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The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

molecular Plant 2024年第7期17卷 1129-1150页

作者： Paula Berman Luis Alejandro de Haro Ana-Rita Cavaco Sayantan Panda Younghui Dong Nikolay Kuzmich Gabriel Lichtenstein Yoav Peleg Hila Harat Adam Jozwiaki Jianghua Cai Uwe Heinig Sagit Meir Ilana Rogachev Asaph Aharoni Department of Plant and Environmental Sciences Weizmann Institute of ScienceRehovot 7610001Israel Life Sciences core facilities Weizmann Institute of ScienceRehovot 7610001Israel The Maurice and Vivienne Wohl Institute for Drug Discovery Weizmann Institute of ScienceRehovot 7610001Israel Present address:Department of Cell and Metabolic Biology Leibniz Institute of Plant BiochemistryWeinberg 306120 Halle(Saale)Germany Department of molecular&Cellular Pharmacology University of Miami Miler School of MedicineMiamiFL 33136USA Department of Botany and Plant Sciences University of California RiversideRiversideCA 92521USA Laboratory of Plant Hormones and Development Regulation of Chongqing School of Life SciencesChongqing UniversityChongqing 401331China

Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy ***,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be *** this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine *** employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway *** identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in ***,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline *** together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.

关键词： mescaline Lophophora williamsi Peyote biosynthetic pathway de novo genome sequencing mo-lecular modeling

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Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

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Journal of Pharmaceutical Analysis 2024年第1期14卷 100-114页

作者： Sze Wan Hung Massimiliano Gaetani Yiran Li Zhouyurong Tan Xu Zheng Ruizhe Zhang Yang Ding Gene Chi Wai Man Tao Zhang Yi Song Yao Wang Jacqueline Pui Wah Chung Tak Hang Chan Roman A.Zubarev Chi Chiu Wang Department of Obstetrics&Gynaecology The Chinese University of Hong KongHong KongChina Division of Physiological Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Chemical Proteomics core facility Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Unit of Chemical Proteomics Science for Life Laboratory(SciLifeLab)StockholmSE 17177Sweden Center for Reproductive medicine Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450003China Department of Chemistry McGill UniversityMontrealH3A2K6Canada Department of Pharmacological&Technological Chemistry I.M.Sechenov First Moscow State Medical UniversityMoscow119146Russia Reproduction and Development Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive medicine The Chinese University of Hong KongHong KongChina

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the *** is a major pathophysiology in *** previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain *** this study,we demonstrated that oral ProEGCG can be effective in preventing and treating ***,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,*** simulation and BioLayer interferometry were used to confirm their binding *** results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)*** vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling ***,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

关键词： molecular targets ProEGCG EGCG Angiogenesis Treatment Endometriosis

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Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate ribose and calcium

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Science Bulletin 2024年第18期69卷 2892-2905页

作者： Cheng Ma Yanping Luo Congyi Zhang Cheng Cheng Ning Hua Xiaocao Liu Jianan Wu Luying Qin Peilin Yu Jianhong Luo Fan Yang Lin-Hua Jiang Guojie Zhang Wei Yang Department of Biophysics and Department of Neurosurgery The Fourth Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Protein facility Core FacilitiesZhejiang University School of MedicineZhejiang UniversityHangzhou 310058China Department of Toxicology and Department of Medical Oncology of The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Department of Neurobiology Affiliated Mental Health CenterCollege of Brain Science and Brain MedicineZhejiang University School of MedicineHangzhou 310058China Department of Biophysics and Kidney Disease Center of The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310058China Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province and Department of Physiology and PathophysiologyXinxiang Medical UniversityXinxiang 453004China Henan Collaborative Innovation Center of Prevention and Treatment of Mental Disorder The Second Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453004China Evolutionary&Organismal Biology Research Center School of MedicineZhejiang UniversityHangzhou 310058China GuiZhou University Medical College Guiyang 550025China

Ion channel activation upon ligand gating triggers a myriad of biological events and,therefore,evolution of ligand gating mechanism is of fundamental ***2,a typical ancient ion channel,is activated by adenosine diphosphate ribose(ADPR)and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates,but the evolutionary process is still *** evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that,the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation,while the N-terminal MHR domain maintains a conserved ligand binding *** gating pattern has also evolved,from one Ca^(2+)-binding site as in sea anemones to three sites as in ***,we identified a new group represented by olTRPM2,which has a novel gating mode and fills the missing link of the channel gating *** conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and *** findings benefit the evolutionary investigations of other channels and proteins.

关键词： TRPM2 channel Activation mode molecular evolution

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MAGI3 Suppresses Glioma Cell Proliferation via Upregulation of PTEN Expression

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Biomedical and Environmental Sciences 2015年第7期28卷 502-509页

作者： MA Qian ZHANG Yan MENG Ran XIE Kun Ming XIONG Ying LIN Song HE Zong Lin K. TAO Tao YANG Ying ZHAO Ji Zong HE Jun Qi Department of biochemistry and molecular Biology Capital Medical University The Center of Prenatal Diagnosis First Affiliated HospitalCollege of MedicineZhengzhou Universit Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University China National Clinical Research Center for Neurological Diseases UC Berkeley San Francisco core facilities Center Capital Medical University

Objective To investigate the role and molecular mechanism of membrane-associated guanylate kinase inverted 3 （MAGI3） in glioma cell proliferation. Methods The expression levels of MAGI3 and PTEN were assessed in glioma samples by Western blotting. MAGI3 was stably transfected into C6 glioma cells to obtain C6-MAGI3 cells. Then, the proliferation, the expression levels of MAGI3 and PTEN, and Akt phosphorylation were evaluated in C6 and C6-MAGI3 cells. Xenograft tumor models were established by subcutaneous injection of C6 and C6-MAGI3 cells into nude mice, and the growth rates of xenografts in the mice were compared. The potential role of MAGI3 expression in PI3K/Akt signaling activation was further investigated by examining the correlation between MAGI3 expression and the expression of PI3K/Akt signaling downstream target genes in a glioma dataset using gene set enrichment analysis （GSEA）. Results Expression levels of MAGI3 and PTEN were significantly downregulated in gliomas. Overexpression of MAGI3 in the glioma C6 cell line upregulated PTEN protein expression, inhibited the phosphorylation of Akt, and suppressed cell proliferation. MAGI3 overexpression also inhibited the growth of C6 glioma tumor xenografts in nude mice. Analysis based on the GEO database confirmed the negative correlation between activation of PI3K/Akt pathway and MAGI3 mRNA levels in human glioma samples. Conclusion The loss of MAGI3 expression in downregulation of PTEN expression, leading potential glioma suppressor. glioma may enhance the proliferation of glioma cells via to the activation of the PI3K/Akt pathway. MAGI3 is a

关键词： Glioma PTEN MAGI3 PDZ Protein-protein interaction PI3K/Akt

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生物信息学资源助力蛋白质磷酸化的系统层次理解

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Science Bulletin 2024年第8期69卷 989-992页

作者：彭迪贾大夏宏光张珞颖黄鹏宇薛宇 Department of Bioinformatics and Systems Biology MOE Key Laboratory of Molecular BiophysicsHubei Bioinformatics and Molecular Imaging Key LaboratoryCollege of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China Key Laboratory of Birth Defects and Related Diseases of Women and Children Department of PaediatricsWest China Second University HospitalState Key Laboratory of BiotherapySichuan UniversityChengdu 610041China Department of biochemistry&Research Center of Clinical Pharmacy of The First Affiliated Hospital Zhejiang University School of MedicineHangzhou 310058China Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300192China Nanjing University Institute of Artificial Intelligence Biomedicine Nanjing 210031China

Protein phosphorylation,catalyzed by protein kinases(PKs),is one of the most prevalent post-translational modifications(PTMs)in *** occurring at different positions in a protein sequence can possess distinct functional impacts,and sitespecific phosphorylation may drastically alter a protein’s conformation,activity,and ***,biologists usually focused on studying regulatory mechanisms of phosphorylation in a limited number of proteins,mainly due to a lack of highthroughput *** the past two decades,advances in liquid chromatography coupled with tandem mass spectrometry(LC-MS/MC)have boomed a revolutionary technology named phosphoproteomics,which can simultaneously quantify thousands of phosphorylation sites(p-sites),and provide a great opportunity for a systems-level understanding of *** LCMS/MC,other approaches such as immunohistochemistry(IHC)and immune-detection by sequencing(ID-seq)have also emerged.

关键词： positions catalyzed translational

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Accelerating Deprotonation Kinetics of RuO_(2)for Efficient Acidic Water Oxidation

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Renewables 2024年第3期2卷 204-212页

作者： Hongnan Jia Zhichang Liao Juan Zhu Wei Luo College of Chemistry and molecular Sciences Wuhan UniversityWuhanHubei 430072

The development of a highly efficient noniridium-based oxygen evolution reaction catalyst is the key to realizing large-scale commercial application of the proton-exchange membrane water ***_(2)is the most promising alternative to IrO_(2),but if usually suffers from lattice-oxygenmediated corrosion and sluggish proton transfer kinetics under acidic ***,we propose an effective strategy of embedding RuO_(2)nanoparticles into a N-doped carbon support,termed as RuO_(2)-NC,to simultaneously prevent Ru dissolution and accelerate the bridging-oxygen-assisted deprotonation *** obtained RuO_(2)-NC electrocatalyst presents high activity with an overpotential of 159 mV to reach 10 mA cm^(−2) and remarkable stability for over 240 *** investigation and theoretical calculations reveal that the electron-rich NC substrate,as an electron donor,provides a buffered charge compensation to protect RuO_(2)from excessive oxidation and lattice oxygen loss by switching into a conventional adsorbate evolution mechanism(AEM).More importantly,the activated bridging oxygen(Obri)sites can facilitate the deprotonation of*OOH intermediates,leading to an optimized bridging-oxygen-assisted deprotonation AEM pathway.

关键词： acidic oxygen evolution reaction electronic donation NC support RuO_(2) adsorbate evolution mechanism bridging-oxygen-assisted deprotonation

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Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue

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Genes & Diseases 2023年第1期10卷 267-283页

作者： Lakshmi Prabhu Matthew Martin Lan Chen Ozlem Demir Jiamin Jin Xiumei Huang Aishat Motolani Mengyao Sun Guanglong Jiang Harikrishna Nakshatri Melissa L.Fishel Steven Sun Ahmad Safa Rommie E.Amaro Mark R.Kelley Yunlong Liu Zhong-Yin Zhang Tao Lu Department of Pharmacology and Toxicology Indiana University School of MedicineIndianapolisIN 46202USA Chemical Genomics core facility Indiana University School of MedicineIndiana University School of MedicineIndianapolisIN 46202USA Department of biochemistry and molecular Biology Indiana University School of MedicineIndiana University School of MedicineIndianapolisIN46202USA Department of Chemistry and biochemistry University of CaliforniaSan DiegoCA 92093USA Department of Radiation Oncology Indiana University School of MedicineIndianapolisIN 46202USA Department of Medical and molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of medicine Indiana University School of MedicineIndianapolisIN 46202USA Department of Pediatrics Herman B Wells Center for Pediatric ResearchIndianapolisiN 46202USA Indiana University Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN46202USA

Market drugs,suchas Foodand Drug Administration(FDA)or European medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer *** potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication *** arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer ***,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in *** this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in ***,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug *** in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic ***,Clo and Can treatment have exhibited marked reduction in tumor growth in ***,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer *** study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.

关键词： Cancer Research NF-kB Pharmacology PRMT5 PRMT5 inhibitors

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Gene Body CG and CHG Methylation and Suppression of Centromeric CHH Methylation are Mediated by DECREASE IN DNA METHYLATION1 in Rice

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molecular Plant 2015年第10期8卷 1560-1562页

作者： Hisataka Numa Katsushi Yamaguchi Shuji Shigenobu Yoshiki Habu Agrogenomics Research Center National Institute of Agrobiological Sciences Tsukuba Ibaraki 305-8602 Japan Functional Genomics facility NIBB Core Research Facilities National Institute for Basic Biology Qkazaki Aichi 444-0867 Japan CREST JST Kawaguchi Saitama 332-0012 Japan

Dear Editor,DECREASE IN DNA METHYLATION1 （DDM1） is a chromatin remodeling protein required for maintenance of cytosine and histone H3K9 methylation in heterochromatin regions in the genome of Arabidopsis thaliana （Gendrel et al., 2002）. A ddm 1 mutant also increases the rate of meiotic recombination in euchromatic but not heterochromatic regions of A. thaliana （Melamed-Bessudo and Levy, 2012）, and changes the state of cytosine methylation of a gene flanked by a LINE element located in a region of euchromatin （Saze and Kakutani, 2007）. These studies indicate that the function of DDM1 is not limited to heterochromatin regions and show that it also acts on euchromatic regions in the genome, although the mechanism determining its target specificity remains obscure. Toward understanding the function of DDM1 in the maintenance of global epigenetic state of the genome in higher plants, we performed a genome-wide analysis of cytosine methylation in an antisense-mediated DDMl-knockdown rice line （asDDM1） that exhibits similar characteristics to that of ddml in A. thaliana （Higo et al., 2012; Habu et al., 2015）. Some intrinsic properties of rice genome differ greatly from those of A. thaliana, for example, the content of repeated sequences and their distribution, and therefore rice provides an opportunity to examine the effect of DDM1 deficiency on genomes with a higher content and broader distribution of repeats.

关键词： genomes broader distribution

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Epigenetic integrity of paternal imprints enhances the developmental potential of androgenetic haploid embryonic stem cells

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Protein & Cell 2022年第2期13卷 102-119页

作者： Hongling Zhang Yuanyuan Li Yongjian Ma Chongping Lai Qian Yu Guangyong Shi Jinsong Li State Key Laboratory of Cell Biology Shanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Animal core facility Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China

The use of two inhibitors of Mek1/2 and Gsk3β(2i)promotes the generation of mouse diploid and haploid embryonic stem cells(ESCs)from the inner cell mass of biparental and uniparental blastocysts,***,a system enabling long-term maintenance of imprints in ESCs has proven ***,we report that the use of a two-step a2i(alternative two inhibitors of Src and Gsk3β,TSa2i)derivation/culture protocol results in the establishment of androgenetic haploid ESCs(AG-haESCs)with stable DNA methylation at paternal DMRs(differentially DNA methylated regions)up to passage 60 that can efficiently support generating mice upon oocyte *** also show coexistence of H3K9me3 marks and ZFP57 bindings with intact DMR ***,we demonstrate that TSa2itreated AG-haESCs are a heterogeneous cell population regarding paternal DMR ***,AGhaESCs with late passages display increased paternal-DMR methylations and improved developmental potential compared to early-passage cells,in part through the enhanced proliferation of H19-DMR hypermethylated ***,we establish AG-haESCs that can longterm maintain paternal imprints.

关键词： paternal imprints androgenetic haploid ESCs DMRs semi-cloned mice alternative 2i

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Effects of Adipose-derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis

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Chinese Medical Journal 2018年第6期131卷 704-712页

作者： Ting Shen Qing-Qing Zheng Jiang Shen Qiu-Shi Li Xing-Hui Song Hong-Bo Luo Chao-Yang Hong Ke Yao Eye Institute of Zhejiang University Eye Center of Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China Department of Ophthalmology Zhejiang Provincial People's Hospital and People's Hospital of Hangzhou Medical College Hangzhou Zhejiang 310014 China School of Ophthalmology and Optometry Wenzhou Medical University Wenzhou Zhejiang 325035 China facility for biochemistry and molecular medicine core facilities School of Medicine Zhejiang University Hangzhou Zhejiang 310058 China

Background： Corneal stromal cells （CSCs） are components of the corneal endothelial microenvironment that can be induced to form a functional tissue-engineered corneal endothelium. Adipose-derived mesenchymal stem cells （ADSCs） have been reported as an important component of regenerative medicine and cell therapy for corneal stromal damage. We have demonstrated that the treatment with ADSCs leads to phenotypic changes in CSCs in vitro. However, the underlying mechanisms of such ADSC-induced changes in CSCs remain unclear. Methods： ADSCs and CSCs were isolated from New Zealand white rabbits and cultured in vitro. An Exosome Isolation Kit, Western blotting, and nanoparticle tracking analysis （NTA） were used to isolate and confirm the exosomes from ADSC culture medium. Meanwhile, the optimal exosome concentration and treatment time were selected. Cell Counting Kit-8 and annexin V-fluorescein isothiocyanate/ propidium iodide assays were used to assess the effect of ADSC-derived exosomes on the proliferation and apoptosis of CSCs. To evaluate the effects ofADSC-derived exosomes on CSC invasion activity, Western blotting was used to detect the expression of matrix metalloproteinases （MMPs） and collagens. Results： ADSCs and CSCs were successfully isolated from New Zealand rabbits. The optimal concentration and treatment time of exosomes for the following study were 100 μg/ml and 96 h, respectively. NTA revealed that the ADSC-derived exosomes appeared as nanoparticles （40-200 nm）, and Western blotting confirmed positive expression of CD9, CDSI, flotillin-1, and HSP70 versus ADSC cytoplasmic proteins （all P〈 0.01 ）. ADSC-derived exosomes （50μg/ml and 100μg/ml） significantly promoted proliferation and inhibited apoptosis （mainly early apoptosis） of CSCs versus non-exosome-treated CSCs （all P 〈 0.05）. Interestingly, MMPs were downregulated and extracellular matrix （ECM）-related proteins including collagens and fibronectin were upregulated in the exosome-treated CSCs versus non-

关键词： Adipose-derived Mesenchymal Stem Cell Corneal Stromal Cells Exosomes Extracellular Matrix Synthesis

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