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Carbonic anhydrase-like enzymes in the formation of Lycopodium alkaloid

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Chinese Journal of Natural Medicines 2024年第3期22卷 193-194页

作者： DONG Huiwen GE Huiming state key laboratory of pharmaceutical biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210023China

Plant alkaloids,renowned for their structural diversity and bioactivity,are prominent in both modern and traditional medicine[1].Unraveling the intricacies of plant alkaloid biosynthesis could pave the way for the discovery of new natural products and *** may also shed light on the roles of existing pathways in host biology and provide valuable tools for metabolic engineering in plants and microbes[2].Unlike other major classes of plant natural products,such as terpenoids and polyketides,the formation of alkaloid scaffolds does not conform to a uniform chemical theme or depend on a singular enzyme class[3].A case in point is the Lycopodium alkaloids in the Lycopodiaceae family,where the enzymes responsible for their core scaffold construction remain unidentified[4].

关键词： Lycopodium alkaloid Carbonic anhydrase-like enzymes Biosynthesis

Sinensetin protects against periodontitis through binding to Bach1 enhancing its ubiquitination degradation and improving oxidative stress

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International Journal of Oral Science 2024年第3期16卷 553-562页

作者： Zhiyao Yuan Junjie Li Fuyu Xiao Yu Wu Zhiting Zhang Jiahong Shi Jun Qian Xudong Wu Fuhua Yan Department of Periodontology Nanjing Stomatological HospitalAffiliated Hospital of Medical SchoolInstitute of StomatologyState Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingChina

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival *** therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative ***(Sin)is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant *** study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular *** found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells(PDLCs)under inflammatory *** Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in *** molecular docking,we identified Bach1 as a strong binding target of Sin,and this binding was further verified by cellular thermal displacement assay and immunofluorescence *** immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter,subsequently upregulating the expression of the key antioxidant factor *** functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant ***,we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1,thereby inducing HO-1 expression and inhibiting oxidative ***,Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

关键词： Bach1 period prompt

Comprehensive integration of single-cell transcriptomic data illuminates the regulatory network architecture of plant cell fate specification

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Plant Diversity 2024年第3期46卷 372-385页

作者： Shanni Cao Xue Zhao Zhuojin Li Ranran Yu Yuqi Li Xinkai Zhou Wenhao Yan Dijun Chen Chao He state key laboratory of pharmaceutical biotechnology School of Life SciencesNanjing UniversityNanjing 210023China National key laboratory of Crop Genetic Improvement Hubei Hongshan LaboratoryHuazhong Agricultural UniversityWuhan 430070China

Plant morphogenesis relies on precise gene expression programs at the proper time and position which is orchestrated by transcription factors(TFs)in intricate regulatory networks in a cell-type specific *** we introduced a comprehensive single-cell transcriptomic atlas of Arabidopsis *** atlas is the result of meticulous integration of 63 previously published scRNA-seq datasets,addressing batch effects and conserving biological *** integration spans a broad spectrum of tissues,including both below-and above-ground *** a rigorous approach for cell type annotation,we identified 47 distinct cell types or states,largely expanding our current view of plant cell *** systematically constructed cell-type specific gene regulatory networks and uncovered key regulators that act in a coordinated manner to control cell-type specific gene *** together,our study not only offers extensive plant cell atlas exploration that serves as a valuable resource,but also provides molecular insights into gene-regulatory programs that varies from different cell types.

关键词： Arabidopsis Single cell transcriptome Gene regulatory network Data integration Plant cell atlas

Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

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Acta Pharmaceutica Sinica B 2024年第2期14卷 881-892页

作者： Zhiwu Tong Xiahong Xie Huiming Ge Ruihua Jiao Tingting Wang Xincun Wang Wenying Zhuang Gang Hu Renxiang Tan state key laboratory of pharmaceutical biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210023China state key laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese MedicineNanjing 210023China Institute of Microbiology Chinese Academy of SciencesBeijing 100101China

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical ***,the success rate is decreasing,presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely‘overlooked’during the characterization ***,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug *** is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor *** a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation *** together,the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson’s disease that is globally prevailing in an alarming manner.

关键词： Fungal RiPPs Biosynthesis Macrocyclic peptide Acalitide Antiparkinsonian

Lime pretreatment of maize stover and solubilization of pretreated solids by enzymatic hydrolysis and Clostridium thermocellum fermentation

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International Journal of Agricultural and Biological Engineering 2024年第4期17卷 288-296页

作者： Guanying Wang Gang Zhang Xiongjun Shao state key laboratory of Biocatalysis and Enzyme Engineering/Hubei key laboratory of Industrial biotechnology School of Life SciencesHubei UniversityWuhan 430062China

Lime pretreatment on maize stover was conducted with various pretreatment conditions selected by central composite *** and lignin contents in pretreated maize stover were relatively *** of glucose monomer and oligomers decreased while concentration of xylooligomers increased in the pretreatment hydrolysate with increasing pretreatment *** overall carbohydrate recovery was at least 85%for the conditions *** removal during pretreatment was found to have a linear correlation with lignin *** had a higher effect in enhancing carbohydrate solubilization for enzymatic hydrolysis than that for *** *** all the pretreated solids,Clostridium thermocellum fermentation was found to result in much higher carbohydrate solubilization than enzymatic hydrolysis with a cellulase loading of 8 mg/g solids and a xylanase loading of 2 mg/g *** solubilization was found to have a linear correlation with lignin removal during lime pretreatment for both enzymatic hydrolysis and *** *** the current challenges,this research provides a new idea for the industrial application of lignocellulosic biorefinery.

关键词： central composite design lime pretreatment enzymatic hydrolysis clostridium thermocellum carbohydrate solubilization

Acarbose glycosylation by AcbE for the production of acarstatins with enhancedα-amylase inhibitory activity

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Synthetic and Systems biotechnology 2024年第2期9卷 359-368页

作者： Xin Zhang Qungang Huang Ziyue Guo Feifei Cai Qianjin Kang Linquan Bai state key laboratory of Microbial Metabolism School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai200240China College of life Science Tarim UniversityAlar843300China

Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus(T2DM).Various acarbose analogs have been identified while exploring compounds with improved pharmacological *** this study,we found that AcbE from Actinoplanes ***50/110 catalyzes the production of acarbose analogs that exhibit significantly improved inhibitory activity towardsα-amylase than *** AcbE mainly catalyzed the formation of two new compounds,namely acarstatins A and B,using acarbose as *** high-resolution mass spectrometry,nuclear magnetic resonance,and glycosidase hydrolysis,we elucidated their chemical structures as O-α-d-maltosyl-(1→4)-acarbose and O-α-d-maltotriosyl-(1→4)-acarbose,*** A and B exhibited 1584-and 1478-fold greater inhibitory activity towards human salivaryα-amylase than ***,both acarstatins A and B exhibited complete resistance to microbiome-derived acarbose kinase 1-mediated phosphorylation and partial resistance to acarbose-preferred glucosidase-mediated ***,acarstatins A and B have great potential as candidate therapeutic agents for T2DM.

关键词： Acarbose analogs α-amylase inhibitory activity Actinoplanes sp. Transglycosylase

Taxonomic dependency and spatial heterogeneity in assembly mechanisms of bacteria across complex coastal waters

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Ecological Processes 2024年第1期13卷 80-97页

作者： Huizhen Yan Dandan Lin Gaoke Gu Yujie Huang Xuya Hu Zhenhao Yu Dandi Hou Demin Zhang Barbara J.Campbell Kai Wang state key laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products School of Marine SciencesNingbo University key laboratory of Marine biotechnology of Zhejiang Province School of Marine Sciences Ningbo University Department of Biological sciences Clemson University

Background Understanding community assembly mechanisms across taxa and space is fundamental for microbial ecology. However, the variability and determinants of assembly processes over taxa and space remain unclear. Here, we investigated taxonomic dependency and spatial heterogeneity in bacterial assembly mechanisms across coastal waters in the East China Sea using neutral and null models with customized visualization *** Overall, bacterial assembly mechanisms varied across broad taxonomic groups(phyla and proteobacterial classes) and space at the regional scale. A determinism–stochasticity balanced mechanism governed total bacterial assembly, while taxonomic dependency existed in assembly mechanisms and ecological processes. Among community ecological features, niche breadth and negative-to-positive cohesion ratio were strongly associated with the determinism-to-stochasticity ratio of bacterial groups. Bacterial assembly mechanisms commonly exhibited spatial heterogeneity, the extent and determinants of which varied across taxonomic groups. Spatial assembly of total bacteria was directly driven by many environmental factors and potential interactions between taxa, but not directly by geographic factors. Overall, the bacterial groups with higher spatial heterogeneity in assembly mechanisms were more related to environmental and/or geographic factors(except Bacteroidetes), while those with lower heterogeneity were more related to ecological *** Our results confirm the pervasiveness of taxonomic dependency and spatial heterogeneity in bacterial assembly, providing a finer understanding about regulation across complex coastal waters.

关键词： Bacterioplankton Assembly mechanism Niche breadth Null model Environmental gradient Biogeography

Discovery of TK-642 as a highly potent,selective,orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3624-3642页

作者： Kai Tang Shu Wang Siqi Feng Xinyu Yang Yueyang Guo Xiangli Ren Linyue Bai Bin Yu Hong-Min Liu Yihui Song school of pharmaceutical sciences&key laboratory of Advanced Drug Preparation Technologies Ministry of EducationZhengzhou UniversityZhengzhou 450001China College of Chemistry Pingyuan LaboratoryState Key Laboratory of Antiviral DrugsZhengzhou UniversityZhengzhou 450001China Tianjian laboratory of Advanced Biomedical sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450000China state key laboratory of pharmaceutical biotechnology Nanjing UniversityNanjing 210023China

Src homology-2-containing protein tyrosine phosphatase 2(SHP2)is a promising therapeutic target for cancer *** this work,we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors,leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent,selective,orally bioavailable allosteric SHP2 inhibitor(SHP2WT IC_(50)=2.7 nmol/L)with favorable pharmacokinetic profiles(F=42.5%;t_(1/2)=2.47 h).Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the“tunnel”allosteric site of ***-642 could effectively suppress cell proliferation(KYSE-520 cells IC_(50)=5.73μmol/L)and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling ***,oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model,with a T/C value of 83.69%.Collectively,TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

关键词： Protein tyrosine phosphatase Pyrazolopyrazine SHP2 inhibitor Esophageal cancer

Metabolic engineering of an industrial bacterium Zymomonas mobilis for anaerobic l-serine production

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Synthetic and Systems biotechnology 2024年第2期9卷 349-358页

作者： Zhen Wang Xia Wang Xiongying Yan Haixia Yi Shuche He Haoyu Zhang Xinli Zhou Qiaoning He Shihui Yang state key laboratory of Biocatalysis and Enzyme Engineering and school of life sciences Hubei UniversityWuhan430062China

Due to the complicated metabolic and regulatory networks of l-serine biosynthesis and degradation,microbial cell factories for l-serine production using non-model microorganisms have not been *** this study,a combination of synthetic biology and process optimization were applied in an ethanologenic bacterium Zymomonas mobilis for l-serine *** blocking the degradation pathway while introducing an exporter EceamA from ***,l-serine titer in recombinant *** was increased from 15.30 mg/L to 62.67 mg/*** was further increased to 260.33 mg/L after enhancing the l-serine biosynthesis ***,536.70 mg/L l-serine was achieved by removing feedback inhibition with a SerA mutant,and an elevated titer of 687.67 mg/L was further obtained through increasing serB copies while enhancing the ***,855.66 mg/L l-serine can be accumulated with the supplementation of the glutamate *** work thus not only constructed an l-serine producer to help understand the bottlenecks limiting l-serine production in *** for further improvement,but also provides guidance on engineering non-model microbes to produce biochemicals with complicated pathways such as amino acids or terpenoids.

关键词： Zymomonas mobilis Metabolic engineering l-serine Feedback inhibition Anaerobic fermentation