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metabolic engineering of yeasts for green and sustainable production of bioactive ginsenosides F2 and 3β,20S-Di-O-Glc-DM

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3167-3176页

作者： Fenglin Jiang Chen Zhou Yan Li Haidong Deng Ting Gong Jingjing Chen Tianjiao Chen Jinling Yang Ping Zhu State Key Laboratory of Bioactive Substance and Function of Natural Medicines NHC Key Laboratory of Biosynthesis of Natural ProductsCAMS Key Laboratory of Enzyme and Biocatalysis of Natural DrugsInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Both natural ginsenoside F2 and unnatural ginsenoside 3β,20S-Di-O-Glc-DM were reported to exhibit anti-tumor activity.Traditional approaches for producing them rely on direct extraction from Panax ginseng,enzymatic catalysis or chemical synthesis,all of which result in low yield and high cost.metabolic engineering of microbes has been recognized as a green and sustainable biotechnology to produce natural and unnatural products.Hence we engineered the complete biosynthetic pathways of F2 and 3β,20S-Di-OGlc-DM in Saccharomyces cerevisiae via the CRISPR/Cas9 system.The titers of F2 and 3β,20S-Di-O-GlcDM were increased from 1.2 to 21.0 mg/L and from 82.0 to 346.1 mg/L at shake flask level,respectively,by multistep metabolic engineering strategies.Additionally,pharmacological evaluation showed that both F2and 3β,20S-Di-O-Glc-DM exhibited anti-pancreatic cancer activity and the activity of 3β,20S-Di-O-GlcDM was even better.Furthermore,the titer of 3β,20S-Di-O-Glc-DM reached 2.6 g/L by fed-batch fermentation in a 3 L bioreactor.To our knowledge,this is the first report on demonstrating the anti-pancreatic cancer activity of F2 and 3β,20S-Di-O-Glc-DM,and achieving their de novo biosynthesis by the engineered yeasts.Our work presents an alternative approach to produce F2 and 3β,20S-Di-O-Glc-DM from renewable biomass,which lays a foundation for drug research and development.

关键词： Ginsenoside UDP-glycosyltransferase metabolic engineering Synthetic biology Saccharomyces cerevisiae CRISPR/Cas9 system Microbial cell factory Anti-pancreatic cancer activity

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metabolic engineering of Yarrowia lipolytica for scutellarin production

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Synthetic and Systems Biotechnology 2022年第3期7卷 958-964页

作者： Yina Wang Xiaonan Liu Bihuan Chen Wei Liu Zhaokuan Guo Xiangyu Liu Xiaoxi Zhu Jiayu Liu Jin Zhang Jing Li Lei Zhang Yadi Gao Guanghui Zhang Yan Wang MIqbal Choudhary Shengchao Yang Huifeng Jiang National and Local Joint engineering Research Center on Germplasm Innovation and Utilization of Chinese Medicinal Materials in Southwest China Yunnan Agricultural UniversityYunnanKunming650201China State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan Yunnan Agricultural UniversityYunnanKunming650201China Key Laboratory of Systems Microbial Biotechnology Tianjin Institute of Industrial BiotechnologyChinese Academy of SciencesTianjin300308China University of Chinese Academy of Sciences Beijing100049China National Center of Technology Innovation for Synthetic Biology Tianjin300308China College of Life Science and Technology Wuhan Polytechnic UniversityWuhanHubei430023China H.E.J.Research Institute of Chemistry International Center for Chemical and Biological SciencesUniversity of KarachiKarachi75270Pakistan

Scutellarin related drugs have superior therapeutic effects on cerebrovascular and cardiovascular diseases.Here,an optimal biosynthetic pathway for scutellarin was constructed in Yarrowia lipolytica platform due to its excellent metabolic potential.By integrating multi-copies of core genes from different species,the production of scutellarin was increased from 15.11 mg/L to 94.79 mg/L and the ratio of scutellarin to the main by-product was improved about 110-fold in flask condition.Finally,the production of scutellarin was improved 23-fold and reached to 346 mg/L in fed-batch bioreactor,which was the highest reported titer for de novo production of scutellarin in microbes.Our results represent a solid basis for further production of natural products on unconventional yeasts and have a potential of industrial implementation.

关键词： Scutellarin Yarrowia lipolytica metabolic engineering Combinatorial gene overexpression

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metabolic engineering of Bacillus amyloliquefaciens for efficient production ofα-glucosidase inhibitor1-deoxynojirimycin

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Synthetic and Systems Biotechnology 2023年第3期8卷 378-385页

作者： Xujie Li Meng Zhang Yu Lu Ningyang Wu Jian’gang Chen Zhixia Ji Yangyang Zhan Xin Ma Junyong Chen Dongbo Cai Shouwen Chen State Key Laboratory of Biocatalysis and Enzyme engineering Environmental Microbial Technology Center of Hubei ProvinceCollege of Life SciencesHubei UniversityWuhan430062China State Key Laboratory of Agricultural Microbiology Huazhong Agricultural UniversityWuhan430070China Department of Urology Zhuhai People’s Hospital(Zhuhai Hospital Affiliated to Jinan University)Zhuhai519000China Wuhan Jun’an Biotechnology Co. Ltd.Wuhan430070China

Owing to the feature of strongα-glucosidase inhibitory activity,1-deoxynojirimycin(1-DNJ)has broad application prospects in areas of functional food,biomedicine,etc.,and this research wants to construct an efficient strain for 1-DNJ production,basing on Bacillus amyloliquefaciens HZ-12.Firstly,using the temperature-sensitive shuttle plasmid T2(2)-Ori,gene ptsG in phosphotransferase system(PTS)was weakened by homologous recombination,and non-PTS pathway was strengthened by deleting its repressor gene iolR,and 1-DNJ yield of resultant strain HZ-S2 was increased by 4.27-fold,reached 110.72 mg/L.Then,to increase precursor fructose-6-phosphate(F-6-P)supply,phosphofructokinase was weaken,fructose phosphatase GlpX and 6-phosphate glucose isomerase Pgi were strengthened by promoter replacement,moreover,regulator gene nanR was deleted,1-DNJ yield was further increased to 267.37 mg/L by 2.41-fold.Subsequently,promoter of 1-DNJ synthetase cluster was optimized,as well as 5′-UTRs of downstream genes in synthetase cluster,and 1-DNJ produced by the final strain reached 478.62 mg/L.Last but not the least,1-DNJ yield of 1632.50 mg/L was attained in 3 L fermenter,which was the highest yield of 1-DNJ reported to date.Taken together,our results demonstrated that metabolic engineering was an effective strategy for 1-DNJ synthesis,this research laid a foundation for industrialization of functional food and drugs based on 1-DNJ.

关键词： 1-Deoxynojirimycin Bacillus amyloliquefaciens metabolic engineering Glucose transport pathway Fructose 6-phosphate 1-DNJ synthetase Gene cluster

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Advances in plastid transformation for metabolic engineering in higher plants

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aBIOTECH 2022年第3期3卷 224-232页

作者： Sheng Yang Yi Deng Shengchun Li State Key Laboratory of Biocatalysis and Enzyme engineering School of Life SciencesHubei UniversityWuhan430062China

The plastid(chloroplast)genome of higher plants is an appealing target for metabolic engineering via genetic transformation.Although the bacterial-type plastid genome is small compared with the nuclear genome,it can accommodate large quantities of foreign genes that precisely integrate through homologous recombination.engineering complex metabolic pathways in plants often requires simultaneous and concerted expression of multiple transgenes,the possibility of stacking several transgenes in synthetic operons makes the transplastomic approach amazing.The potential for extraordinarily high-level transgene expression,absence of epigenetic gene silencing and transgene containment due to the exclusion of plastids from pollen transmission in most angiosperm species further add to the attractiveness of plastid transformation technology.This minireview describes recent advances in expanding the toolboxes for plastid genome engineering,and highlights selected high-value metabolites produced using transplastomic plants,including artemisinin,astaxanthin and paclitaxel.

关键词： Plastid transformation metabolic engineering Multiple transgenes High-level expression

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Characterizing and engineering promoters for metabolic engineering of Ogataea polymorpha

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Synthetic and Systems Biotechnology 2022年第1期7卷 498-505页

作者： Chunxiao Yan Wei Yu Xiaoxin Zhai Lun Yao Xiaoyu Guo Jiaoqi Gao Yongjin J.Zhou School of Biological engineering Dalian Polytechnic UniversityDalian116034PR China Division of Biotechnology Dalian Institute of Chemical PhysicsChinese Academy of Sciences457 Zhongshan RoadDalian116023PR China CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023PR China Dalian Key Laboratory of Energy Biotechnology Dalian Institute of Chemical PhysicsCAS457 Zhongshan RoadDalian116023PR China University of Chinese Academy of Sciences Beijing100049China

Bio-manufacturing via microbial cell factory requires large promoter library for fine-tuned metabolic engi-neering.Ogataea polymorpha,one of the methylotrophic yeasts,possesses advantages in broad substrate spec-trum,thermal-tolerance,and capacity to achieve high-density fermentation.However,a limited number of available promoters hinders the engineering of O.polymorpha for bio-productions.Here,we systematically characterized native promoters in O.polymorpha by both GFP fluorescence and fatty alcohol biosynthesis.Ten constitutive promoters(P_(PDH),P_(PYK),P_(FBA),P_(PGM),P_(GLK),P_(TRI),P(GPI),P_(ADH1),P_(TEF1) and P_(GCW14))were obtained with the activity range of 13%–130% of the common promoter P_(GAP)(the promoter of glyceraldehyde-3-phosphate de-hydrogenase),among which P_(PDH) and P_(GCW14) were further verified by biosynthesis of fatty alcohol.Furthermore,the inducible promoters,including ethanol-induced P_(ICL1),rhamnose-induced P_(LRA3) and P_( LRA4),and a bidirectional promoter(P_(Mal)-P_(Per))that is strongly induced by sucrose,further expanded the promoter toolbox in O.polymorpha.Finally,a series of hybrid promoters were constructed via engineering upstream activation sequence(UAS),which increased the activity of native promoter P LRA3 by 4.7–10.4 times without obvious leakage expression.Therefore,this study provided a group of constitutive,inducible,and hybrid promoters for metabolic engineering of O.polymorpha,and also a feasible strategy for rationally regulating the promoter strength.

关键词： Ogataea polymorpha Promoter Hybrid promoter Upstream activation sequence metabolic engineering Fatty alcohols

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Lipid nanoparticle-mediated CRISPR/Cas9 gene editing and metabolic engineering for anticancer immunotherapy

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 641-652页

作者： Hyemin Ju Dongyoon Kim Yu-Kyoung Oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea

metabolic engineering of the tumor microenvironment has emerged as a new strategy.Lactate dehydrogenase A(LDHA)is a prominent target for metabolic engineering.Here,we designed a cationic lipid nanoparticle formulation for LDHA gene editing.The plasmid DNA delivery efficiency of our lipid nanoparticle formulations was screened by testing the fluorescence of lipid nanoparticles complexed to plasmid DNA encoding green fluorescence protein(GFP).The delivery efficiency was affected by the ratios of three components:a cationic lipid,cholesterol or its derivative,and a fusogenic lipid.The lipid nanoparticle designated formulation F3 was complexed to plasmid DNA co-encoding CRISPR-associated protein 9 and LDHA-specific sgRNA,yielding the lipoplex,pCas9-sgLDHA/F3.The lipoplex including GFP-encoding plasmid DNA provided gene editing in HeLa-GFP cells.Treatment of B16F10 tumor cells with pCas9-sgLDHA/F3 yielded editing of the LDHA gene and increased the pH of the culture medium.pCas9-sgLDHA/F3 treatment activated the interferon-gamma and granzyme production of T cells in culture.In vivo,combining pCas9-sgLDHA/F3 with immune checkpoint-inhibiting anti-PD-L1 antibody provided a synergistic antitumor effect and prolonged the survival of tumor model mice.This study suggests that combining metabolic engineering of the tumor microenvironment with immune checkpoint inhibition could be a valuable antitumor strategy.

关键词： Gene editing Lipid nanoparticle metabolic engineering Lactate dehydrogenase A Tumor microenvironment

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Enrichment of health-promoting lutein and zeaxanthin in tomato fruit through metabolic engineering

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Synthetic and Systems Biotechnology 2022年第4期7卷 1159-1166页

作者： Yanjun Wu Yong Yuan Wenqian Jiang Xin Zhang Siyan Ren Hsihua Wang Xiaolan Zhang Yang Zhang Key Laboratory of Bio-resource and Eco-environment of Ministry of Education College of Life SciencesSichuan UniversityChengdu610064China Sanya Institute of China Agricultural University Sanya572025China Beijing Key Laboratory of Growth and Developmental Regulation for Protected Vegetable Crops College of HorticultureChina Agricultural UniversityBeijing100193China

Carotenoids constitute a large group of natural pigments widely distributed in nature.These compounds not only provide fruits and flowers with distinctive colors,but also have significant health benefits for humans.Lutein and zeaxanthin,both oxygen-containing carotenoids,are considered to play vital roles in promoting ocular development and maintaining eye health.However,humans and mammals cannot synthesize these carotenoid derivatives,which can only be taken from certain fruits or vegetables.Here,by introducing four endogenous synthetic genes,SlLCYE,SlLCYB,SlHYDB,and SlHYDE under fruit-specific promoters,we report the metabolic engineering of lutein/zeaxanthin biosynthesis in tomato fruit.Transgenic lines overexpression of one(SlLCYE),two(SlLCYE and SlLCYB;SlLCYB and SlHYDB),and all these four synthetic genes re-established the lutein/zeaxanthin biosynthetic pathways in the ripe tomato fruit and thus resulted in various types of carotenoid riched lines.metabolic analyses of these engineered tomato fruits showed the strategy involved expression of SlLCYE tends to produceα-carotene and lutein,as well as a higher content of β-carotene and zeaxanthin was detected in lines overexpressing SlLCYB.In addition,the different combinations of engineered tomatoes with riched carotenoids showed higher antioxidant capacity and were associated with a significantly extended shelf life during postharvest storage.This work provides a successful example of accurate metabolic engineering in tomato fruit,suggesting the potential utility for synthetic biology to improve agronomic traits in crops.These biofortified tomato fruits could be also exploited as new research subjects for studying the health benefits of carotenoid derivatives.

关键词： Solanum lycopersicum Tomato fruit metabolic engineering Lutein Zeaxanthin Antioxidant capacity

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Serotonin enrichment of rice endosperm by metabolic engineering

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The Crop Journal 2023年第6期11卷 1943-1948页

作者： Qingqing Yang Yan Tan Ying Ye Dongsheng Zhao Qiaoquan Liu Key Laboratory of Crop Genomics and Molecular Breeding of Jiangsu Province/Zhongshan Biological Breeding Laboratory/Key Laboratory of Plant Functional Genomics of the Ministry of Education College of AgricultureYangzhou UniversityYangzhou 225009JiangsuChina Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops/Jiangsu Key Laboratory of Crop Genetics and Physiology Yangzhou UniversityYangzhou 225009JiangsuChina

In animals,serotonin is a neurotransmitter and mood regulator.In plants,serotonin functions in energy acquisition,tissue maintenance,delay of senescence,and response to biotic and abiotic stresses.In this study,we examined the effect of serotonin enrichment of rice endosperm on plant growth,endosperm development,and grain quality.To do so,TDCs and T5H were selected as targets for serotonin fortification.Overexpression of TDC1 or TDC3 increased serotonin accumulation relative to overexpression of T5H in rice grain.Transgenic lines of target genes driven by the Gt1 promoter showed better field performance than those driven by the Ubi promoter.Overexpression of T5H showed little effect on plant growth or grain physicochemical quality.In neuronal cell culture assays,serotonin induced neuroprotective action against apoptosis.Breeding of rice cultivars with high serotonin content may be beneficial for health and nutrition.

关键词： Rice endosperm Serotonin metabolic engineering TDCs T5H

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metabolic engineering in woody plants: challenges, advances, and opportunities

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aBIOTECH 2021年第3期2卷 299-313页

作者： Shu Yu Cody S.Bekkering Li Tian Department of Plant Sciences Mail Stop 3University of CaliforniaDavisCA 95616USA

Woody plant species represent an invaluable reserve of biochemical diversity to which metabolic engineering can be applied to satisfy the need for commodity and specialty chemicals,pharmaceuticals,and renewable energy.Woody plants are particularly promising for this application due to their low input needs,high biomass,and immeasurable ecosystem services.However,existing challenges have hindered their widespread adoption in metabolic engi neering efforts,such as long generation times,large and highly heterozygous genomes,and difficulties in transfor mation and regeneration.Recent advances in omics approaches,systems biology modeling and plant transformation and regeneration methods provide effective approaches in overcoming these outstanding challenges.Promises brought by developments in this space are steadily opening the door to widespread metabolic engineering of woody pl ants to meet the global need for a wide range of sustainably sourced chemicals and materials.

关键词： Woody plant metabolic engineering Bioeconomy Sustainability

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Manipulation of IME4 expression, a global regulation strategy for metabolic engineering in Saccharomyces cerevisiae

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药学学报:英文版 2023年第6期13卷 2795-2806页

作者： Jianxun Zhu Tianyue An Wenlong Zha Ke Gao Ting Li Jiachen Zi State Key Laboratory of Bioactive Substance and Function of Natural Medicines CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugsand NHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Jinan UniversityGuangzhou 510632China

metabolic engineering has been widely used for production of natural medicinal molecules.However, engineering high-yield platforms is hindered in large part by limited knowledge of complex regulatory machinery of metabolic network. N~6-Methyladenosine(m^(6)A) modification of RNA plays critical roles in regulation of gene expression. Herein, we identify 1470 putatively m^(6)A peaks within 1151 genes from the haploid Saccharomyces cerevisiae strain. Among them, the transcript levels of 94 genes falling into the pathways which are frequently optimized for chemical production, are remarkably altered upon overexpression of IME4(the yeast m^(6)A methyltransferase). In particular, IME4 overexpression elevates the mRNA levels of the methylated genes in the glycolysis, acetyl-CoA synthesis and shikimate/aromatic amino acid synthesis modules. Furthermore, ACS1 and ADH2, two key genes responsible for acetyl-CoA synthesis, are induced by IME4 overexpression in a transcription factor-mediated manner.Finally, we show IME4 overexpression can significantly increase the titers of isoprenoids and aromatic compounds. Manipulation of m^(6)A therefore adds a new layer of metabolic regulatory machinery and may be broadly used in bioproduction of various medicinal molecules of terpenoid and phenol classes.

关键词： RNA m^(6)A modification metabolic engineering Saccharomyces cerevisiae Isoprenoids Aromatic compounds

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