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Development of a dual temperature control system for isoprene biosynthesis in Saccharomyces cerevisiae

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Frontiers of Chemical Science and Engineering 2022年第7期16卷 1079-1089页

作者： Jiaxi Lin Zhen Yao Xiaomei Lyu lidan ye Hongwei Yu Institute of Bioengineering College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310027China Hangzhou Global Scientific and Technological Innovation Center Zhejiang UniversityHangzhou 311200China Key Laboratory of Systems Microbial Biotechnology Tianjin Institute of Industrial BiotechnologyChinese Academy of SciencesTianjin 300308China School of Food Science and Technology Jiangnan UniversityWuxi 214122China

Conflict between cell growth and product accumulation is frequently encountered in the biosynthesis of secondary metabolites. To address the growth-production conflict in yeast strains harboring the isoprene synthetic pathway in the mitochondria, the dynamic control of isoprene biosynthesis was explored. A dual temperature regulation system was developed through engineering and expression regulation of the transcriptional activator Gal4p. A cold-sensitive mutant, Gal4ep19, was created by directed evolution of Gal4p based on an internally developed growth-based high-throughput screening method and expressed under the heat-shock promoter PSSA4 to control the expression of PGAL-driven pathway genes in the mitochondria. Compared to the control strain with constitutively expressed wild-type Gal4p, the dual temperature regulation strategy led to 34.5% and 72% improvements in cell growth and isoprene production, respectively. This study reports the creation of the first cold-sensitive variants of Gal4p by directed evolution and provides a dual temperature control system for yeast engineering that may also be conducive to the biosynthesis of other high-value natural products.

关键词： transcriptional activator directed evolution dynamic control heat-shock isoprene

Combinatorial metabolic engineering of Saccharomyces cerevisiae for improved production of 7-dehydrocholesterol

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Engineering Microbiology 2023年第4期3卷 29-37页

作者： Yuehao Gu Shuhui Chen Xue Jiao Qi Bian lidan ye Hongwei Yu Key Laboratory of Biomass Chemical Engineering(Education Ministry) College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310058China Institute of Bioengineering College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310058China

7-Dehydrocholesterol(7-DHC),a key pharmaceutical intermediate in the production of vitamin D3,has a wide range of *** explore fermentative synthesis of 7-DHC,a 7-DHC-producing Saccharomyces cerevisiae strain was constructed by blocking the competitive pathway,eliminating rate-limiting steps,altering global reg-ulation,and pathway *** blocking the competitive pathway by disrupting ERG5 and ERG6 and introducing DHCR24 from Gallus gallus,*** produced 139.72 mg/L(17.04 mg/g dry cell weight,hereafter abbreviated as DCW)*** alteration of global regulation by deleting ROX1 and overexpressing UPC2-1 increased 7-DHC production to 217.68 mg/L(37.56 mg/g DCW).To remove the accu-mulated squalene,the post-squalene pathway was strengthened by co-overexpression of PGAL1-driven ERG11 and PGAL10-driven ERG1,which improved 7-DHC titer and yield to 281.73 mg/L and 46.78 mg/g DCW,respectively,and reduced squalene content by 90.12%.We surmised that the sterol precursors in the plasma membrane and peroxisomes may not be accessible to the pathway enzymes,thus we re-localized DHCR24p and Erg2p-GGGGS-Erg3p to the plasma membrane and peroxisomes,boosting 7-DHC production to 357.53 mg/L(63.12 mg/g DCW).Iron supplementation further increased 7-DHC production to 370.68 mg/L in shake flasks and 1.56 g/L in fed-batch *** study demonstrates the power of global regulation and subcellular relocalization of key enzymes to improve 7-DHC synthesis in yeast.

关键词： 7-Dehydrocholesterol Saccharomyces cerevisiae Metabolic engineering Global regulation Pathway re-localization

A novel Trmt5-deficient zebrafish model with spontaneous inflammatory bowel disease-like phenotype

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Signal Transduction and Targeted Therapy 2023年第3期8卷 928-931页

作者： Qiong Zhao Hui Chang Jing Zheng Ping Li lidan ye Ruolang Pan Di Li Jian-Zhong Shao Robert Chunhua Zhao ye Chen Department of Genetics and Department of Genetic and Metabolic DiseaseThe Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China College of Life Sciences Key Laboratory for Cell and Gene Engineering of Zhejiang ProvinceZhejiang UniversityHangzhou 310052China Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders Institute of GeneticsZhejiang UniversityHangzhou 310052China Key Laboratory for Food Microbial Technology of Zhejiang Province Zhejiang Gongshang UniversityHangzhouChina Institute of Bioengineering College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310027China Zhejiang Provincial Key Laboratory of Cell‐Based Drug and Applied Technology Development Institute for Cell‐Based Drug Development of Zhejiang ProvinceHangzhouChina

Dear Editor,Inflammatory bowel disease(IBD),a complex syndrome characterized by chronic inflammation of the gastrointestinal tract,is considered a global health problem,especially prevalent in western developed countries and with accelerating incidence in the developing world over the last decade.1 To date,the primary etiology of IBD remains elusive.

关键词： inflammation bowel gastrointestinal

Redesign of a short-chain dehydrogenase/reductase for asymmetric synthesis of ethyl (R)-2-hydroxy-4-phenylbutanoate based on per-residue free energy decomposition and sequence conservatism analysis

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Green Synthesis and Catalysis 2020年第2期1卷 150-159页

作者： Bingmei Su Lian Xu Xinqi Xu Lichao Wang Aipeng Li Juan Lin lidan ye Hongwei Yu College of Chemical Engineering Fuzhou UniversityFuzhou 350116China College of Biological Science and Engineering Fuzhou UniversityFuzhou 350116China Institute of Bioengineering College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310027China School of Life Sciences Northwestern Polytechnical UniversityXi’an 710072China

As an important building block for the synthesis of angiotensin-converting enzyme inhibitors,ethyl(R)-2-hy-droxyl-4-phenylbutanoate[(R)-HPBE]has attracted increasing *** key to industrial biosynthesis of(R)-HPBE is a biocatalyst that efficiently reduces ethyl 2-oxo-4-phenylbutanoate(OPBE)with high *** paper proposed a strategy for identifying key residues involved in enantioselectivity control based on per-residue free energy decomposition and sequence conservatism *** this strategy,4 noncon-servative sites with high energy contribution to binding of OPBE were chosen as engineering targets,generating variant Mu27 with 99%conversion and 98%(R)ee value at substrate loading of up to 500 mmol/*** simu-lations suggested the higher stability and formation probability of Mu27-OPBEproR prereaction state as key rea-sons for the excellent R-enantioselectivity of Mu27 towards *** success in this study provides a viable approach for rational design of alcohol dehydrogenases with high enantioselectivity towards unnatural substrates.

关键词： Ethyl(R)-2-hydroxy-4-phenylbutanoate Rational design Enantioselectivity Short-chain dehydrogenase/reductase Per-residue free energy decomposition Sequence conservatism analysis

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代谢改造酿酒酵母合成萜类化合物的研究进展

生物工程学报 2021年第6期37卷 2085-2104页

作者：陈明凯叶丽丹于洪巍浙江大学化学工程与生物工程学院浙江杭州310027

萜类化合物是一类种类繁多、功能多样的化合物,部分具有抗癌、增强免疫力等作用,具有良好的生物活性,在食品、保健品以及医疗等领域应用广泛。近年来,随着对萜类化合物生物合成途径研究的深入,研究人员采用代谢工程手段构建了多种萜类... 详细信息

萜类化合物是一类种类繁多、功能多样的化合物,部分具有抗癌、增强免疫力等作用,具有良好的生物活性,在食品、保健品以及医疗等领域应用广泛。近年来,随着对萜类化合物生物合成途径研究的深入,研究人员采用代谢工程手段构建了多种萜类产物的高产酿酒酵母工程菌株,部分已经达到或者接近工业化生产水平。因此,采用合成生物学相关技术手段合成萜类化合物,有望取代化学合成或者传统的提取模式,成为天然萜类产物的新型生产方法。文中以常见的几种萜类产物为例,介绍并探讨萜类产物的生物合成策略以及合成生物学方面的研究进展。

关键词：萜类化合物酿酒酵母代谢改造调控策略生物合成

合成生物学中动态代谢途径调控策略的研究进展

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生物产业技术 2019年第1期 55-61页

作者：周萍萍叶丽丹于洪巍扬州大学生物科学与技术学院扬州225009 浙江大学化学工程与生物工程学院杭州310027

随着合成生物学的发展,越来越多的天然高附加值化学品和大宗化学品可以通过在微生物底盘细胞中构建人工合成途径来进行生产。然而外源途径基因的不平衡表达以及有毒中间代谢产物的积累往往会影响宿主细胞的正常生长,这也是合成生物学研... 详细信息

随着合成生物学的发展,越来越多的天然高附加值化学品和大宗化学品可以通过在微生物底盘细胞中构建人工合成途径来进行生产。然而外源途径基因的不平衡表达以及有毒中间代谢产物的积累往往会影响宿主细胞的正常生长,这也是合成生物学研究中的一个共性难题。因此设计可控的基因表达系统,在特定时刻启动或者关闭人工合成途径,对于避免细胞生长和产物合成之间的相互干扰至关重要。重点介绍了最新的动态代谢调控策略及其在代谢途径调控中的应用,并对其发展趋势进行了展望。

关键词：合成生物学人工合成途径不平衡表达动态代谢调控

单侧椎弓根旁入路BKP手术对骨质疏松性胸腰椎压缩骨折患者疼痛程度、胸腰椎功能及骨折恢复的影响

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临床医学工程 2024年第4期31卷 437-438页

作者：叶兴益李丽丹福州市罗源县医院骨科福建福州350600

目的探讨单侧椎弓根旁入路骨填充网袋椎体成形术(BKP)治疗骨质疏松性胸腰椎压缩骨折(OVCF)患者的临床效果。方法74例OVCF患者随机分为两组。在单侧椎弓根旁入路下,观察组行BKP治疗,对照组行经皮椎体后凸成形术(PKP)治疗。结果两组术后的... 详细信息

目的探讨单侧椎弓根旁入路骨填充网袋椎体成形术(BKP)治疗骨质疏松性胸腰椎压缩骨折(OVCF)患者的临床效果。方法74例OVCF患者随机分为两组。在单侧椎弓根旁入路下,观察组行BKP治疗,对照组行经皮椎体后凸成形术(PKP)治疗。结果两组术后的VAS评分、ODI评分及伤椎Cobb角均低于术前,伤椎前缘高度均高于术前(P0.05)。观察组的骨水泥注入量多于对照组,骨水泥渗漏发生率低于对照组(P<0.05)。结论单侧椎弓根旁入路BKP手术在缓解OVCF患者疼痛、恢复伤椎前缘高度、改善腰椎功能方面可以取得与PKP相似的效果,并能够降低骨水泥渗漏发生率。

关键词：骨质疏松性胸腰椎压缩骨折单侧椎弓根旁入路骨填充网袋椎体成形术疼痛程度

B cells biology in systemic lupus erythematosus—from bench to bedside

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Science China(Life Sciences) 2015年第11期58卷 1111-1125页

作者： ZHAO lidan ye YanXia ZHANG Xuan Department of Rheumatology & Clinical Immunology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Systemic lupus erythematosus(SLE) is a debilitating autoimmune disease that can involve multi-organs. B cells play a central role in the immunopathogenesis via antibody-dependent and antibody-independent ways. Excessive autoantibodies production, hyperresponsiveness and prolonged survival of autoreactive B cells are characteristics of SLE. In this article, mechanisms of self-tolerance loss of B cells and promising B cell-targeting therapies in lupus are reviewed and discussed.

关键词： systemic lupus erythematosus B cell pathogenesis target therapy

生物催化技术制备手性酸医药化学品的研究进展

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合成化学 2023年第6期31卷 476-496页

作者：江千姿王博姜灵于洪巍叶丽丹浙江大学化学工程与生物工程学院浙江杭州310027 山东科技大学化学与生物工程学院山东青岛266590 浙江工业大学绿色制药协同创新中心浙江湖州313200

手性酸是一类重要的有机化合物,在医药工业、农药工业等领域有着广泛的应用。生物催化法制备手性酸因其具有立体选择性高、反应条件温和和环境友好等优点而受到科研工作者的高度重视。本文综述了近年来利用生物催化技术制备手性酸医药... 详细信息

手性酸是一类重要的有机化合物,在医药工业、农药工业等领域有着广泛的应用。生物催化法制备手性酸因其具有立体选择性高、反应条件温和和环境友好等优点而受到科研工作者的高度重视。本文综述了近年来利用生物催化技术制备手性酸医药化学品的研究进展,重点研究了生物催化技术制备非甾体抗炎药、非天然氨基酸以及其他手性酸的方法,并对该领域的研究情况进行了总结与展望。

关键词：生物催化手性酸医药化学品非甾体抗炎药固定化酶 3-环己烯-1-甲酸普瑞巴林