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高通量技术在萜类合成酶筛选中的应用

微生物学报 2024年第2期64卷 408-431页

作者：李贝邓子新徐敏侯安伟中国科学院天津工业生物技术研究所天津300308 合成生物学海河实验室天津300308 江西省科学院微生物研究所江西南昌330096

萜类化合物种类繁多,生物活性多样,在食品、药品与化妆品等行业中具有广泛的应用。萜类化合物多来源于植物,然而随着合成生物学的快速发展,相较于传统的天然植物提取与化学合成方法,利用工程微生物进行萜类化合物异源合成的方法显得更... 详细信息

萜类化合物种类繁多,生物活性多样,在食品、药品与化妆品等行业中具有广泛的应用。萜类化合物多来源于植物,然而随着合成生物学的快速发展,相较于传统的天然植物提取与化学合成方法,利用工程微生物进行萜类化合物异源合成的方法显得更为经济与环保。萜类合成酶的催化活性及合成产物的结构特性是萜类化合物异源合成的关键。通过蛋白定向进化与理性设计可以有针对性地优化萜类合成酶的催化性能及产物专一性,但该方案需要一个特异的筛选方法来实现蛋白突变体库的高通量筛选。近年来,一系列高通量筛选方法的建立使得萜类合成酶的筛选变得更加灵敏与高效。本文对近期建立的萜类合成酶高通量筛选方法进行了综述,简要概述了各种筛选方法的基本原理与优缺点,并对高通量筛选技术在萜类合成酶改造中的应用做出了展望。

关键词：高通量筛选萜类合成酶定向进化萜类化合物

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麦角硫因在游动放线菌底盘中的高效合成

微生物学报 2024年第8期64卷 2752-2767页

作者：刘震常莹莹邓子新刘天罡武汉大学药学院组合生物合成与新药发现教育部重点实验室湖北武汉430071 上海交通大学生命科学技术学院微生物代谢国家重点实验室上海200240

【目的】麦角硫因是一种稀有的天然氨基酸类强抗氧化剂,在机体内发挥着重要的生理功能,并在食品、医药、化妆品领域得到广泛应用。然而,传统的从蕈菇中提取和化学合成的方法存在收率低、成本高等问题,本研究期望利用代谢工程改造,提高... 详细信息

【目的】麦角硫因是一种稀有的天然氨基酸类强抗氧化剂,在机体内发挥着重要的生理功能,并在食品、医药、化妆品领域得到广泛应用。然而,传统的从蕈菇中提取和化学合成的方法存在收率低、成本高等问题,本研究期望利用代谢工程改造,提高游动放线菌(Actinoplanes sp.)HS中麦角硫因的产量。【方法】首先通过生物信息学分析,锁定了Actinoplanes ***中可能参与麦角硫因合成的基因;接着在大肠杆菌(Escherichia coli)BL21(DE3)中进行异源表达,进一步鉴定了这些基因的功能;最后将鉴定功能的基因组合后在Actinoplanes ***中进行高表达,对突变株产量进行测定,并通过在发酵培养基中添加不同浓度的前体,探究其对发酵产量的影响。【结果】Actinoplanes ***中基因BC03-04016、BC03-04015、BC03-04014、BC03-04013所编码的酶可以合成麦角硫因前体组氨酸甜菜碱半胱氨酸亚砜(hercynine-cysteine-sulphoxide,HER-Cys-Sul),基因BC03-04046和BC03-04917所编码的酶都具有裂解碳硫键的功能,可以催化前体HER-Cys-Sul形成终产物麦角硫因。将编码麦角硫因合成的基因高表达后得到的突变株YC313和YC314,其麦角硫因产量分别达到125 mg/L和108 mg/L,较出发菌株Actinoplanes ***分别提高至2.9倍和2.5倍。在发酵培养基中额外添加0.35 g/L的甲硫氨酸后,YC313菌株的麦角硫因产量相较于原始培养基提高了24%;额外添加10 g/L的黄豆饼粉后,相较于原始培养基麦角硫因产量提高了19%。【结论】本研究对Actinoplanes ***中麦角硫因合成的相关基因及其功能进行了鉴定,通过代谢工程改造得到了两株麦角硫因高产菌株,并进一步研究了前体供应对麦角硫因产量的影响,为以游动放线菌为底盘生产麦角硫因提供了策略支持。

关键词：麦角硫因游动放线菌高产菌株

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DNA硫修饰结合蛋白的序列偏好性表征及应用

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科学通报 2024年第21期69卷 3064-3066页

作者：帅玉婷贺新义邓子新刘光上海交通大学生命科学技术学院微生物代谢国家重点实验室上海200240

DNA表观修饰在生命体中广泛存在,它们往往通过其特异性的识别蛋白来发挥功能^([1~3]).DNA硫修饰(phosphorothioate DNA,PT-DNA)是一种近年来发现的新型DNA大分子修饰,其化学本质是DNA磷酸二酯键中的一个非桥接氧原子被硫原子取代所形成... 详细信息

DNA表观修饰在生命体中广泛存在,它们往往通过其特异性的识别蛋白来发挥功能^([1~3]).DNA硫修饰(phosphorothioate DNA,PT-DNA)是一种近年来发现的新型DNA大分子修饰,其化学本质是DNA磷酸二酯键中的一个非桥接氧原子被硫原子取代所形成的磷硫酰化修饰^([4,5]);DNA硫修饰可以被硫结合结构域(sulfur binding domain,SBD)特异性识别和结合,从而参与细菌限制修饰系统等生命过程^([6~8]).

关键词：限制修饰系统磷酸二酯键硫原子发挥功能结合蛋白特异性识别化学本质偏好性

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儿童情绪绘本中安慰语的语用策略分析——以“儿童情绪管理与性格培养绘本”丛书为例

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桂林师范高等专科学校学报 2024年第1期38卷 81-88,94页

作者：邓子欣李旭东华理工大学文法与艺术学院江西南昌330013

安慰策略是指说话人为安慰听话人而实施的安慰计划,选择合适的安慰策略可以更好地消除他人的消极情绪。本文选取“儿童情绪管理与性格培养绘本”丛书中的安慰语为语料,以面子理论、礼貌原则和言语行为理论为理论基础,对实施安慰语的策... 详细信息

安慰策略是指说话人为安慰听话人而实施的安慰计划,选择合适的安慰策略可以更好地消除他人的消极情绪。本文选取“儿童情绪管理与性格培养绘本”丛书中的安慰语为语料,以面子理论、礼貌原则和言语行为理论为理论基础,对实施安慰语的策略进行了分类:第一类,针对听话人A的安慰策略;第二类,针对事件B的安慰策略;第三类,针对消极情绪C及其产生的消极影响D的安慰策略。实施安慰语策略的特点包括:一是始终遵循得体准则,灵活运用礼貌原则;二是多种策略相互作用,实施鼓励和回避策略的频率较高;三是遵循儿童情绪发展的规律,实施否决策略的频率较低。

关键词：安慰语安慰策略语用分析情绪儿童

羊毛硫肽SapB类多肽促进链霉菌形态分化作用的研究

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微生物学报 2024年第1期64卷 268-282页

作者：单泓俊王俊博林百欣王柯惠邓子新由德林孔令新上海交通大学生命科学技术学院微生物代谢国家重点实验室上海200030

【目的】链霉菌属于革兰氏阳性菌,以复杂的形态分化过程和强大的次级代谢产物合成能力为主要特征。链霉菌的形态分化与次级代谢产物的产生密切相关。Ⅲ型羊毛硫肽SapB能够促进天蓝色链霉菌气生菌丝体形成,暗示这类多肽可以作为靶标用于... 详细信息

【目的】链霉菌属于革兰氏阳性菌,以复杂的形态分化过程和强大的次级代谢产物合成能力为主要特征。链霉菌的形态分化与次级代谢产物的产生密切相关。Ⅲ型羊毛硫肽SapB能够促进天蓝色链霉菌气生菌丝体形成,暗示这类多肽可以作为靶标用于形态分化改造工程开发。本研究表征了SapB类多肽对多种链霉菌形态分化的影响,为该类多肽的工程化应用提供理论基础。【方法】生物信息学分析多个链霉菌基因组中SapB类多肽的生物合成基因簇,构建SapB类多肽的异源表达载体,利用接合转移方法导入不同链霉菌中进行异源表达,探究SapB类多肽对链霉菌形态分化的影响。【结果】SapB类多肽在不同程度上促进了多个链霉菌由营养菌丝向气生菌丝分化,表现为气生菌丝体数量的增多和分化速度的加快,缩短了链霉菌形态分化周期。【结论】SapB类多肽的过表达有助于缩短链霉菌形态分化周期,可用于针对链霉菌形态分化的工程改造。

关键词：链霉菌形态分化气生菌丝羊毛硫肽 SapB

Methylation in hangtaimycin biosynthesis and its antibacterial activities

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Synthetic and Systems Biotechnology 2023年第4期8卷 682-687页

作者： Minghe Luo Yulu Dong zixin deng Yuhui Sun School of Pharmacy and Bioengineering Chongqing University of TechnologyChongqingChina Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Educationand School of Pharmaceutical SciencesWuhan UniversityWuhanChina

About two-thirds of small molecule drugs contain methyl group and it plays a very important role in the drug ***,methyltransferases catalyzing the methylation have always attracted great ***(HTM)is a potent hepatoprotective *** study showed that its biosynthetic gene cluster contained three methyltransferase domains,but their characteristics in HTM biosynthetic pathway has not been *** this study,we clarified multi-methylations in HTM biosynthesis in *** showed that the two S-adenosylmethionine-dependent methyltransferases(SAM-MTs)of HtmA2(-module 6)-MT domain and HtmB2(-module 18)-MT domain are responsible for the installation of methyl group at C-45 and N-12,respectively,whereas the FK506 methyltransferase(FKMT)type O-methyltransferase of HtmB1(-module 16)-MT domain take care of the methylation at O-21 of *** also reported the antibacterial activities of HTM in this study,and found that it showed activities against ***,*** and *** with MIC of 4μg/mL,4μg/mL,and 64μg/mL,respectively.

关键词： Hangtaimycin Methylation S-Adenosylmethionine-dependent methyltransferases FK506 methyltransferase type O-methyltransferase Antibacterial Biosynthesis

Reprograming yeast for anti-cancer vinblastine synthesis

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Life Metabolism 2022年第3期1卷 207-208页

作者： Tian Ma zixin deng CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China State Key Laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic&Developmental Sciencesand School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200030China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of EducationZhongnan Hospitaland School of Pharmaceutical SciencesWuhan UniversityWuhanHubei 430072China

In a recent study published in Nature,Zhang et *** an innovative approach by reprogramming and engineering yeast strain for combined biosynthesis of vindoline and catharanthine,followed by an additional in vitro chemical step for the successful synthesis of the anti-cancer *** and utilization of plant resources have played indispensable roles in the treatment of human diseases,which had been an amazing focus of biomedical research for *** indole alkaloids(MIAs),the plant secondary metabolites that mainly exist in Gentianales,had been a popular family of the medicinal drug research because of their remarkable structural diversities and biological activities.

关键词： synthesis programming alkaloids

Exploiting synthetic regulatory elements for non-dominant microorganisms

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Synthetic and Systems Biotechnology 2022年第2期7卷 839-840页

作者： Xuyuan Wang Mersa Darbandsari Lixin Zhang zixin deng State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai200237China School of Life Sciences and Biotechnology Shanghai Jiao Tong UniversityShanghai200240China

Engineered genetic devices and gene circuits can reprogram cellular behaviors towards different applications in synthetic biology domains,such as detection of small molecular metabolites,biosynthesis of chemicals or proteins valuable for agriculture,food,chemical and pharmaceutical *** of the main barriers for these approaches is the lack of genetic regulatory elements with ideal characteristics in different *** of these synthetic elements has been rapidly boosted in the last few years,fueled mostly by generating of artificial promoters,libraries of ribosome binding site(RBS)or 5’untranslated regions(UTRs),genetic switches,protein degrons,*** of the flexibility of usage and great number of regulatory components accessible,many synthetic biology studies and applications have been conducted in microorganisms utilizing the model Escherichia coli or Saccharomyces cerevisiae.

关键词： elements utilizing generating

Evaluation and optimization of analytical procedure and sample preparation for polar Streptomyces albus J1074 metabolome profiling

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Synthetic and Systems Biotechnology 2022年第3期7卷 949-957页

作者： Shuai Fu Ziheng An Liangliang Wu Zilei Xiang zixin deng Ran Liu Tiangang Liu Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical SciencesWuhan UniversityWuhan430072Hubei ProvinceChina Hubei Engineering Laboratory for Synthetic Microbiology Wuhan Institute of BiotechnologyWuhan430075Hubei ProvinceChina State Key Laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic and Developmental SciencesSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai200030China CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong518055China

Metabolomics is an essential discipline in omics technology that promotes research on the biology of microbial *** albus J1074 is a model organism used in fundamental research and industrial ***,a comprehensive and standardized method for analyzing the metabolome of *** J1074 is yet to be ***,we comprehensively evaluated and optimized the analytical procedure and sample preparation for profiling polar metabolites using hydrophilic interaction liquid chromatography(HILIC)coupled with high-resolution mass spectrometry(HRMS).We systematically examined the HILIC columns,quenching solutions,sample-to-quenching ratios,and extraction ***,the optimal protocol was used to investigate the dynamic intracellular polar metabolite profile of the engineered *** J1074 strains during spinosad(spinosyn A and spinosyn D)fermentation.A total of 3648 compounds were detected,and 83 metabolites were matched to the *** intracellular metabolomic profiles of engineered *** J1074 strains(ADE-AP and OE3)were detected;furthermore,their metabolomes in different stages were analyzed to reveal the reasons for their differences in their spinosad production,as well as the current metabolic limitation of heterologous spinosad production in *** *** HILIC-HRMS method is a valuable tool for investigating polar metabolomes,and provides a reference methodology to study other Streptomyces metabolomes.

关键词： Metabolomics Streptomyces Spinosad Hydrophilic interaction liquid chromatography High resolution mass spectrometry