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[前沿资讯 ] 魏茨曼科学研究所报道高效Kemp消除酶的完整计算设计 进入全文
科学网
魏茨曼科学研究所Sarel J. Fleishman研究团队报道了高效Kemp消除酶的完整计算设计。2025年6月18日，国际知名学术期刊《自然》发表了这一成果。 该研究团队提出了一个完全计算的工作流程，用于在TIM桶折叠中设计高效的酶，从天然蛋白质中提取主干片段，而无需通过突变文库筛选进行优化。三种Kemp消能设计的效率均大于 2,000 M−1 s−1。最有效的方法显示了来自任何天然蛋白质的140多个突变，包括一个新的活性位点。它具有高稳定性（大于85°C）和显著的催化效率（12,700 M−1 s−1）和速率（2.8s-1），比以前的计算设计高出两个数量级。 此外，设计一种在所有以前的Kemp消除设计中被认为是必不可少的残留物，可将效率提高到105 M−1 s−1，比率提高到30 s−1，实现与天然酶相当的催化参数，挑战基本的生物催化假设。通过克服设计方法上的限制，他们的策略使通过最小的实验努力就能编程出稳定、高效、全新的酶。 据了解，到目前为止，计算设计的酶表现出较低的催化速率，并且需要大量的实验优化才能达到与天然酶相似的活性水平。这些结果暴露了设计方法的局限性，并表明他们对生物催化基础知识的理解存在重大差距。
[前沿资讯 ] 天津工业生物技术研究所等开发高效裂殖壶菌CRISPR/Cas9基因编辑技术创制高产多不饱和脂肪酸的细胞工厂 进入全文
中国科学院天津工业生物技术研究所
中国科学院天津工业生物技术研究所李德茂研究员团队与哈尔滨工业大学陈国福团队合作成功开发出了高效的裂殖壶菌CRISPR/Cas9体系，并利用其介导的代谢工程创制了高产多不饱和脂肪酸的细胞工厂。研究团队首先开发了一种新型的农杆菌介导的筛选系统，基于醋酸盐的转化子筛选方式，将S. limacinum SR21的转化效率提高77.13%。其次通过挖掘内源Pol III型启动子（tRNAGly）并利用其驱动的CRISPR/Cas9 表达系统，实现了对裂殖壶菌的基因编辑，编辑效率达48.38%。最后，将已建立的遗传操作系统应用于裂殖壶菌生产DHA和EPA的代谢工程。其中，针对EPA，研究团队对裂殖壶菌中不完整的脂肪酸合成酶（FAS）途径进行重新组合，实现了从FAS源EPA的从头生物合成。针对DHA，通过实施“推-拉-阻”的代谢工程策略方式强化了裂殖壶菌的油脂合成途径。与野生型菌株相比，工程菌株的油脂含量、DHA比例和多不饱和脂肪酸含量分别提高至77.14%、55.10%和70.47%。该研究为推进裂殖壶菌多不饱和脂肪酸生物合成的商业化应用奠定了关键技术基础。
[前沿资讯 ] 天津工业生物技术研究所成功开发新型代谢工程靶点设计算法 进入全文
中国科学院天津工业生物技术研究所
中国科学院天津工业生物技术研究所生物设计中心以自然界“节能高效”的自由能与酶资源的精准协同调控为灵感，提出ET-OptME框架，首次将酶约束与热力学约束协同引入代谢靶点设计算法，显著提升预测的生理真实性和实验可行性。ET-OptME由两个核心算法组成：ET-EComp通过比较不同状态下的酶浓度范围识别上调/下调酶，ET-ESEOF则扫描目标通量增加过程中的酶浓度变化趋势，捕捉调控信号。该框架还引入“蛋白中心”策略，跳出传统的反应层级靶点预测，解决了预测的多功能酶时可能出现的难以统一调控方向的难题。在谷氨酸棒状杆菌的五种工业产物案例中，ET-OptME在最小精确度指标上比计量学算法提升292%以上，准确度提高106%；与当前先进的酶约束算法相比，ET-OptME也保持70%的精度优势和47%的准确度优势。本研究还在代谢层面深入分析了关键靶点如pyc、gapA与leuA预测成功的原因，展示出酶-热约束靶点预测算法在提升路径效率和避免代谢瓶颈上的显著优势。
[前沿资讯 ] 天津工业生物技术研究所在技术驱动非粮原料生物制造微生物蛋白的前沿综述 进入全文
中国科学院天津工业生物技术研究所
中国科学院天津工业生物技术研究所吴信研究员团队从技术迭代的角度，全面梳理了微生物蛋白生物制造的变革，系统总结了利用液态（甲醇）、气态（CO2、甲烷）和固态（木质纤维素）等非粮原料规模化合成微生物蛋白的前沿技术突破，揭示了合成生物学与交叉技术创新如何重塑微生物蛋白生物制造系统。本团队前期的工作围绕甲醇作为一种可再生的C1化合物以及与二氧化碳氢化合成技术的重大突破，通过碳氮协同耦合代谢工程与基因组扰动等多重策略，有效提升天然甲基营养菌中甲醇向单细胞蛋白的定向转化效率，进而突破工业菌株性能极限，为利用甲醇作为碳源生物制造微生物蛋白大规模工业化生产提供了关键技术支持；在气态非粮生物制造微生物蛋白方面，通过构建大肠杆菌中的光-暗反应能量适配器，实现光驱动CO2同化的全细胞催化过程；通过电催化-生物耦合技术，可将电化学还原CO2生成的甲酸盐与微生物同化模块精准对接，为气态非粮原料的转化技术开辟了负碳生物制造微生物蛋白的新维度；在固态非粮原料生物合成微生物蛋白技术方面，该团队通过机器学习模型，基于木质纤维素结构特性破译出降解酶系组成的新算法，进而摆脱复杂性底物结构-多样性酶系构效关系的实验先验，精准定制了多种地源性木质纤维素来源的微生物蛋白，达到地源性农业废弃物资源利用与微生物蛋白生物合成“一草双收”效果。这些创新转化模式不仅提升了农业废弃物资源化利用经济价值，更开辟了农业废弃物规模化生物合成微生物蛋白的工业化新路径。
[科研项目 ] 美国匹兹堡大学“通过基于蛋白质纳米隔室的酶封装技术促进生物降解去除有机污染物”项目获美国国家科学基金会55万美元资助 进入全文
U.S. National Science Foundation
Many natural microorganisms, such as bacteria and fungi, can be used to degrade toxic pollutants and remediate contaminated sites. These microorganisms use a series of enzymes, called cascade enzymes, to break down pollutants step by step into less toxic end products. However, this process is slow and often allows toxic intermediates to accumulate. The goal of this CAREER project is to make biodegradation more efficient. The project will develop a new biotechnology, called protein nano-compartment (PNC)-based cargo encapsulation. Cascade enzymes will be encapsulated within PNCs, which will enable the enzymes to degrade pollutants and intermediates at similar rates. Toxic intermediates will not accumulate in the environment. The research will be integrated with education of students from middle schools and colleges. Successful completion of this project will create a more efficient, robust, and faster environmental remediation technology to protect human and environmental health. This CAREER project plans to apply PNC-based enzyme co-localization to accelerate biodegradation efficiency in removing organic water contaminants. The central hypothesis is that attaching enzymes with affinity tags of varying molecular properties will allow their tunable co-localization within PNCs, thereby enabling optimization and enhancement of the kinetics and stability of enzyme cascades for contaminant degradation. The study will integrate techniques in biodegradation, synthetic biology, and metabolic flux analysis to systematically characterize the effect of PNC co-localization on enzyme cascade efficiency. The proposed work will establish quantitative correlations between affinity tag properties and enzyme encapsulation efficiency. Building on these correlations, the study will explore how to strategically control the co-localization of biodegradative cascade enzymes within PNCs and analyze how this co-localization affects their kinetics in contaminant removal and stability against environmental factors under controlled in vitro conditions. Lastly, the PNC co-localization of biodegradative cascade enzymes will be assessed under cellular environments, and isotope-labeled metabolic flux analysis will be employed to develop a fundamental understanding of how the in vivo co-localization affects the rate, flux, and specificity of organic contaminant biodegradation in cells. The project includes an education plan aiming to 1) foster the education of college students in STEM and their participation in environmental engineering; 2) educate and train next-generation environmental engineers on the fundamentals, real-world applications, and opportunities of PNC encapsulation and biodegradation; and 3) promote public awareness and understanding of biodegradation as a sustainable solution for environmental protection and remediation. These educational activities will be integrated throughout to improve academic success and broaden participation of college students in research, stimulate STEM interest in 6-12 graders, train a future workforce on biodegradation through research projects, and build a biodegradation website for public education and outreach. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
[学术文献 ] Growth of the maternal intestine during reproduction 进入全文
Cell
The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.
