90 results on '"Xiachang Wang"'
Search Results
2. Endophytic Microbes from Medicinal Plants in Fenghuang Mountain as a Source of Antibiotics
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Aiping Yang, Yu Hong, Fengjuan Zhou, Ling Zhang, Youjuan Zhu, Chang Wang, Yang Hu, Li Yu, Lihong Chen, and Xiachang Wang
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antibiotics ,endophyte ,medicinal plant ,strain diversity ,Streptomyces ,Penicillium ,Organic chemistry ,QD241-441 - Abstract
One of the largest concerns with world health today is still antibiotic resistance, which is making it imperative to find efficient alternatives as soon as possible. It has been demonstrated that microbes are reliable sources for the creation of therapeutic antibiotics. This research intends to investigate the endophytic microorganisms from several medicinal plants in Fenghuang Mountain (Jiangsu Province, China) and to discover new antibiotics from their secondary metabolites. A total of 269 endophytic strains were isolated from nine distinct medicinal plants. Taxonomic analysis revealed that there were 20 distinct species among these endophytes, with Streptomyces being the most common genus. Three of the target strains were chosen for scale-up fermentation after preliminary screening of antibacterial activities and the metabolomics investigation using LC-MS. These strains were Penicillium sp. NX-S-6, Streptomyces sp. YHLB-L-2 and Streptomyces sp. ZLBB-S-6. Twenty-three secondary metabolites (1–23), including a new sorbicillin analogue (1), were produced as a result of antibacterial activity-guided isolation. Through spectroscopic analysis using MS and NMR, the structures of yield compounds were clarified. According to antibacterial data, S. aureus or B. subtilis were inhibited to varying degrees by sorrentanone (3), emodic acid (8), GKK1032 B (10), linoleic acid (14), toyocamycin (17) and quinomycin A (21). The most effective antimicrobial agent against S. aureus, B. subtilis, E. coli and A. baumannii was quinomycin A (21). In addition, quinomycin A showed strong antifungal activity against Aspergillus fumigatus, Cryptococcus neoformans, and two clinical isolated strains Aspergillus fumigatus #176 and #339, with MIC as 16, 4, 16 and 16 µg/mL, respectively. This is the first time that bioprospecting of actinobacteria and their secondary metabolites from medicinal plants in Fenghuang Mountain was reported. The finding demonstrates the potential of endophytic microbes in medical plants to produce a variety of natural products. Endophytic microbes will be an important source for new antibiotics.
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- 2023
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3. Gypenosides Synergistically Reduce the Extracellular Matrix of Hepatic Stellate Cells and Ameliorate Hepatic Fibrosis in Mice
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Han Li, Hanghang Wang, Aiping Yang, Mingzhen Xue, Junyang Wang, Qi Lv, Jian Liu, Lihong Hu, Yinan Zhang, and Xiachang Wang
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gypenoside ,liver fibrosis ,PP2Cα ,extracellular matrix ,synergistic effect ,Organic chemistry ,QD241-441 - Abstract
Liver fibrosis resulting from chronic liver damage is becoming one of the major threats to health worldwide. Active saponin constituents isolated from Gynostemma pentaphyllum were found to possess a protective effect in liver diseases. Here, we obtained a naturally abundant gypenoside, XLVI, and evaluated its liver protection activity in both animal and cellular models. The results showed that it ameliorated acute and chronic liver injuries and lightened the process of fibrogenesis in vivo. XLVI can inhibit TGF-β-induced activation of hepatic stellate cells and ECM deposition in vitro. The underlying mechanism study verified that it upregulated the protein expression of protein phosphatase 2C alpha and strengthened the vitality of the phosphatase together with a PP2Cα agonist gypenoside NPLC0393. These results shed new light on the molecular mechanisms and the potential therapeutic function of the traditional herb Gynostemma pentaphyllum in the treatment of liver fibrosis.
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- 2023
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4. Editorial: Bioactive Natural Products from Microbes: Isolation, Characterization, Biosynthesis and Structure Modification
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Xiachang Wang, Yuanyuan Lu, Khaled A. Shaaban, Guojun Wang, Xuekui Xia, and Youjuan Zhu
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microbes ,natural product ,structure elucidation and modification ,activity evaluation ,biosynthesis ,Chemistry ,QD1-999 - Published
- 2022
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5. Huoshanmycins A‒C, New Polyketide Dimers Produced by Endophytic Streptomyces sp. HS-3-L-1 From Dendrobium huoshanense
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Youjuan Zhu, Yichao Kong, Yu Hong, Ling Zhang, Simin Li, Shurong Hou, Xiabin Chen, Tian Xie, Yang Hu, and Xiachang Wang
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huoshanmycin ,polyketide ,Streptomyces ,Dendrobium huoshanense ,endophyte ,Chemistry ,QD1-999 - Abstract
Three new polyketide dimers named huoshanmycins A‒C (1–3) were isolated from a plant endophytic Streptomyces sp. HS-3-L-1 in the leaf of Dendrobium huoshanense, which was collected from the Cultivation base in Jiuxianzun Huoshanshihu Co., Ltd. The dimeric structures of huoshanmycins were composed of unusual polyketides SEK43, SEK15, or UWM4, with a unique methylene linkage. Their structures were elucidated through comprehensive 1D-/2D-NMR and HRESIMS spectroscopic data analysis. The cytotoxicity against MV4-11 human leukemia cell by the Cell Counting Kit-8 (CCK8) method was evaluated using isolated compounds with triptolide as positive control (IC50: 1.1 ± 0.4 μM). Huoshanmycins A and B (1, 2) displayed moderate cytotoxicity with IC50 values of 32.9 ± 7.2 and 33.2 ± 6.1 μM, respectively.
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- 2022
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6. The Anti-colitis Effect of Schisandra chinensis Polysaccharide Is Associated With the Regulation of the Composition and Metabolism of Gut Microbiota
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Lianlin Su, Chunqin Mao, Xiachang Wang, Lin Li, Huangjin Tong, Jing Mao, De Ji, Tulin Lu, Min Hao, Ziyan Huang, Chenghao Fei, Kewei Zhang, and Guojun Yan
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Schisandra chinensis ,polysaccharide ,ulcerative colitis ,gut microbiota ,short chain fatty acid ,inflammation ,Microbiology ,QR1-502 - Abstract
Background: The pathogenesis of inflammatory bowel disease (IBD) is linked to an intricate association of environmental, microbial, and host-related factors. Polysaccharide affects host immunity by regulating the composition and metabolism of gut microbiota is the common mechanism of disease resistance. However, the efficacy and mechanism of Schisandra chinensis polysaccharide (SCP) in the treatment of inflammatory bowel disease have not been studied.Objective: To explore the effect and mechanism of SCP on dextran sodium sulfate (DSS) - induced ulcerative colitis (UC) in mice.Materials/Methods: In this study, we established a mouse model of UC, and used SCP for treatment intervention. The biochemical indexes related to inflammation were determined by ELISA kit, and the therapeutic effect of SCP on UC was clarified. Then, 16S rDNA sequencing was used to study the effect of SCP on the composition and diversity of gut microbiota. At the same time, GC-MS was used to determine the content of short chain fatty acids in intestinal contents. Finally, the relationship among gut microbiota, short chain fatty acids and inflammatory factors was analyzed, and to comprehensively explain the effect and mechanism of SCP on UC.Results: The results showed that SCP could significantly improve the physiological state of UC mice and regulate the level of inflammatory factors to normal levels. Meanwhile, SCP could significantly regulate the imbalance of gut microbiota and increase the content of SCFAs. In addition, the results of the correlation between gut microbiota and SCFAs showed that butyric acid, isobutyric acid and valeric acid had the highest correlation with gut microbiota.Conclusion: In conclusion, this research showed that SCP can inhibit inflammatory bowel disease by regulating the composition and metabolism of gut microbiota, and indicating that SCP may be used as adjuvant therapy for IBD patients.
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- 2020
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7. Light-promoted photocatalyst-free and redoxneutral hydrosulfonylation of unactivated alkenes using sulfinic acid.
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Yibo Song, Cheng Li, Xueyuan Hu, Hongdie Zhang, Yujian Mao, Xiachang Wang, Chen Wang, Lihong Hu, and Jianming Yan
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SULFINIC acids ,ALKENES ,LIGHT absorption ,NATURAL products ,RADICALS (Chemistry) ,BRONSTED acids - Abstract
A hydrosulfonylation reaction of unactivated alkenes with sulfinic acids was realized under light irradiation. This reaction features photocatalyst- and additive-free conditions. A diverse set of unactivated alkenes can be transformed into alkyl-substituted sulfones with good yields and anti-Markovnikov regioselectivity. The present protocol was amenable to gram-scale synthesis, as well as late-stage modification of drugs and natural products. Preliminary mechanistic studies on UV-visible light absorption suggested the key role of sulfinic acid as a light-absorbing species. DFT calculations also shed light on the mechanism of this reaction, which may involve a radical chain pathway. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Rapid evaluation of Radix Paeoniae Alba and its processed products by near-infrared spectroscopy combined with multivariate algorithms
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Jiuba Zhang, Yu Li, Bin Wang, Jiantao Song, Mingxuan Li, Peng Chen, Zheyuan Shen, Yi Wu, Chunqin Mao, Hui Cao, Xiachang Wang, Wei Zhang, and Tulin Lu
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Biochemistry ,Analytical Chemistry - Published
- 2023
9. Hygromycin A derivatives isolated from Streptomyces sp. PC-22 in the rhizosphere soil of Pulsatilla chinensis
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Xiaoqian, Ding, Tianjie, Yuan, Weiwei, Chen, Xiachang, Wang, Yiwen, Chu, Xiao, Liu, Yang, Hu, and Lihong, Hu
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Pharmacology ,Soil ,Staphylococcus aureus ,Cinnamates ,Rhizosphere ,Drug Discovery ,Microbial Sensitivity Tests ,Hygromycin B ,Pulsatilla ,Soil Microbiology ,Streptomyces ,Anti-Bacterial Agents ,Bacillus subtilis - Abstract
On the basis of the one strain-many compounds (OSMAC) strategy, two new hygromycin A derivatives (3, 4), together with six known compounds were isolated from a medicinal plant inter rhizospheric Streptomyces in Pulsatilla chinensis. The structures of 3 and 4 were elucidated using NMR and HRESIMS analyses. A plausible biosynthetic pathway for these compounds was discussed. All the compounds were evaluated for their antimicrobial and cytotoxic activities. Compound 5 exhibited potent inhibitory activity against S. aureus and B. subtilis with the MICs of 16 and 8 μg ml
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- 2022
10. Sinoflavonoids NJ and NK, anti-inflammatory prenylated flavonoids from the fruits of Podophyllum hexandrum Royle
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Junyang Wang, Han Li, Yanhui Li, Aiping Yang, Sheng Bao, Yuntian Zhang, Qing Du, Zongping Zheng, and Xiachang Wang
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Organic Chemistry ,Plant Science ,Biochemistry ,Analytical Chemistry - Abstract
Two new prenylated flavonoids named sinoflavonoids NJ and NK (1–2), along with ten known compounds were isolated from the fruits of Podophyllum hexandrum Royle. The chemical structures were determined through NMR spectroscopic data and MS analysis. Sinoflavonoid NJ (1) with an unusual 5,11-dioxabenzo[b]fluoren-10-one skeleton was firstly reported from Berberidaceae. The isolated flavonoids were tested with LPS-induced RAW 264.7 mouse macrophages model for their anti-inflammatory activity. Sinoflavonoid NJ (1) showed the most potent inhibition on nitric oxide production with IC50 value as 0.06 μM.
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- 2023
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11. Enzymatic Cβ–H Functionalization of <scp>l</scp>-Arg and <scp>l</scp>-Leu in Nonribosomally Derived Peptidyl Natural Products: A Tale of Two Oxidoreductases
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Christian Rohrbacher, Christian Schütz, Martin Büschleb, Stefan Koppermann, Zheng Cui, Christian Ducho, Han Nguyen, Pierre P.M. Junghanns, Steven G. Van Lanen, Jon S. Thorson, Minakshi Bhardwaj, Xiachang Wang, and Anke Lemke
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chemistry.chemical_classification ,010405 organic chemistry ,Stereochemistry ,Dehydrogenase ,Peptide ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Cyclase ,Catalysis ,0104 chemical sciences ,Amino acid ,Hydroxylation ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Biosynthesis ,chemistry ,Dioxygenase ,Nonribosomal peptide - Abstract
Muraymycins are peptidyl nucleoside antibiotics that contain two Cβ-modified amino acids, (2S,3S)-capreomycidine and (2S,3S)-β-OH-Leu. The former is also a component of chymostatins, which are aldehyde-containing peptidic protease inhibitors that─like muraymycin─are derived from nonribosomal peptide synthetases (NRPSs). Using feeding experiments and in vitro characterization of 12 recombinant proteins, the biosynthetic mechanism for both nonproteinogenic amino acids is now defined. The formation of (2S,3S)-capreomycidine is shown to involve an FAD-dependent dehydrogenase:cyclase that requires an NRPS-bound pathway intermediate as a substrate. This cryptic dehydrogenation strategy is both temporally and mechanistically distinct in comparison to the biosynthesis of other capreomycidine diastereomers, which has previously been shown to proceed by Cβ-hydroxylation of free l-Arg catalyzed by a member of the nonheme Fe2+- and α-ketoglutarate (αKG)-dependent dioxygenase family and (eventually) a dehydration-mediated cyclization process catalyzed by a distinct enzyme(s). Contrary to our initial expectation, the sole nonheme Fe2+- and αKG-dependent dioxygenase candidate Mur15 encoded within the muraymycin gene cluster is instead demonstrated to catalyze specific Cβ hydroxylation of the Leu residue to generate (2S,3S)-β-OH-Leu that is found in most muraymycin congeners. Importantly, and in contrast to known l-Arg-Cβ-hydroxylases, the Mur15-catalyzed reaction occurs after the NRPS-mediated assembly of the peptide scaffold. This late-stage functionalization affords the opportunity to exploit Mur15 as a biocatalyst, proof of concept of which is provided.
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- 2021
12. Cytotoxic Guaianolide Sesquiterpenoids from Ainsliaea fragrans
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Xiachang Wang, Ning Ding, Jian Liu, Junyang Wang, Lihong Hu, Xiabin Chen, Youjuan Zhu, Huimin Zhao, Shurong Hou, and Yisheng Yang
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Pharmacology ,Chemistry ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,Data interpretation ,Ainsliaea fragrans ,Trimer ,Sesquiterpene ,Analytical Chemistry ,chemistry.chemical_compound ,Complementary and alternative medicine ,Drug Discovery ,Michael reaction ,Ic50 values ,Molecular Medicine ,Cytotoxic T cell ,Cytotoxicity - Abstract
Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide (1) is an unusual guaianolide sesquiterpene trimer generated with a novel C-C linkage at C2'-C15″, which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC50 values in the range of 0.4-8.3 μM.
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- 2021
13. Myrrhterpenes A and B, anti-inflammatory cadinane sesquiterpenes from the resin of Commiphora myrrha
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Caihong Li, Sheng Bao, Xiachang Wang, Yuntian Zhang, Yang Hu, Junyang Wang, Ju Luan, Lihong Chen, and Han Li
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Traditional medicine ,biology ,medicine.drug_class ,Plant Science ,biology.organism_classification ,Biochemistry ,Anti-inflammatory ,Nitric oxide ,chemistry.chemical_compound ,chemistry ,Commiphora myrrha ,medicine ,Agronomy and Crop Science ,Biotechnology - Abstract
Two new cadinane sesquiterpenes named myrrhterpenes A and B (1, 2), along with eighteen known analogs were isolated from the resin of Commiphora myrrha. Their structures were determined by various NMR and MS spectrometry analysis, as well as by comparison with related compounds. Anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that two new compounds displayed potent inhibition on nitric oxide production.
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- 2021
14. UPLC fingerprint combined with principal component analysis for quality control of Rheum palmatum
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Shiyang Li, Lu Chen, Yanhui Li, Tao Hu, Xiaoyan Zhang, Lihong Chen, and Xiachang Wang
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Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Analytical Chemistry - Published
- 2021
15. Quantification and Pharmacokinetics Study of Pedunculoside in Rats by Using UPLC-MS/MS
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Huimin Zhao, Xiachang Wang, Caihong Li, Ning Ding, Jiajia Dong, Qichun Zhang, Lihong Hu, Lina Gao, Aiping Yang, Xuyu Zhu, Peng Ren, and Tulin Lu
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Chromatography ,Pharmacokinetics ,Chemistry ,Biophysics ,Pharmaceutical Science ,Molecular Medicine ,Uplc ms ms ,Pedunculoside ,Biochemistry - Abstract
Background: Pedunculoside (PE) is a triterpene saponin from the barks of Ilex rotunda, a Traditional Chinese Medicine called Jiubiying, which is used for the treatment of cold and fever, tonsillitis, sore throat, acute and chronic hepatitis, etc. Previous studies have confirmed that crude extract orally has a significant therapeutic effect on myocardial infarction. Methods: A simple, sensitive, and specific method by using UPLC-MS/MS to study the pharmacokinetics of PE in rats was developed and validated, with ilexsaponin A as an internal standard. Methanol was used as a protein precipitation reagent for blood sample extraction. A Waters Acquity C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation with a gradient elution of CH3CN: 0.1% formic acid (0.3 mL·min-1). Negative ion electrospray ionization was used for detection in multiple reaction monitoring mode. Results: PE was linear within the concentration range of 0.14-1118.00 ng/mL. The LLOQ was 0.14 ng/mL for the plasma samples. The intra-day and inter-day precision were ranged from 1.18% to 10.48%, while the accuracy ranged from -1.32% to 1.68%, indicating satisfactory precision and accuracy of the assay. The extraction recoveries for PE and IS were ranged from 81.40% to 86.65%, with no significant variation among the three concentrations, respectively. PE remained stable at room temperature (25°C) for 3 h, in auto-sampler (4°C) for 24 h, after three freeze-thaw cycles, and in long-term storage at ‒20°C for 30 days. The PK results of PE indicated its poor oral bioavailability (3.37%). Conclusion: Non-compartmental pharmacokinetics parameters indicated that PE was rapidly distributed to the tissues and metabolized. The pharmacokinetic data of this paper highlighted the first-time report of PE oral bioavailability with two different administration manners, which will help to better understand how PE metabolized in rats and exert its pharmacological effect in vivo.
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- 2021
16. Dendrocrepidamine, a novel octahydroindolizine alkaloid from the roots of Dendrobium crepidatum
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Xiaoqian Ding, Yu-Qing Zou, Yang Hu, Xiachang Wang, Chaofeng Zhang, Xiao Liu, and Jian Liu
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Pharmacology ,Ethanol ,Lipopolysaccharide ,biology ,010405 organic chemistry ,Stereochemistry ,Alkaloid ,Organic Chemistry ,Pharmaceutical Science ,General Medicine ,Lung injury ,Dendrobium crepidatum ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Nitric oxide ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Complementary and alternative medicine ,chemistry ,In vivo ,Drug Discovery ,Molecular Medicine ,Bibenzyl - Abstract
A novel octahydroindolizine alkaloid, named dendrocrepidamine (1) with an unusual 18,19,19'-cyclopropanone-dendrocrepine skeleton, was isolated from the ethanol extract of the roots of Dendrobium crepidatum, along with six known compounds (2-7). The structure of 1 was elucidated through HR-ESIMS, NMR spectroscopic data and computational calculations. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells with IC50 values in the range of 3.04-54.89 µM. In vivo, crepidatin (6) (80, 40 and 10 mg/kg) showed a significant protective effect against LPS-induced acute lung injury (ALI) in mice.
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- 2021
17. Tetramycins C-E, three new tetraene macrolides from Streptomyces ahygroscopicus Z117
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Xiaoyu Pan, Yanhui Li, Shijie Yu, Huan Qi, Yu Liu, Xiachang Wang, Jidong Wang, Yongyong Zhang, and Zheng Ma
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Organic Chemistry ,Drug Discovery ,Biochemistry - Published
- 2023
18. The crystal structure of <scp>AbsH3</scp> : A putative flavin adenine dinucleotide‐dependent reductase in the abyssomicin biosynthesis pathway
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Jon S. Thorson, Wenlong Cai, George N. Phillips, Yanyan Zhu, Steven G. Van Lanen, Jonathan A. Clinger, Mitchell D. Miller, Chang-Guo Zhan, and Xiachang Wang
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Flavin adenine dinucleotide ,chemistry.chemical_classification ,0303 health sciences ,Natural product ,biology ,030302 biochemistry & molecular biology ,Flavin group ,Reductase ,biology.organism_classification ,Biochemistry ,Streptomyces ,03 medical and health sciences ,chemistry.chemical_compound ,Biosynthesis ,chemistry ,Structural Biology ,Oxidoreductase ,Gene cluster ,Molecular Biology ,030304 developmental biology - Abstract
Natural products and natural product-derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide-dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC-6-2.
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- 2020
19. Chartspiroton, a Tetracyclic Spiro-naphthoquinone Derivative from a Medicinal Plant Endophytic Streptomyces
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Tian Xie, Xiachang Wang, Sheng Bao, Huimin Zhao, Tianjie Yuan, Yang Hu, Jian Liu, Qichun Zhang, Shurong Hou, Aiping Yang, Xiabin Chen, Peng Ren, and Lihong Hu
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chemistry.chemical_classification ,biology ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,010402 general chemistry ,biology.organism_classification ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,Streptomyces ,Naphthoquinone ,0104 chemical sciences ,chemistry.chemical_compound ,Polyketide ,chemistry ,Moiety ,Physical and Theoretical Chemistry ,Benzofuran ,Derivative (chemistry) ,Lactone - Abstract
A novel 6/6/5/6 tetracyclic polyketide named chartspiroton (1) was isolated from a medicinal plant endophytic Streptomyces in Dendrobium officinale. The complete structure assignment with absolute stereochemistry was elucidated through spectroscopic data, computational calculations, and single-crystal X-ray diffraction. Chartspiroton features an unprecedented naphthoquinone derivative spiro-fused with a benzofuran lactone moiety. A plausible polyketide biosynthetic pathway for 1 suggested intriguing oxidative rearrangement steps to form the five-membered lactone ring.
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- 2020
20. Insecticidal Endostemonines A–J Produced by Endophytic Streptomyces from Stemona sessilifolia
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Chang Wang, Xiachang Wang, Li Shiyang, Lihong Hu, Huimin Zhao, Sheng Bao, Aiping Yang, Yinan Zhang, Nan Zhang, Tianjie Yuan, Ning Ding, and Siwang Zhang
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0106 biological sciences ,Traditional medicine ,business.industry ,010401 analytical chemistry ,Pest control ,Stemona sessilifolia ,General Chemistry ,Biology ,Secondary metabolite ,Pesticide ,biology.organism_classification ,01 natural sciences ,Streptomyces ,Endophyte ,0104 chemical sciences ,Crop protection ,Aphis gossypii ,medicine ,General Agricultural and Biological Sciences ,business ,010606 plant biology & botany ,medicine.drug - Abstract
The discovery of new, safe, and effective pesticides is one of the main means for modern crop protection and parasitic disease control. During the search for new insecticidal secondary metabolites from endophytes in Stemona sessilifolia (a traditional Chinese medicine with a long history as an insecticide), 10 new insecticidal endostemonines A-J (1-10) were identified from an endophytic Streptomyces sp. BS-1. Their structures were determined by comprehensive spectroscopic analysis. Endostemonines A-J represent the first reported naturally occurring pyrrole-2-carboxylic ester derivatives, which consisted of different fatty acid chains at the C-2 of pyrrole ring were produced by traditional Chinese medicine endophytic microbes. All new tested compounds exhibited strong lethal activity against Aphis gossypii (LC50 value range of 3.55-32.00 mg/L after 72 h). This research highlighted the discovery of pesticide natural products from insecticidal medicinal plant endophytes for the first time, paving a new pathway for the development of pest control.
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- 2020
21. Antimicrobial Acetophenone and Phenalenone Derivatives from a Soil-Derived Fungus Penicillium Verrucisporum JX1
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Jiarong Pan, Yongyong Zhang, Huiping Hu, Yuting Tang, Hengyi Lin, Zheng Ma, Penglai Fan, and Xiachang Wang
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Pharmacology ,Organic Chemistry ,Analytical Chemistry - Published
- 2022
22. Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces
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Bruce E. Hatcher, Gregory C. Copley, Jon S. Thorson, Xiachang Wang, James C. Hower, Yang Liu, Madan K. Kharel, Qing-Bai She, Steven G. Van Lanen, Larissa V. Ponomareva, Khaled A. Shaaban, Sherif I. Elshahawi, S. Randal Voss, and Qing Ye
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Antifungal Agents ,Pharmaceutical Science ,Quinolones ,Gram-Positive Bacteria ,01 natural sciences ,Streptomyces ,Article ,Analytical Chemistry ,Cell Line, Tumor ,Drug Discovery ,Humans ,Deoxynyboquinone ,Cytotoxicity ,Pharmacology ,Molecular Structure ,biology ,Strain (chemistry) ,010405 organic chemistry ,Chemistry ,Spectrum Analysis ,Regeneration (biology) ,Organic Chemistry ,Translation (biology) ,biology.organism_classification ,Anti-Bacterial Agents ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Biochemistry ,Cell culture ,Molecular Medicine ,Phosphorylation ,Drug Screening Assays, Antitumor - Abstract
We report the isolation and characterization of three new nybomycins (nybomycins B–D, 1–3) and six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; β-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4β]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the Rock Creek (McCreary County, KY) underground coal mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) bacterial activity, whereas rubromycins 6–8 displayed little to no cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) bacterial and antifungal activity. Assessment of the impact of 3 or 5 cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (5)-mediated downstream inhibition of 4E-BP1p. Evaluation of 1–9 in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical telomerase inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.
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- 2019
23. Enzymatic C
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Zheng, Cui, Han, Nguyen, Minakshi, Bhardwaj, Xiachang, Wang, Martin, Büschleb, Anke, Lemke, Christian, Schütz, Christian, Rohrbacher, Pierre, Junghanns, Stefan, Koppermann, Christian, Ducho, Jon S, Thorson, and Steven G, Van Lanen
- Subjects
Biological Products ,Molecular Structure ,Leucine ,Peptide Synthases ,Arginine ,Peptides ,Article - Abstract
Muraymycins are peptidyl nucleoside antibiotics that contain two C(β)-modified amino acids, (2S,3S)-capreomycidine and (2S,3S)-β-OH-Leu. The former is also a component of chymostatins, which are aldehyde-containing peptidic protease inhibitors that—like muraymycin—are derived from nonribosomal peptide synthetases (NRPSs). Using feeding experiments and in vitro characterization of twelve recombinant proteins, the biosynthetic mechanism for both nonproteinogenic amino acids is now defined. The formation of (2S,3S)-capreomycidine is shown to involve an FAD-dependent dehydrogenase:cyclase that requires an NRPS-bound pathway intermediate as a substrate. This cryptic dehydrogenation strategy is both temporally and mechanistically distinct in comparison to the biosynthesis of other capreomycidine diastereomers, which has previously been shown to proceed by C(β)-hydroxylation of free l-Arg catalyzed by a member of the non-heme Fe(2+)- and α-ketoglutarate (αKG)-dependent dioxygenase family and (eventually) a dehydration-mediated cyclization process catalyzed by a distinct enzyme(s). Contrary to our initial expectation, the sole non-heme Fe(2+)- and αKG-dependent dioxygenase candidate Mur15 encoded within the muraymycin gene cluster is instead demonstrated to catalyze specific C(β) hydroxylation of the Leu residue to generate (2S,3S)-β-OH-Leu that is found in most muraymycin congeners. Importantly, and in contrast to known l-Arg-C(β)-hydroxylases, the Mur15-catalyzed reaction occurs after the NRPS-mediated assembly of the peptide scaffold. This late-stage functionalization affords the opportunity to exploit Mur15 as a biocatalyst, proof of concept of which is provided.
- Published
- 2021
24. Huoshanmycins A‒C, New Polyketide Dimers Produced by Endophytic
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Youjuan, Zhu, Yichao, Kong, Yu, Hong, Ling, Zhang, Simin, Li, Shurong, Hou, Xiabin, Chen, Tian, Xie, Yang, Hu, and Xiachang, Wang
- Abstract
Three new polyketide dimers named huoshanmycins A‒C (
- Published
- 2021
25. Cytotoxic Guaianolide Sesquiterpenoids from
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Ning, Ding, Junyang, Wang, Jian, Liu, Youjuan, Zhu, Shurong, Hou, Huimin, Zhao, Yisheng, Yang, Xiabin, Chen, Lihong, Hu, and Xiachang, Wang
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China ,Sesquiterpenes, Guaiane ,Molecular Structure ,Cell Line, Tumor ,Humans ,Asteraceae ,Antineoplastic Agents, Phytogenic - Abstract
Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of
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- 2021
26. Jatrophacine, a 4,5
- Author
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Yang, Hu, Huimin, Zhao, Aiping, Yang, Qi, Lv, Ning, Ding, Tu-Lin, Lu, Lihong, Hu, and Xiachang, Wang
- Subjects
Mice ,RAW 264.7 Cells ,Molecular Structure ,Phytochemicals ,Anti-Inflammatory Agents ,Animals ,Jatropha ,Diterpenes ,Plant Roots - Abstract
A new diterpenoid named jatrophacine (
- Published
- 2021
27. Metabolite identification of iridin in rats by using UHPLC-MS/MS and pharmacokinetic study of its metabolite irigenin
- Author
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Ning Zhang, Xinyu Ge, Junyang Wang, Xiachang Wang, Tao Hu, Lihong Hu, and Xingxing Diao
- Subjects
Male ,Metabolite ,Clinical Biochemistry ,Glucuronidation ,Urine ,Biochemistry ,Analytical Chemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Feces ,Pharmacokinetics ,In vivo ,Limit of Detection ,Tandem Mass Spectrometry ,Animals ,Iridin ,Chromatography, High Pressure Liquid ,Demethylation ,Flavonoids ,Chromatography ,Reproducibility of Results ,Cell Biology ,General Medicine ,Isoflavones ,Rats ,Metabolic pathway ,chemistry ,Linear Models ,Female - Abstract
Iridin, one of the main bioactive components isolated from Belamcanda chinensis (L.) DC, exerts various pharmacological activities, such as anti-inflammation, antioxidant, and antitumor. However, the metabolism and pharmacokinetics of iridin are still unknown. After 100 mg/kg administration of iridin orally, the plasma, urine, and fecal bio-samples from Sprague–Dawley (SD) rats were collected and detected by ultrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS). The pharmacokinetics of the major metabolite irigenin (aglycon of iridin) and a total of thirteen metabolites of iridin were identified, including five metabolites in plasma, ten metabolites in urine, and six metabolites in feces. The most principal metabolic pathway of iridin was glucuronidation after demethylation and was mediated by UDP-glucuronosyltransferases (UGTs) 1A7, 1A8, 1A9 and 1A10. This study highlights the first-time investigation of the metabolism of iridin in vivo, and the pharmacokinetics of irigenin (the major metabolite of iridin) in rats. These results provide robust evidence for further research and clinical application of iridin.
- Published
- 2021
28. Terragines F-G produced by endophytic
- Author
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Youjuan, Zhu, Shiyang, Li, Yichao, Kong, Huimin, Zhao, Yuanzhuo, Hu, Jingyi, Meng, Xiabin, Chen, Shurong, Hou, and Xiachang, Wang
- Subjects
Fermentation ,Endophytes ,Succinimides ,Bacillus ,Dendrobium - Abstract
Two new terragine analogs (
- Published
- 2021
29. Baraphenazines A–G, Divergent Fused Phenazine-Based Metabolites from a Himalayan Streptomyces
- Author
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Sherif I. Elshahawi, Khaled A. Shaaban, Larissa V. Ponomareva, Jon S. Thorson, Xiachang Wang, Steven G. Van Lanen, Muhammad Abbas, S. Randal Voss, Imran Sajid, Yinan Zhang, and Zheng Cui
- Subjects
Stereochemistry ,Metabolite ,Phenazine ,Pharmaceutical Science ,01 natural sciences ,Streptomyces ,Article ,Analytical Chemistry ,chemistry.chemical_compound ,Quinoxalines ,Drug Discovery ,Pharmacology ,chemistry.chemical_classification ,Molecular Structure ,biology ,010405 organic chemistry ,Extramural ,Organic Chemistry ,biology.organism_classification ,Bacterial strain ,Anti-Bacterial Agents ,0104 chemical sciences ,Amino acid ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Phenazines ,Molecular Medicine - Abstract
The structures and bioactivities of three unprecedented fused 5-hydroxyquinoxaline/alpha-keto acid amino acid metabolites (baraphenazines A–C, 1–3), two unique diastaphenazine-type metabolites (baraphenazines D and E, 4 and 5) and two new phenazinolin-type (baraphenazines F and G, 6 and 7) metabolites from the Himalayan isolate Streptomyces sp. PU-10A are reported. This study highlights the first reported bacterial strain capable of producing diastaphenazine-type, phenazinolin-type, and izumiphenazine A-type metabolites and presents a unique opportunity for the future biosynthetic interrogation of late-stage phenazine-based metabolite maturation.
- Published
- 2019
30. Ruthenium(<scp>ii</scp>)-catalyzed C–O/C–S cyclization for the synthesis of 5-membered O-containing and S-containing heterocycles
- Author
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Yu Wen, Yinan Zhang, Lihong Hu, Junwei Wang, Jian Liu, Xiachang Wang, Fengjun He, Lina Gao, and Liang Gao
- Subjects
010405 organic chemistry ,Chemistry ,Organic Chemistry ,chemistry.chemical_element ,Substrate (chemistry) ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Catalysis ,Ruthenium ,chemistry.chemical_compound ,Furan ,Functional group ,Organic synthesis ,Thiazole ,Oxazole - Abstract
An efficient and convenient method for the synthesis of oxazole derivatives from enamides has been established via a ruthenium-catalyzed C–O cyclization. This protocol allows for a wide functional group compatibility, broad substrate scope and ease of operation. This catalytic method is also applicable to other 5-membered O-containing and S-containing heterocyclic systems involving thiazole and furan scaffolds, thus this strategy can be broadly applied to organic synthesis and medicinal chemistry.
- Published
- 2019
31. Terragines F–G produced by endophytic Bacillus sp. SH-1.2-ROOT-18 from Dendrobium officinale
- Author
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Xiachang Wang, Jingyi Meng, Huimin Zhao, Li Shiyang, Yichao Kong, Xiabin Chen, Youjuan Zhu, Yuanzhuo Hu, and Shurong Hou
- Subjects
Natural product ,biology ,010405 organic chemistry ,Stereochemistry ,Metabolite ,Organic Chemistry ,Plant Science ,Bacillus sp ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Endophyte ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Dendrobium officinale ,chemistry ,Succinimide ,Base (exponentiation) ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Two new terragine analogs (1‒2) with special succinimide and aminopentane moieties were isolated from the fermentation broth of Bacillus sp. SH-1.2-ROOT-18, an endophyte previously discovered from the root of Dendrobium officinale. The structures were elucidated base on comprehensive 1 D/2D NMR and MS data analysis. Complete NMR assignments for the first reported naturally occurring metabolite 3 was also provided.
- Published
- 2021
- Full Text
- View/download PDF
32. The triterpenoid sapogenin (2α-OH-Protopanoxadiol) ameliorates metabolic syndrome via the intestinal FXR/GLP-1 axis through gut microbiota remodelling
- Author
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Sheng Bao, Xinwen Zhang, Xiachang Wang, Chen-dong Zhou, Wei Liu, Shui-mei Sun, Jing-Ya Li, Jia Li, Haowen Jiang, Lihong Hu, Jia Liu, Yinan Zhang, Dakai Chen, and Zhifu Xie
- Subjects
Male ,Taurocholic Acid ,Cancer Research ,Metabolite ,Immunology ,Drug development ,Pharmacology ,Gut flora ,Diet, High-Fat ,Article ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Glucagon-Like Peptide 1 ,RNA, Ribosomal, 16S ,medicine ,Animals ,Secretion ,lcsh:QH573-671 ,Metabolic Syndrome ,chemistry.chemical_classification ,Mice, Inbred ICR ,biology ,lcsh:Cytology ,Plant Extracts ,Diabetes ,RNA-Binding Proteins ,Cell Biology ,Glucagon ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,Gynostemma ,Intestines ,Mice, Inbred C57BL ,Transplantation ,Enzyme ,chemistry ,Nuclear receptor ,Drug Design ,Farnesoid X receptor ,Metabolic syndrome - Abstract
Gypenosides, extracts of Gynostemma yixingense, have been traditionally prescribed to improve metabolic syndrome in Asian folk and local traditional medicine hospitals. However, the mechanism of its action remains unclarified. In this work, our results indicated that chronic administration of 2α-OH-protopanoxadiol (GP2), a metabolite of gypenosides in vivo, protected mice from high-fat diet-induced obesity and improved glucose tolerance by improving intestinal L-cell function. Mechanistically, GP2 treatment inhibited the enzymatic activity of bile salt hydrolase and modulated the proportions of the gut microbiota, which led to an increase in the accumulation of tauro-β-muricholic acid (TβMCA) in the intestine. TβMCA induced GLP-1 production and secretion by reducing the transcriptional activity of nuclear receptor farnesoid X receptor (FXR). Transplantation of GP2-remodelled fecal microbiota into antibiotic-treated mice also increased the intestinal TβMCA content and improved intestinal L-cell function. These findings demonstrate that GP2 ameliorates metabolic syndrome at least partly through the intestinal FXR/GLP-1 axis via gut microbiota remodelling and also suggest that GP2 may serve as a promising oral therapeutic agent for metabolic syndrome.
- Published
- 2020
33. The Crystal Structure of AbsH3: a Putative FAD-dependent Reductase in the Abyssomicin Biosynthesis Pathway
- Author
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George N. Phillips, Wenlong Cai, Chang-Guo Zhan, Xiachang Wang, Yanyan Zhu, Jonathan A. Clinger, Mitchell D. Miller, Jon S. Thorson, and Steven G. Van Lanen
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Biological Products ,Natural product ,biology ,Stereochemistry ,Crystal structure ,Reductase ,biology.organism_classification ,Streptomyces ,Cycloaddition ,Article ,Biosynthetic Pathways ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,Gene cluster ,Flavin-Adenine Dinucleotide ,Oxidoreductases - Abstract
Natural products and natural product-derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide-dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC-6-2.
- Published
- 2020
34. Author response for 'The Crystal Structure of <scp>AbsH3</scp> : a Putative <scp>FAD</scp> ‐dependent Reductase in the Abyssomicin Biosynthesis Pathway'
- Author
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Xiachang Wang, Steven G. Van Lanen, Chang-Guo Zhan, Wenlong Cai, Yanyan Zhu, Mitchell D. Miller, Jonathan A. Clinger, Jon S. Thorson, and George N. Phillips
- Subjects
chemistry.chemical_compound ,Biochemistry ,Biosynthesis ,Chemistry ,Crystal structure ,Reductase - Published
- 2020
35. New peptidendrocins and anticancer chartreusin from an endophytic bacterium of
- Author
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Huimin, Zhao, Xiabin, Chen, Xiaoling, Chen, Youjuan, Zhu, Yichao, Kong, Sifang, Zhang, Xingyu, Deng, Pengfei, Ouyang, Wei, Zhang, Shurong, Hou, Xiachang, Wang, and Tian, Xie
- Subjects
Original Article - Abstract
BACKGROUND: Endophyte has now become a potential source for the discovery of novel natural products, as they participate in biochemical pathways of their hosts and produce analogous or novel bioactive compounds. As an epiphytic plant, Dendrobium officinale is one of precious Chinese medicines with various activities. It is well known for containing diverse endophytes, but so far not much is known about their secondary metabolites. METHODS: the plant tissues were cut and cultured on agar plates to isolate and purify the endophytic bacteria from Dendrobium officinale. Taxonomical identification of strains was performed by 16s rRNA. At the same time, the crude extracts of the strains were tested for antibacterial and cytotoxic activities to screen out one endophyte, Streptomyces sp. SH-1.2-R-15 for further study. After scale-up fermentation, isolation, purification and structure elucidation by using MS, 1D/2D-NMR spectroscopic method, secondary metabolites were identified and submitted for biological activity test. RESULTS: Fifty-eight endophytic strains representing 9 genera were obtained, with 50% of strains were Streptomyces. One of the most active strain, Streptomyces sp. 1.2-R-15, was selected for bioassay-guided isolation, which led to the discovery of two new peptide-type compounds 1 and 2, as well as a bioactive chartreusin, and four other known natural products. Their structures were determined by comprehensive spectroscopic techniques. Chartreusin showed potent cytotoxicity against Hep3B2.1-7 (IC(50) =18.19 µM) and H1299 (IC(50) =19.74 µM) cancer cell lines, and antibacterial activity against S. aureus (IC(50) =23.25 µM). CONCLUSIONS: This study highlights the endophytic bacteria from medical plant D. officinale have potential bioactivity and natural product diversity, thus implicates them as a valuable source for new anticancer and antibiotics agents.
- Published
- 2020
36. Chartspiroton, a Tetracyclic Spiro-naphthoquinone Derivative from a Medicinal Plant Endophytic
- Author
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Huimin, Zhao, Aiping, Yang, Jian, Liu, Sheng, Bao, Ren, Peng, Yang, Hu, Tianjie, Yuan, Shurong, Hou, Tian, Xie, Qichun, Zhang, Xiabin, Chen, Xiachang, Wang, and Lihong, Hu
- Subjects
Lactones ,Plants, Medicinal ,Molecular Structure ,Polyketides ,Spectrum Analysis ,Crystallography, X-Ray ,Streptomyces ,Biosynthetic Pathways ,Naphthoquinones - Abstract
A novel 6/6/5/6 tetracyclic polyketide named chartspiroton (
- Published
- 2020
37. Insecticidal Endostemonines A-J Produced by Endophytic
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Huimin, Zhao, Aiping, Yang, Nan, Zhang, Shiyang, Li, Tianjie, Yuan, Ning, Ding, Siwang, Zhang, Sheng, Bao, Chang, Wang, Yinan, Zhang, Xiachang, Wang, and Lihong, Hu
- Subjects
Insecticides ,Aphids ,Endophytes ,Stemonaceae ,Animals ,Secondary Metabolism ,Heterocyclic Compounds, 3-Ring ,Streptomyces - Abstract
The discovery of new, safe, and effective pesticides is one of the main means for modern crop protection and parasitic disease control. During the search for new insecticidal secondary metabolites from endophytes in
- Published
- 2020
38. Pyridoxal-5'-phosphate-dependent alkyl transfer in nucleoside antibiotic biosynthesis
- Author
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Xiachang Wang, Jon S. Thorson, Minakshi Bhardwaj, Zheng Cui, Xiaodong Liu, Daniel Wiegmann, Giuliana Niro, Christian Ducho, Anke Lemke, Yinan Zhang, Jonathan Overbay, and Steven G. Van Lanen
- Subjects
S-Adenosylmethionine ,Alkylation ,Stereochemistry ,Biochemical Phenomena ,Disaccharide ,nucleoside ,Biosynthesis ,Article ,Phosphates ,S-adenosyl-l-methionine ,03 medical and health sciences ,chemistry.chemical_compound ,Methionine ,antibiotic ,γ-replacement ,Phosphorylation ,Molecular Biology ,Alkyl ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,030302 biochemistry & molecular biology ,Glycosidic bond ,Nucleosides ,Cell Biology ,pyridoxal-5′-phosphate ,Recombinant Proteins ,Anti-Bacterial Agents ,chemistry ,aza-addition ,Pyridoxal Phosphate ,Linker ,Nucleoside ,Alkyltransferase - Abstract
Several nucleoside antibiotics are structurally characterized by a 5″-amino-5″-deoxyribose (ADR) appended via a glycosidic bond to a high-carbon sugar nucleoside (5′S,6′S)-5′-C-glycyluridine (GlyU). GlyU is further modified with an N-alkylamine linker, the biosynthetic origin of which has yet to be established. By using a combination of feeding experiments with isotopically labeled precursors and characterization of recombinant proteins from multiple pathways, the biosynthetic mechanism for N-alkylamine installation for ADR–GlyU-containing nucleoside antibiotics has been uncovered. The data reveal S-adenosyl-l-methionine (AdoMet) as the direct precursor of the N-alkylamine, but, unlike conventional AdoMet- or decarboxylated AdoMet-dependent alkyltransferases, the reaction is catalyzed by a pyridoxal-5′-phosphate-dependent aminobutyryltransferase (ABTase) using a stepwise γ-replacement mechanism that couples γ-elimination of AdoMet with aza-γ-addition onto the disaccharide alkyl acceptor. In addition to using a conceptually different strategy for AdoMet-dependent alkylation, the newly discovered ABTases require a phosphorylated disaccharide alkyl acceptor, revealing a cryptic intermediate in the biosynthetic pathway. Rather than a typical S-adenosylmethionine-dependent alkyltransferase, the installation of the N-alkylamine linker in several nucleoside antibiotics is catalyzed via γ-replacement by a pyridoxal-5′-phosphate-dependent aminobutyryltransferase.
- Published
- 2019
39. Enzymatic Synthesis of the Ribosylated Glycyl-Uridine Disaccharide Core of Peptidyl Nucleoside Antibiotics
- Author
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Jonathan Overbay, Xiaodong Liu, Steven G. Van Lanen, Xiachang Wang, Zheng Cui, Jon S. Thorson, Daniel Wiegmann, Anke Lemke, Wenlong Cai, Christian Ducho, and Giuliana Niro
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Ribose ,Organic Chemistry ,Pyrimidine Phosphorylases ,Glycine ,Glycosidic bond ,010402 general chemistry ,01 natural sciences ,Article ,Uridine ,Anti-Bacterial Agents ,Substrate Specificity ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,Biochemistry ,Uridine monophosphate ,Transferase ,Peptides ,Nucleoside ,Transaldolase - Abstract
Muraymycins belong to a family of nucleoside antibiotics that have a distinctive disaccharide core consisting of 5-amino-5-deoxyribofuranose (ADR) attached to 6'- N-alkyl-5'- C-glycyluridine (GlyU). Here, we functionally assign and characterize six enzymes from the muraymycin biosynthetic pathway involved in the core assembly that starts from uridine monophosphate (UMP). The biosynthesis is initiated by Mur16, a nonheme Fe(II)- and α-ketoglutarate-dependent dioxygenase, followed by four transferase enzymes: Mur17, a pyridoxal-5'-phosphate (PLP)-dependent transaldolase; Mur20, an aminotransferase; Mur26, a pyrimidine phosphorylase; and Mur18, a nucleotidylyltransferase. The pathway culminates in glycosidic bond formation in a reaction catalyzed by an additional transferase enzyme, Mur19, a ribosyltransferase. Analysis of the biochemical properties revealed several noteworthy discoveries including that (i) Mur16 and downstream enzymes can also process 2'-deoxy-UMP to generate a 2-deoxy-ADR, which is consistent with the structure of some muraymycin congeners; (ii) Mur20 prefers l-Tyr as the amino donor source; (iii) Mur18 activity absolutely depends on the amine functionality of the ADR precursor consistent with the nucleotidyltransfer reaction occurring after the Mur20-catalyzed aminotransfer reaction; and (iv) the bona fide sugar acceptor for Mur19 is (5' S,6' S)-GlyU, suggesting that ribosyltransfer occurs prior to N-alkylation of GlyU. Finally, a one-pot, six-enzyme reaction was utilized to generate the ADR-GlyU disaccharide core starting from UMP.
- Published
- 2018
40. Discovery and structure-activity relationships study of thieno[2,3-b]pyridine analogues as hepatic gluconeogenesis inhibitors
- Author
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Fei Ma, Yinan Zhang, Min Lei, Jian Liu, Lihong Hu, Xu Shen, Tingting Zhou, Xiachang Wang, and Jing Chen
- Subjects
0301 basic medicine ,Thienopyridine ,Pyridines ,Cell ,Mice, Obese ,Pharmacology ,01 natural sciences ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Diabetes mellitus ,Drug Discovery ,medicine ,Animals ,Hypoglycemic Agents ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Drug discovery ,Chemistry ,Organic Chemistry ,Gluconeogenesis ,General Medicine ,Gluconeogenesis Inhibition ,Glucose Tolerance Test ,medicine.disease ,Small molecule ,0104 chemical sciences ,Glucose ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Phosphoenolpyruvate carboxykinase - Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC50 = 33.8 μM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC50 = 16.8 μM) and 9d (IC50 = 12.3 μM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents.
- Published
- 2018
41. Antibacterial Muraymycins from Mutant Strains of Streptomyces sp. NRRL 30471
- Author
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Xiachang Wang, Stefan Koppermann, Steven G. Van Lanen, Christian Ducho, Zheng Cui, and Jon S. Thorson
- Subjects
Staphylococcus aureus ,Stereochemistry ,Mutant ,Pharmaceutical Science ,Mutagenesis (molecular biology technique) ,Microbial Sensitivity Tests ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Streptomyces ,Article ,Analytical Chemistry ,Drug Discovery ,Escherichia coli ,medicine ,Pharmacology ,chemistry.chemical_classification ,Aquifex aeolicus ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Fatty acid ,Nucleosides ,biology.organism_classification ,Anti-Bacterial Agents ,0104 chemical sciences ,Complementary and alternative medicine ,Molecular Medicine ,Antibacterial activity - Abstract
Muraymycins are nucleoside antibiotics isolated from Streptomyces sp. NRRL 30471 and several mutant strains thereof that were generated by random, chemical mutagenesis. Reinvestigation of two mutant strains using new media conditions led to the isolation of three new muraymycin congeners, named B8, B9, and C6 (1-3), as well as a known muraymycin, C1. Structures of the compounds were elucidated by HRMS and 1D and 2D NMR spectroscopic analyses. Complete 2D NMR assignments for the known muraymycin C1 are also provided for the first time. Compounds 1 and 2, which differ from other muraymycins by having an elongated, terminally branched fatty acid side chain, had picomolar IC50 values against Staphylococcus aureus and Aquifex aeolicus MraY and showed good antibacterial activity against S. aureus (MIC = 2 and 6 μg/mL, respectively) and Escherichia coli Δ tolC (MIC = 4 and 2 μg/mL, respectively). Compound 3, which is characterized by an N-acetyl modification of the primary amine of the dissacharide core that is shared among nearly all of the reported muraymycin congeners, greatly reduced its inhibitory and antibacterial activity compared to nonacylated muraymycin C1, which possibly indicates this modification is used for self-resistance.
- Published
- 2018
42. Chemical Constituents of Stachyurus chinensis
- Author
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Zheng Ma, Xiachang Wang, Chouqiang Li, Junwei Sun, and Yongyong Zhang
- Subjects
Stachyurus chinensis ,Chemistry ,Chemical constituents ,Environmental chemistry ,Plant Science ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Published
- 2021
43. Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe
- Author
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Xiachang Wang, Chang-Guo Zhan, Sherif I. Elshahawi, James C. Hower, Ziyuan Zhou, Jon S. Thorson, Yinan Zhang, Sean Parkin, Bruce E. Hatcher, M. Ryan Woodcock, Larissa V. Ponomareva, Madan K. Kharel, S. Randal Voss, Qingchao Qiu, Khaled A. Shaaban, and Xiabin Chen
- Subjects
Cyclopentenone ,Stereochemistry ,Cell Survival ,Lactams, Macrocyclic ,Molecular Conformation ,Kentucky ,Cyclopentanes ,010402 general chemistry ,Streptomyces ,01 natural sciences ,Catalysis ,Article ,Benzilic acid rearrangement ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,HSP90 Heat-Shock Proteins ,Cytotoxicity ,biology ,010405 organic chemistry ,Ansamycin ,Stereoisomerism ,General Chemistry ,General Medicine ,Geldanamycin ,biology.organism_classification ,Mycothiol ,0104 chemical sciences ,Coal ,chemistry ,Chemical engineering ,Biocatalysis - Abstract
Four cyclopentenone-containing ansamycin polyketides (mccrearamycins A-D), and six new geldanamycins (Gdms B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.
- Published
- 2017
44. Enzymatic Cβ–H Functionalization of l-Arg and l-Leu in Nonribosomally Derived Peptidyl Natural Products: A Tale of Two Oxidoreductases.
- Author
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Zheng Cui, Han Nguyen, Bhardwaj, Minakshi, Xiachang Wang, Büschleb, Martin, Lemke, Anke, Schütz, Christian, Rohrbacher, Christian, Junghanns, Pierre, Koppermann, Stefan, Ducho, Christian, Thorson, Jon S., and Van Lanen, Steven G.
- Published
- 2021
- Full Text
- View/download PDF
45. Spoxazomicin D and Oxachelin C, Potent Neuroprotective Carboxamides from the Appalachian Coal Fire-Associated Isolate Streptomyces sp. RM-14-6
- Author
-
Xiachang Wang, James C. Hower, Manjula Sunkara, Mark A. Prendergast, Larissa V. Ponomareva, Matthew S. Tremblay, Gregory C. Copley, Yinan Zhang, Jianjun Zhang, Madan K. Kharel, Sherif I. Elshahawi, Meredith A. Saunders, Tuan Tran, Khaled A. Shaaban, Andrew J. Morris, and Jon S. Thorson
- Subjects
Antifungal Agents ,Stereochemistry ,Pharmaceutical Science ,Coal fire ,010402 general chemistry ,01 natural sciences ,Streptomyces ,Neuroprotection ,Article ,Spoxazomicin D ,Analytical Chemistry ,Phenols ,Drug Discovery ,Humans ,Cytotoxicity ,Nuclear Magnetic Resonance, Biomolecular ,Oxazoles ,Pharmacology ,Appalachian Region ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,biology.organism_classification ,Anti-Bacterial Agents ,0104 chemical sciences ,Sodium salt ,Coal ,Neuroprotective Agents ,Complementary and alternative medicine ,Biochemistry ,Unfolded protein response ,Molecular Medicine ,Peptides ,Oligopeptides ,Two-dimensional nuclear magnetic resonance spectroscopy ,Ethers - Abstract
The isolation and structure elucidation of six new bacterial metabolites [spoxazomicin D (2), oxachelins B and C (4, 5), and carboxamides 6–8] and 11 previously reported bacterial metabolites (1, 3, 9–12a, and 14–18) from Streptomyces sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for 2, 11, and 12a,b. Complete 2D NMR assignments for the known metabolites lenoremycin (9) and lenoremycin sodium salt (10) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds [exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035] as phenol-dihydrooxazoles. Bioactivity analysis [including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection] revealed 2 and 5 as potent neuroprotectives and lenoremycin (9) and its sodium salt (10) as potent UPR modulators, highlighting new functions for phenol-oxazolines/salicylates and polyether pharmacophores.
- Published
- 2016
46. Jatrophacine, a 4,5-seco-rhamnofolane diterpenoid with potent anti-inflammatory activity from Jatropha curcas
- Author
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Lihong Hu, Yang Hu, Tu-Lin Lu, Qi Lv, Xiachang Wang, Huimin Zhao, Ning Ding, and Aiping Yang
- Subjects
biology ,Traditional medicine ,010405 organic chemistry ,Chemistry ,medicine.drug_class ,Organic Chemistry ,Euphorbiaceae ,Plant Science ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Terpenoid ,Anti-inflammatory ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,medicine ,Jatropha curcas - Abstract
A new diterpenoid named jatrophacine (1), with an unusual 4,5-seco- rhamnofolane skeleton, was isolated from the roots of Jatropha curcas, together with eleven known diterpenoids. The structure of the new compound was elucidated through a detailed analysis of its 1 D- and 2 D-NMR spectra. The X-ray structure of jatrophol (2) is also presented. Anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that compound 1 strongly inhibited the production of nitric oxide (IC50 = 0.53 μM).
- Published
- 2019
- Full Text
- View/download PDF
47. Puromycins B-E, Naturally Occurring Amino-Nucleosides Produced by the Himalayan Isolate Streptomyces sp. PU-14G
- Author
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Muhammad Abbas, Larissa V. Ponomareva, Imran Sajid, Xiachang Wang, Sherif I. Elshahawi, Jon S. Thorson, and Khaled A. Shaaban
- Subjects
0301 basic medicine ,Stereochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,01 natural sciences ,Streptomyces ,Article ,Analytical Chemistry ,Mycobacterium ,03 medical and health sciences ,Drug Discovery ,Pakistan ,Pharmacology ,biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Nucleosides ,Isolation (microbiology) ,biology.organism_classification ,0104 chemical sciences ,030104 developmental biology ,Complementary and alternative medicine ,Molecular Medicine ,Puromycin - Abstract
The isolation and structure elucidation of four new naturally occurring amino-nucleoside [puromycins B-E (1-4)] metabolites from a Himalayan isolate ( Streptomyces sp. PU-14-G, isolated from the Bara Gali region of northern Pakistan) is reported. Consistent with prior reports, comparative antimicrobial assays revealed the need for the free 2″-amine for anti-Gram-positive bacteria and antimycobacterial activity. Similarly, comparative cancer cell line cytotoxicity assays highlighted the importance of the puromycin-free 2″-amine and the impact of 3'-nucleoside substitution. These studies extend the repertoire of known naturally occurring puromycins and their corresponding SAR. Notably, 1 represents the first reported naturally occurring bacterial puromycin-related metabolite with a 3'- N-amino acid substitution that differs from the 3'- N-tyrosinyl of classical puromycin-type natural products. This discovery suggests the biosynthesis of 1 in Streptomyces sp. PU-14G may invoke a uniquely permissive amino-nucleoside synthetase and/or multiple synthetases and sets the stage for further studies to elucidate, and potentially exploit, new biocatalysts for puromycin chemoenzymatic diversification.
- Published
- 2018
48. Anti-inflammatory octahydroindolizine alkaloid enantiomers from Dendrobium crepidatum
- Author
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Xiachang Wang, Yang Hu, Xiaoqian Ding, Hua Yang, Lihong Hu, Minyan Liu, Jian Liu, and Chaofeng Zhang
- Subjects
Models, Molecular ,Circular dichroism ,Lipopolysaccharide ,Stereochemistry ,medicine.drug_class ,Anti-Inflammatory Agents ,Lung injury ,Nitric Oxide ,01 natural sciences ,Biochemistry ,Anti-inflammatory ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Alkaloids ,In vivo ,Drug Discovery ,medicine ,Animals ,Molecular Biology ,010405 organic chemistry ,Chemistry ,Alkaloid ,Organic Chemistry ,Indolizines ,Stereoisomerism ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,RAW 264.7 Cells ,Enantiomer ,Dendrobium - Abstract
Six pairs of octahydroindolizine-type alkaloid enantiomers (1–6) including three new compounds [(−)-1/(+)-1, 2] were isolated from the stems of Dendrobium crepidatum. Their structures including the absolute configurations were elucidated by extensive spectroscopic analyses and comparison between the experimental and calculated electronic circular dichroism (ECD). All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells. It was found that compounds (+)-1, 2 and (+)-6 exhibited pronounced inhibition on NO production with IC50 values in the range of 3.62–16.11 µM, being more active than the positive control, dexamethasone (IC50 = 47.04 µM). In vivo, compound 6 (100, 50 and 10 mg/kg) showed protective effects against LPS-induced acute lung injury (ALI) in mice.
- Published
- 2020
49. Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects
- Author
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Yubin Guo, Larissa V. Ponomareva, Jing Chen, Luksana Chaiswing, Khaled A. Shaaban, Bradley D. Anderson, Jon S. Thorson, Markos Leggas, Xiachang Wang, Haining Zhu, Qiou Wei, Yanan Cao, Yinan Zhang, Qing Ye, Qing-Bai She, Jamie Horn, and Daret K. St. Clair
- Subjects
Male ,Cell Survival ,Clinical Biochemistry ,Transplantation, Heterologous ,Mice, Nude ,Antineoplastic Agents ,Cell Cycle Proteins ,mTORC1 ,Biology ,Peroxiredoxin 1 ,Mechanistic Target of Rapamycin Complex 1 ,01 natural sciences ,Biochemistry ,Article ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Phosphorylation ,RNA, Small Interfering ,Molecular Biology ,Protein kinase B ,Glutaredoxins ,Adaptor Proteins, Signal Transducing ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,010405 organic chemistry ,Glutathione ,Peroxiredoxins ,0104 chemical sciences ,Cell biology ,chemistry ,Tumor progression ,Cancer cell ,Molecular Medicine ,RNA Interference ,Reactive Oxygen Species ,Naphthoquinones ,Signal Transduction - Abstract
Summary Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.
- Published
- 2018
50. Self-Resistance during Muraymycin Biosynthesis: a Complementary Nucleotidyltransferase and Phosphotransferase with Identical Modification Sites and Distinct Temporal Order
- Author
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Anke Lemke, Xiaodong Liu, Jon S. Thorson, Stefan Koppermann, Christian Ducho, Steven G. Van Lanen, Xiachang Wang, Jürgen Rohr, and Zheng Cui
- Subjects
0301 basic medicine ,Disaccharide ,Transferases (Other Substituted Phosphate Groups) ,Phosphotransferase ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,Biosynthesis ,Transferases ,Mechanisms of Resistance ,Gene cluster ,Translocase ,Pharmacology (medical) ,Nucleotide ,Phosphorylation ,Adenylylation ,Pharmacology ,chemistry.chemical_classification ,biology ,Nucleotides ,Phosphotransferases ,Nucleosides ,Nucleotidyltransferase ,Nucleotidyltransferases ,Streptomyces ,Anti-Bacterial Agents ,030104 developmental biology ,Infectious Diseases ,Biochemistry ,chemistry ,biology.protein ,Peptides - Abstract
Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5′- C -glycyluridine (GlyU) appended to a 5″-amino-5″-deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins, the GlyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures, annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a Mg·ATP-dependent nucleotidyltransferase and a Mg·ATP-dependent phosphotransferase, respectively, both modifying the 3″-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as cosubstrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analyses revealed that Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetical biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced (170-fold and 51-fold, respectively) MraY inhibitory activities and reduced antibacterial activities, compared with the respective unmodified muraymycins. The results are consistent with Mur29-catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms, with a distinct temporal order during muraymycin biosynthesis.
- Published
- 2018
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