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Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

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 potentials.However,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 effort.Here,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 molecules.Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such 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 strategy.Taken 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

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Acatulides A-G,neuroprotective macrolides from Acaulium album H-JQSF

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Chinese Chemical Letters 2024年第3期35卷 379-383页

作者： Zhi-Wu Tong Ting-Ting Wang Pei Yang Jia-Lin Sun Chen-Peng Zhang Salman Khan Xin-Cun Wang Rui-Hua Jiao Hui-Ming Ge Wen-Ying Zhuang Gang Hu Ren Xiang Tan state key laboratory of Pharmaceutical Biotechnology Institute of Functional BiomoleculesNanjing UniversityNanjing 210023China state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese MedicineNanjing 210023China Insitute of Microbiology Chinese Academy of SciencesBeijing 100101China

Fungal symbionts co-evolve with hosts and microbial co-inhabitants to acquire an unpredictable potential for producing novel bioactive metabolites,but the knowledge about the topic remains patchy and superficial.Here we present the chemical characterization of acatulides A-G(1-7)as architecturally unprecedented macrolides from the solid-state culture of Acaulium album H-JQSF,an arthropod-associated fungus.The acatulide structures were elucidated by spectroscopic analysis,modified Mosher's method and single-crystal X-ray diffraction.The plausible biosynthetic pathways for compounds 1-4 are proposed.Interestingly,acatulides B-D(2-4)and G(7)were demonstrated to be neuroprotective against the 1-methyl-4-phenylpyridinium(MPP+)-induced damage to SH-SY5Y cells and nematode Caenorhabditis elegans(C.elegans).

关键词： Acaulium album Macrolides Acatulides A–G Mosher’s method Neuroprotective

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Post-ingestion conversion of dietary indoles into anticancer agents

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National Science Review 2022年第4期9卷 128-138页

作者： Li Ping Lin Dan Liu Jia Cheng Qian Liang Wu Quan Zhao Ren Xiang Tan state key laboratory of Pharmaceutical Biotechnology Institute of Functional BiomoleculesNanjing University state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese Medicine

There are health benefits from consuming cruciferous vegetables that release indole-3-carbinol(I3 C), but the in vivo transformation of I3 C-related indoles remains underinvestigated. Here we detail the post-ingestion conversion of I3 C into antitumor agents, 2-(indol-3-ylmethyl)-3,3′-diindolylmethane(LTr1) and 3,3′-diindolylmethane(DIM), by conceptualizing and materializing the reaction flux derailing(RFD) approach as a means of unraveling these stepwise transformations to be non-enzymatic but p H-dependent and gut microbe-sensitive. In the upper(or acidic) gastrointestinal tract, LTr1 is generated through Michael addition of 3-methyleneindolium(3 MI, derived in situ from I3 C) to DIM produced from I3 C via the formaldehyde-releasing(major) and CO-liberating(minor) pathways. In the large intestine,‘endogenous’ I3 C and DIM can form, respectively, from couplings of formaldehyde with one and two molecules of indole(a tryptophan catabolite). Acid-producing gut bacteria such as Lactobacillus acidophilus facilitate the H+-promotable steps. This work updates our understanding of the merits of I3 C consumption and identifies LTr1 as a drug candidate.

关键词： indole-3-carbinol reaction flux derailing (RFD) approach 2-(indol-3-ylmethyl)-3 3′-diindolylmethane (LTr1) anticancer Lactobacillus acidophilus

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Carbon-nitrogen bond formation to construct novel polyketide-indole hybrids from the indole-3-carbinol exposed culture of Daldinia eschscholzii

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Synthetic and Systems Biotechnology 2022年第2期7卷 750-755页

作者： Li Ping Lin Min Wu Nan Jiang Wei Wang Ren Xiang Tan state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese MedicineNanjing210023China state key laboratory of Pharmaceutical Biotechnology Institute of Functional BiomoleculesNanjing UniversityNanjing210023China key laboratory of Cardiovascular&Cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing211166China key laboratory of Marine Drugs Ministry of EducationOcean University of ChinaQingdao266003China

A plenty of cytochrome P450s have been annotated in the Daldinia eschosholzii genome.Inspired by the fact that some P450s have been reported to catalyze the carbon-nitrogen(C-N)bond formation,we were curious about whether hybrids through C-N bond formation could be generated in the indole-3-carbinol(I3C)exposed culture of D.eschscholzii.As expected,two skeletally undescribed polyketide-indole hybrids,designated as indolpolyketone A and B(1 and 2),were isolated and assigned to be constructed through C-N bond formation.Their structures were elucidated by 1D and 2D NMR spectra.The absolute configurations of 1 and 2 were determined by comparing the recorded and calculated electronic circular dichroism(ECD)spectra.Furthermore,the plausible biosynthetic pathways for 1 and 2 were proposed.Compounds 1 and 2 exhibited significant antiviral activity against H1N1 with IC_(50) values of 45.2 and 31.4μM,respectively.In brief,compounds 1 and 2 were reported here for the first time and were the first example of polyketide-indole hybrids pieced together through C-N bond formation in the I3C-exposed culture of D.eschscholzii.Therefore,this study expands the knowledge about the chemical production of D.eschscholzii through precursor-directed biosynthesis(PDB).

关键词： Polyketide-indole hybrids Daldinia eschosholzii Indole-3-carbinol C-N bond formation P450 Precursor-directed biosynthesis

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Dalestones A and B, two anti-inflammatory cyclopentenones from Daldinia eschscholzii with an edited strong promoter for the global regulator LaeA-like gene

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Chinese Journal of Natural Medicines 2019年第5期17卷 387-393页

作者： ZHOU Zhen-Zhen ZHU Hong-Jie YANG Cheng-Long LIU Yan-Jun JIANG Nan XIAO Yong-Sheng SHI Li-Yun JIAO Rui-Hua GE Hui-Ming TAN Ren-Xiang state key laboratory of Pharmaceutical Biotechnology Institute of Functional Biomolecules Nanjing University state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese Medicine School of Pharmacy Nanjing Medical University

Replacement of the native promoter of the global regulator Lae A-like gene of Daldinia eschscholzii by a strong gpdA promoter led to the generation of two novel cyclopentenone metabolites, named dalestones A and B, whose structures were assigned by a combination of spectroscopic analysis, modified Mosher's reaction, and electronic circular dichroism(ECD). Dalestones A and B inhibit the gene expression of TNF-α and IL-6 in LPS-induced RAW264.7 macrophages.

关键词： Daldinia eschscholzii Global regulator Cyclopentenone

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Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2880-2899页

作者： Qi Lv Yao Xing Jian Liu Dong Dong Yue Liu Hongzhi Qiao Yinan Zhang Lihong Hu Jiangsu key laboratory for Functional Substance of Chinese Medicine Stake Key Laboratory Cultivation Base for TCM Quality and EfficacySchool of PharmacyNanjing University of Chinese MedicineNanjing 210023China

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potential therapy,the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial.By focusing on the flavonoid lonicerin,one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb.,here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2(EZH2)histone methyltransferase.EZH2-mediated modification of H3 K27 me3 promotes the expression of autophagy-related protein 5,which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation.Mutations of EZH2 residues(His 129 and Arg685)indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin.More importantly,in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis,which is compromised by administration of EZH2 overexpression plasmid.Thus,these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.

关键词： Lonicerin Colitis NLRP3 inflammasome Autophagy EZH2

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Antiosteoporotic Tetrahydroxanthone Dimers from Aspergillus brunneoviolaceus FB-2 Residing in Human Gut

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Chinese Journal of Chemistry 2021年第6期39卷 1580-1586页

作者： Xiao-Jing Lv Fei Ding Ying-Jie Wei Ren-Xiang Tan state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese MedicineNanjingJiangsu 210023China state key laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjingJiangsu 210023China

A complex community of human-associated microorganisms plays diversely important roles in maintaining health,and the metabolites help to define whether a particular human-associated microbe is a friend or a foe.This work shows that Aspergillus brunneoviolaceus FB-2,derived from the stool of a healthy individual,produces a family of antiosteoporotic xanthone dinners including penibishexahydroxanthone A(1)and brunneoxanthones A-E(2-6,undescribed previously).The structures of 1-6 were elucidated by MS and NMR spectroscopic analysis,and the absolute configuration of 2 was established by X-ray crystallography.Compounds 4-6 are relatively rare examples of highly oxidized heterodimeric xanthones with an 8-ketone functionality.Finally,the prednisolone-induced osteoporotic zebrafish enabled our demonstration that the antiosteoporotic effects of 1-6 are dose-dependent.

关键词： Aspergillus brunneoviolaceus Gut-associated fungus Natural products Structure elucidation Biological activity

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Tunable System for Electrochemical Reduction of Ketones and Phthalimides

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Chinese Journal of Chemistry 2021年第12期39卷 3297-3302页

作者： Yaxin Wang Jianyou Zhao Tianjiao Qiao Jian Zhang Gong Chen state key laboratory cultivation base for tcm quality and efficacy College of PharmacyNanjing University of Chinese MedicineNanjingJiangsu 210023China state key laboratory of Elemento-Organic Chemistry Research Institute of Elemento-Organic ChemistryNankai UniversityTianjin 300071China

Herein,we report an efficient,tunable system for electrochemical reduction of ketones and phthalimides at room temperature without the need for stoichiometric external reductants.By utilizing NaN_(3) as the electrolyte and graphite felt as both the cathode and the anode,we were able to selectively reduce the carbonyl groups of the substrates to alcohols,pinacols,or methylene groups by judiciously choosing the solvent and an acidic additive.The reaction conditions were compatible with a diverse array of functional groups,and phthalimides could undergo one-pot reductive cyclization to afford products with indolizidine scaffolds.Mechanistic studies showed that the reactions involved electron,proton,and hydrogen atom transfers.Importantly,an N_(3)/HN_(3) cycle operated as a hydrogen atom shuttle,which was critical for reduction of the carbonyl groups to methylene groups.

关键词： Electrochemistry Reduction Ketones Phthalimides Radical reactions

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Bioactive Alkaloids from Indole-3-carbinol Exposed Culture of Daldinia eschscholzii

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Chinese Journal of Chemistry 2018年第8期36卷 749-753页

作者： Li Ping Lina Ren Xiang Tan state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese Medicine Nanjing Jiangsu 210023 China Institute of Functional Biomolecules State Key Laboratory of Pharmaceutical Biotechnology Nanjing University Nanjing Jiangsu 210023 China

Two new and rare bioactive indoles named dalesindoloids A （1） and B （3）, along with 3-（1H-indole-3ylmethyl）-2-oxindole （2）, were characterized from the indole-3-carbinot （13C）-exposed culture of Daldinia eschscholzii. The absolute configuration of 2 was determined by quantum chemical calculations of the electronic circular dichroism （ECD） spectrum. Dalesindoloids A and B were cytotoxic against the leukemia HL-60 cell line with the IC50 values of 1.0 and 7.4 μmol/L, respectively, with the former being inhibitory on Staphylococcus aureus （MIC： 9.1 μmol/L）. The simultaneous characterization of the alkaloids from the 13C-exposed fungal culture highlighted that the 2,3-epoxyindoline motif can be transformed into both lactam and indolin-3-one moieties. This is the first-time description of the 2,3-epoxyindoline chemical versatility and Wagner-Meerwein rearrangement （WMR） reaction in the microbial culture.

关键词： indole alkaloids indole-3-carbinol Daldinia eschscholzii anticancer antibacterial

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Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii

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Acta Pharmaceutica Sinica B 2019年第2期9卷 369-380页

作者： Liping Lin Nan Jiang Huimin Wu Yaning Mei Jie Yang Renxiang Tan state key laboratory cultivation base for tcm quality and efficacy Nanjing University of Chinese Medicine state key laboratory of Pharmaceutical Biotechnology Nanjing University School of Pharmacy Nanjing Medical University Department of Clinical laboratory the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Academy of Traditional Chinese Medicine

Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).

关键词： Polyketide-indole hybrids Indole-3-carbinol Daldinia eschscholzii 8-Amino-7-oxononanoate synthase Decarboxylative Claisen condensation Antibacterial Anticancer

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