The optimum temperature is at 60°C, but the enzyme is inactivated at this temperature with a half-life time of 5min. Contrary to other known 7α-HSDHs, for example from Clostridium sardiniense or E. coli, the enzyme from C. difficile does not display a substrate inhibition...
April 2017: Enzyme and Microbial Technology
Deshuai Lou, Jun Tan, Liancai Zhu, Shunlin Ji, Bochu Wang
BACKGROUND: 7α-Hydroxysteroid dehydrogenases (7α-HSDHs) can stereoselectively catalyze steroids, aromatic α-ketoesters, and benzaldehyde analogues playing a critical role in the biotransformation and poor thermostability that hinders their biomedical and industrial applications. OBJECTIVE: This study was to investigate how to enhance the thermostability of 7α-HSDH from Clostridium absonum (CA 7α-HSDH). METHOD: Based on the three-dimensional structure of CA 7α-HSDH, recently reported program MAESTRO was used to compute the ΔΔG and predict the single-point mutants that could enhance its thermostability...
2017: Protein and Peptide Letters
Ming-Min Zheng, Ke-Cai Chen, Ru-Feng Wang, Hao Li, Chun-Xiu Li, Jian-He Xu
Ursodeoxycholic acid (UDCA) is the main active ingredient of natural bear bile powder with multiple pharmacological functions. 7β-Hydroxysteroid dehydrogenase (HSDH) is a key biocatalyst for the synthesis of UDCA. However, all the 7β-HSDHs reported commonly suffer from poor activity and thermostability, resulting in limited productivity of UDCA. In this study, a multiobjective directed evolution (MODE) strategy was proposed and applied to improve the activity, thermostability, and pH optimum of a 7β-HSDH...
February 15, 2017: Journal of Agricultural and Food Chemistry
Raees Khan, Hyun Gi Kong, Yong-Hoon Jung, Jinhee Choi, Kwang-Yeol Baek, Eul Chul Hwang, Seon-Woo Lee
Triclosan (TCS) is a widely used antimicrobial agent and TCS resistance is considered to have evolved in diverse organisms with extensive use of TCS, but distribution of TCS resistance has not been well characterized. Functional screening of the soil metagenome in this study has revealed that a variety of target enoyl acyl carrier protein reductases (ENR) homologues are responsible for the majority of TCS resistance. Diverse ENRs similar to 7-α-hydroxysteroid dehydrogenase (7-α-HSDH), FabG, or the unusual YX7K-type ENR conferred extreme tolerance to TCS...
2016: Scientific Reports
Deshuai Lou, Bochu Wang, Jun Tan, Liancai Zhu, Xiaoxi Cen, Qingzhi Ji, Yue Wang
7α-hydroxysteroid dehydrogenase (7α-HSDH) can catalyse the oxidation of C7 α-OH of the steroid nucleus in the bile acid metabolism. In the paper we determined the crystal structure of 7α-HSDH from Clostridium absonum (CA 7α-HSDH) complexed with taurochenodeoxycholic acid (TCDCA) and NADP(+) by X-ray diffraction, which, as a tetramer, possesses the typical α/β folding pattern. The four subunits of an asymmetric unit lie in the fact that there are the stable hydrophobic interactions between Q-axis-related subunits...
March 10, 2016: Scientific Reports
P Miro, M L Marin, M A Miranda
The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs...
March 7, 2016: Organic & Biomolecular Chemistry
Teresa J Clark, Yan Lu
Biosynthesis of aspartate (Asp)-derived amino acids lysine (Lys), methionine (Met), threonine (Thr), and isoleucine involves monofunctional Asp kinases (AKs) and dual-functional Asp kinase-homoserine dehydrogenases (AK-HSDHs). Four-week-old loss-of-function Arabidopsis (Arabidopsis thaliana) mutants in the AK-HSDH2 gene had increased amounts of Asp and Asp-derived amino acids, especially Thr, in leaves. To explore mechanisms behind this phenotype, we obtained single mutants for other AK and AK-HSDH genes, generated double mutants from ak-hsdh2 and ak mutants, and performed free and protein-bound amino acid profiling, transcript abundance, and activity assays...
August 2015: Plant Physiology
Alain Labbé, Jorge G Ganopolsky, Christopher J Martoni, Satya Prakash, Mitchell L Jones
We performed an analysis to determine the importance of bile acid modification genes in the gut microbiome of inflammatory bowel disease and type 2 diabetic patients. We used publicly available metagenomic datasets from the Human Microbiome Project and the MetaHIT consortium, and determined the abundance of bile salt hydrolase gene (bsh), 7 alpha-dehydroxylase gene (adh) and 7-alpha hydroxysteroid dehydrogenase gene (hsdh) in fecal bacteria in diseased populations of Crohn's disease (CD), Ulcerative Colitis (UC) and Type 2 diabetes mellitus (T2DM)...
2014: PloS One
Thorsten Eggert, Daniel Bakonyi, Werner Hummel
Ursodeoxycholic acid, a secondary bile acid, is used as a drug for the treatment of various liver diseases, the optimal dose comprises the range of 8-10mg/kg/day. For industrial syntheses, the structural complexity of this bile acid requires the use of an appropriate starting material as well as the application of regio- and enantio-selective enzymes for its derivatization. Most strategies for the synthesis start from cholic acid or chenodeoxycholic acid. The latter requires the conversion of the hydroxyl group at C-7 from α- into β-position in order to obtain ursodeoxycholic acid...
December 10, 2014: Journal of Biotechnology
Dalong Zhang, Rui Zhang, Jie Zhang, Liying Chen, Chunxia Zhao, Wenyue Dong, Qing Zhao, Qiaqing Wu, Dunming Zhu
11β-Hydrocortisone (11β-HC) is an important anti-inflammatory drug and intermediate for the synthesis of other steroids. One of the methods for the synthesis of 11β-HC is the asymmetric reduction of cortisone catalyzed by a highly regioselective and stereoselective 11β-hydroxysteroid dehydrogenase (11β-HSDH). However, this process has been prohibited by the poor soluble expression of the membrane-anchoring protein 11β-HSDH in prokaryotes. To overcome this obstacle, a mutant III-1G1 (Phe80Leu/Thr105Ser/Ala260Thr/Tyr274Stop) truncated at position 274 with improved yield of soluble protein was stepwise obtained from the 11β-HSDH from guinea pig by random mutagenesis combining with structural complementation assay and C-terminal truncating library screening...
November 2014: Applied Microbiology and Biotechnology
Deshuai Lou, Bochu Wang, Jun Tan, Liancai Zhu
7α-hydroxysteroid dehydrogenase (7α-HSDH, EC, one of the short-chain dehydrogenase/reductase superfamily, catalyzes the dehydrogenation of C7 hydroxyl group of the steroid skeleton of bile acids. Clostridium absonum 7α-HSDH (Ca 7α-HSDH) was cloned and heterologously expressed in Escherichia coli. The function of carboxyterminal (C-terminal) and Arg38 of Ca 7α-HSDH was investigated through truncations and site-directed mutagenesis, respectively. When 2 and 6 amino acids of C-terminal were removed, the catalytic efficiency (k(cat)/K(m)) of Ca 7α-HSDH remained 19...
2014: Protein and Peptide Letters
Zhen Chen, Sugima Rappert, An-Ping Zeng
Allosteric proteins, which can sense different signals, are interesting biological parts for synthetic biology. In particular, the design of an artificial allosteric enzyme to sense an unnatural signal is both challenging and highly desired, for example, for a precise and dynamical control of fluxes of growth-essential but byproduct pathways in metabolic engineering of industrial microorganisms. In this work, we used homoserine dehydrogenase (HSDH) of Corynebacterium glutamicum, which is naturally allosterically regulated by threonine and isoleucine, as an example to demonstrate the feasibility of reengineering an allosteric enzyme to respond to an unnatural inhibitor L-lysine...
February 20, 2015: ACS Synthetic Biology
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