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[前沿资讯 ] 新型工程酶变体可拓展环亚胺酸结构多样性 进入全文
科学网
中国科学院上海药物研究所研究员廖苍松课题组与中国科学院天津工业生物技术研究所研究员盛翔课题组合作，利用聚焦理性迭代位点特异性突变（FRISM）策略，对脱羧醛缩酶UstD进行了半理性工程改造，调控了UstD对邻位二酮亲电试剂的区域选择性和立体选择性，获得的工程酶变体具有极佳的选择性和较广的底物谱，拓展了环亚胺酸的结构多样性。1月15日，相关研究在线发表于《德国应用化学》。研究团队使用FRISM的半理性策略开展酶工程改造研究，通过酶变体设计探索底物结合口袋的残基对选择性的调控机制。经过三轮突变后得到的UstD2.0AAM对产物1c的转化率为46%，选择性为90%，对产物2b的转化率为72%，选择性为94%。研究人员解析了2b的立体构型，并高选择性地合成了共计30种在α和γ位置具有立体中心的环状亚胺酸，实现了百毫克规模的制备反应，收率达89%。分子动力学模拟研究表明，ApUstD和UstD2.0AAM两种酶活性位点空腔大小和疏水性存在明显差异，这些差异导致了底物在口袋内具有不同的结合构象，也是不同酶表现出不同反应选择性的根本原因。
[学术文献 ] Multi-Modal CLIP-Informed Protein Editing 进入全文
Health Data Science
Background: Proteins govern most biological functions essential for life, and achieving controllable protein editing has made great advances in probing natural systems, creating therapeutic conjugates, and generating novel protein constructs. Recently, machine learning-assisted protein editing (MLPE) has shown promise in accelerating optimization cycles and reducing experimental workloads. However, current methods struggle with the vast combinatorial space of potential protein edits and cannot explicitly conduct protein editing using biotext instructions, limiting their interactivity with human feedback. Methods: To fill these gaps, we propose a novel method called ProtET for efficient CLIP-informed protein editing through multi-modality learning. Our approach comprises 2 stages: In the pretraining stage, contrastive learning aligns protein–biotext representations encoded by 2 large language models (LLMs). Subsequently, during the protein editing stage, the fused features from editing instruction texts and original protein sequences serve as the final editing condition for generating target protein sequences. Results: Comprehensive experiments demonstrated the superiority of ProtET in editing proteins to enhance human-expected functionality across multiple attribute domains, including enzyme catalytic activity, protein stability, and antibody-specific binding ability. ProtET improves the state-of-the-art results by a large margin, leading to substantial stability improvements of 16.67% and 16.90%. Conclusions: This capability positions ProtET to advance real-world artificial protein editing, potentially addressing unmet academic, industrial, and clinical needs.
[科技报告 ] OECD Synthetic biology in focus: Policy issues and opportunities in engineering life 进入全文
OECD
Synthetic biology promises to revolutionise a swath of industrial activities and create new ones by tailoring living systems to produce a range of products to boost economies, transform health and contribute to solving grand societal challenges. In 2023 and 2024, over sixty experts from around the globe came together regularly to explore where synthetic biology will have the most impact, identify the challenges and opportunities in developing and deploying synthetic biology around the world, and to explore areas where policy could help. This working paper provides a synthesis of this scoping activity, providing an accessible text for those new to the rapidly evolving area of synthetic biology.
[科技报告 ] The Stanford Emerging Technology Review 2025 (Biotechnology and Synthetic Biology) 进入全文
Stanford University
KEY TAKEAWAYS • Biotechnology is poised to emerge as a general-purpose technology by which anything bioengineers learn to encode in DNA can be grown whenever and wherever needed— essentially enabling the production of a wide range of products through biological processes across multiple sectors. • The US government is still working to grasp the scale of this bio-opportunity and has relied too heavily on private-sector investment to support the foundational technology innovation needed to unlock and sustain progress. • Biotechnology is one of the most important areas of technological competition between the United States and China, and China is investing considerably more resources. Lacking equivalent efforts domestically, the United States runs the risk of Sputnik-like strategic surprises in biotechnology. Overview Biotechnology partners with biology to create products and services, like engineering skin microbes to fight cancer or brewing medicines from yeast. This industry, already 5 percent of US GDP, is poised for significant growth. Synthetic biology, a subset of biotechnology focusing on enhancing living systems, relies on DNA sequencing and synthesis. DNA sequencers are machines that read or decode specific DNA molecules, while synthesizers write user-specifi ed sequences of DNA. Rapid progress in these technologies is driving innovation and expanding biotechnology’s potential applications. Biology as a manufacturing process is distributed; leaves do not come from a central production facility but rather grow on trees everywhere. However, commercial biotechnology has become centralized and capital intensive. This contrast suggests a potential paradigm shift toward a more distributed approach in biotechnology, aligning it more closely with nature’s decentralized production model. Synthetic biology merges biology, engineering, and computer science to modify and create living systems, developing novel biological functions served by amino acids, proteins, and cells not found in nature. This fi eld creates reusable biological “parts,” streamlining design processes and reducing the need to start from scratch, thus advancing biotechnology’s capabilities and efficiency. Synthetic biology has applications in medicine, agriculture, manufacturing, and sustainability. DNA and RNA synthesis underlies all mRNA vaccines, including those for COVID-19. Synthetic biology can also cultivate drought-resistant crops and enable cells to be programmed to manufacture medicines or fuel on an agile, distributed basis. Key Developments Distributed biomanufacturing This offers unprecedented production flexibility in both location and timing. Fermentation production sites can be established anywhere with access to sugar and electricity. This approach enables swift responses to sudden demands like disease outbreaks requiring specific medications. Such adaptability revolutionizes manufacturing, making it more efficient and responsive to urgent needs. Biology as a general-purpose technology Currently, biotechnology is used to make medicines, foods, and a narrow range of sustainable materials. But anything whose synthesis can be encoded in DNA could be grown. For example, some bacteria are capable of growing arrays of tiny magnets, and select sea sponges grow glass filaments similar to human-made fiber-optic cables. These and other examples suggest the potential for biology to be recognized as a general-purpose technology that could become the foundation of a more resilient manufacturing base. Biological large language models (BioLLMs) Large language models (LLMs), which are a form of artificial intelligence, have emerged that are being trained on natural DNA, RNA, and protein sequences. Called BioLLMs, they can generate new biologically significant sequences that are helpful points of departure for designing useful proteins.
[学术文献 ] Integrating protein language models and automatic biofoundry for enhanced protein evolution 进入全文
Nature Communications
Traditional protein engineering methods, such as directed evolution, while effective, are often slow and labor-intensive. Advances in machine learning and automated biofoundry present new opportunities for optimizing these processes. This study devises a protein language model-enabled automatic evolution platform, a closed-loop system for automated protein engineering within the Design-Build-Test-Learn cycle. The protein language model ESM-2 makes zero-shot prediction of 96 variants to initiate the cycle. The biofoundry constructs and evaluates these variants, and feeds the results back to a multi-layer perceptron to train a fitness predictor, which then makes prediction of second round of 96 variants with improved fitness. With the tRNA synthetase as a model enzyme, four-rounds of evolution carried out within 10 days lead to mutants with enzyme activity improved by up to 2.4-fold. Our system significantly enhances the speed and accuracy of protein evolution, driving faster advancements in protein engineering for industrial applications.
[学术文献 ] Semirationally Engineering an Efficient P450 Peroxygenase for Regio- and Enantioselective Hydroxylation of Steroids 进入全文
ACS Catalysis
Enzymatic direct hydroxylation of unactivated C–H bonds in steroids provides a promising approach to enrich their structural and functional diversity, together with higher physiological and pharmacological activity. Here, we construct an efficient peroxide-driven P450 hydroxylase for the regio- and enantioselective hydroxylation of steroids. The NADH-dependent CYP154C5 monooxygenase is smoothly transformed into its peroxygenase mode by combining the strategies of H2O2 tunnel engineering and the introduction of a catalytic aspartate residue, which avoids the use of expensive nicotinamide cofactors and redox partner proteins. The variant F92A/R114A/E282A/T248D (AAA/T248D) quantitatively converted testosterone and nandrolone into the corresponding 16α-hydroxylation products, showing the best catalytic efficiency (kcat/Km) for testosterone hydroxylation among all known natural and engineered P450 peroxygenases to date. Crystal structural analysis and molecular dynamics simulations suggest that H2O2 tunnel engineering plays a crucial role in promoting the flow of H2O2 into active centers, and the introduced aspartate residue may participate in the activation of H2O2. Moreover, the milligram-scale preparation of 16α-hydroxytestosterone by AAA/T248D gave a substrate conversion rate (>98%) and an isolated yield (90%), suggesting potential for synthetic application. This work not only establishes a feasible semirational approach to engineered non-natural P450 peroxygenases but also provides a potentially practical approach for the enzymatic synthesis of hydroxylated steroid compounds.
