MOLECULAR NEUROBIOLOGY
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2025
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IF 4.3
Chen Xue,Zhou Xing-Yue,Lan Cai,Fu Hai-Jun,Li Zhi-Chao,Chen Meng-Yi,Wen Yong-Ping,Yu Lu,Qin Da-Lian,Wu An-Guo,Wu Jian-Ming,Zhou Xiao-Gang
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata , as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.
研究领域:
神经科学
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药理学
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分子生物学
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神经退行性疾病
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细胞生物学
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天然产物化学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Qiong Wang,Mei Zhao,Hossain M. Zabed,Xinrui Tang,Jiaojiao Chen,Jiayin Wang,Haoyang Li,Xianghui Qi
The discovery of novel heat-resistant lipases has the potential to broaden their applications in the food industry and other fields. This study identified a novel heat-resistant lipase PFHL from Pseudomonas fluorescens HK44 based on data-driven mining, which was subsequently expressed in Escherichia coli for its molecular insights into substrate specificity. The purified PFHL demonstrated optimal activity at 60 °C and pH 7.0 with a half-life of 2.52 h and retained 48.23% of its relative activity at 90 °C. The enzyme exhibited a substrate preference for medium-chain fatty acid esters, displaying a catalytic efficiency kcat/Km of 134.31 mM–1·min–1 toward 4-nitrophenyl laurate (pNPC12), 1.45-fold higher than that for 4-nitrophenyl palmitate (pNPC16). Additionally, molecular docking and molecular dynamics simulations were performed to elucidate the mechanism underlying its substrate specificity and catalytic efficiency. The results revealed that pNPC12 fit the catalytic pocket better than pNPC16, and the complex exhibited greater stability during the simulation. Up to seven hydrogen bonds were formed, and the substrate was able to rapidly reach and position itself within the catalytic pocket. These findings offer valuable insights into PFHL’s substrate preferences, laying the groundwork for its rational design and further optimization to enhance its suitability for industrial applications in the future.
研究领域:
生物技术
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酶学
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结构生物学
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工业酶
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食品科学
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计算生物学
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ENZYME AND MICROBIAL TECHNOLOGY
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2025
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IF 3.7
Yingying Zhu,Dawei Ni,Zeyu Li,Zhebin Hao,Liang Wang,Wanmeng Mu
Indigo is an important blue pigment widely used in textile, food, and medicine industries. Biological production of indigo attracts increasing attention recently. Cell factory production of indigo encounters the problem of the toxicity of the precursor indole. Enzymatic production is the alternative biological approach, however, NADPH regeneration should be solved. In this study, flavin-containing monooxygenase from Methylophaga aminisulfidivorans was used for enzymatic production of indigo from indole and formate dehydrogenase from Pseudomonas sp. 101 was co-expressed for NADPH regeneration. Indigo production was enhanced by combination of molecular modification, promoter engineering, and translation initiation region engineering. Finally, 0.183 g/L of indigo was produced from 0.5 g/L of indole and 0.5 mM of sodium formate, with the conversion ratio of 32.5 %. This study demonstrates a feasible and effective strategy for enzymatic production of indigo.
研究领域:
生物催化
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酶促合成
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代谢工程
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工业微生物学
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应用生物化学
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AICHE JOURNAL
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2025
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IF 4
Hanchi Chen,Shijie Lu,Liying Zha,Yazhou Lu,Qixin Wang,Linjiang Zhu,Xiaolong Chen
This study presents an approach combining molecular dynamics (MD) simulations and near-attack conformation (NAC) analysis to mine and engineer UDP-glucosyltransferases. Using the MD-NAC strategy, we identified that Bs YjiC from Bacillus subtilis possesses menthol glycosylating activity for the first time, and it exhibited a 28% higher k cat / K M value compared to the known l- menthol glycosylating enzyme, Bl YjiC from Bacillus licheniformis . The strategy was further employed to modify Bs YjiC by preventing nonproductive substrate motion and stabilizing NACs through engineering key residues identified by MD. Based on this strategy, 14 positive mutants were identified out of 16 candidates, and the double mutant A76D/V108L (M2) demonstrated a 10.64-fold increase in k cat / K M value compared to the starting point. Whole-cell cascade reactions with sucrose synthase yield 160 mM glucoside after catalyzing for 96 h, demonstrating its application merit. This work underscores MD-driven enzyme engineering as a promising strategy to overcome limitations of static structure-based approaches.
研究领域:
结构生物学
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计算生物学
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酶工程
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生物化学
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合成生物学
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WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
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2025
·Vol. 41
·期 8
·1-13
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IF 4.2
Jiang Cheng,Li Luli,Li Jialu
Chitinolytic enzymes are capable of hydrolyzing the cell walls of pathogenic fungi, disrupting the exoskeletons of insect pests, and producing N-acetyl-β-D-glucosamine oligomers or monomers. In this study, a new β-N-acetylhexosaminidase gene encoding an enzyme from glycoside hydrolase family 20 (GH 20) was identified from the biocontrol fungus Chaetomium globosum W7. The corresponding protein was designated CgNagase20 and was heterologously expressed in Escherichia coli . The molecular mass of the protein was approximately 66.7 kDa, and this enzyme exhibited maximal activity at 55 °C and pH 4.0. Heavy metal ions, particularly Fe 3+ , Ag + , and Hg 2+ , were found to strongly inhibit CgNagase20 activity. CgNagase20 exhibits typical substrate specificity of β-N-acetylhexosaminidase (EC 3.2.1.52), acting on N-acetylglucosides and N-acetylgalactosides, with monosaccharides as the sole end products. The Vmax and Km values for CgNagase20 when acting on 4-nitrophenyl N-acetyl-β-D-glucosaminide (pNP-βGlcNAc) were calculated to be 118.85 µmol/min/mg protein and 1.59 mM, respectively. Additionally, CgNagase20 demonstrated antifungal activity, significantly inhibiting spore germination and hyphal growth of Fusarium sporotrichioides , the causative agent of potato dry rot. In conclusion, CgNagase20 represents the first β-N-acetylhexosaminidase identified and characterized from C. globosum , with potential applications in both the industrial and agricultural sectors.
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Biomaterials Science
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2025
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IF 5.7
Yan Wang,Suyuan Su,Chaofeng Wang,Congyang Mao,Xiangmei Liu,Hanpeng Liu,Zhaoyang Li,Shengli Zhu,Hui Jiang,Zhenduo Cui,Yufeng Zheng,Shuilin Wu
Persistent bacterial infections and the imbalance in immune regulation induced by oxidative stress present a significant challenge in diabetic wound healing. In this study, we developed a novel dual-network hydrogel system composed of chitosan/polyacrylic acid (PEC) and polyoxometalate PMo12 (PMo12-PEC) loaded with baicalein (BA), designated as PMo12-BA-PEC, for the treatment of methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds. The hydrogel demonstrated enhanced mechanical strength and elasticity, facilitating effective wound adherence and accommodating tissue movement. Upon 808 nm near-infrared (NIR) light irradiation, the photothermal properties of PMo12 enabled controlled low-temperature hyperthermia and accelerated BA release. Remarkably, the hydrogel achieved an antibacterial efficacy of 99.45% ± 0.12% against MRSA following 5 minutes of NIR exposure, while exhibiting potent antioxidant and anti-inflammatory capabilities to scavenge reactive oxygen species and mitigate inflammatory responses. Comprehensive evaluation revealed that the PMo12-BA-PEC hydrogel significantly promoted angiogenesis, enhanced collagen deposition, inhibited bacterial growth, and modulated immune regulation, thereby accelerating the wound healing process in diabetic rat models. These findings suggest that the PMo12-BA-PEC hydrogel represents a promising biomaterial platform for clinical management of diabetic wounds and potential treatment of oxidative stress-related disorders.
研究领域:
生物医学工程
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药理学
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免疫学
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Qingao Xue,Ze Liang,Yi Zhang,Fei Wang,Fulian Wang,Lili Liu,Guang Yang,Lei Yan
The membrane fusion process mediated by the SARS-CoV-2 spike protein is a key therapeutic target. Its heptad repeat 1 (HR1) domain forms a conserved trimeric groove critical for forming the fusion-competent six-helix bundle with HR2. We used DNA-encoded library screening to identify small molecules binding HR1. Hits including Rabeprazole-related compound E (Rab RCE), Omeprazole, Alvimopan, and Olmesartan were characterized. Biophysical assays confirmed binding, while computational simulations revealed distinct interaction modes, with Alvimopan showing high predicted affinity. Cell-cell fusion assays demonstrated potent inhibitory activity for Olmesartan and Rab RCE. Notably, Rabeprazole and Rab RCE showed partial antiviral activity against SARS-CoV-2 variants and HCoV-OC43, rescuing virus-induced apoptosis. Mechanistically, Rabeprazole competitively occupies the HR2-binding groove on HR1, blocking fusion. Our findings identify HR1-targeting molecules like Rabeprazole as promising leads for broad-spectrum coronaviral fusion inhibitors.
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SCIENCE
·
2026
·Vol. 391
·期 6780
·
IF 45.8
Qihan Jin,Yukai Wang,Dachuan Chen,Jinyang Liao,Zhanyuan Cui,Yuxuan Fan,Anping Zeng,Mingqi Xie,Longxing Cao
Small molecule–regulated protein oligomerization provides a powerful mechanism for manipulating biological processes by controlling protein proximity with high temporal precision. However, such systems only rarely exist in nature and remain a substantial challenge for de novo design. In this work, we describe a computational method for designing protein homooligomers whose assembly is regulated by small-molecule ligands with matching symmetry. We designed protein homotrimers regulated by the Food and Drug Administration (FDA)–approved drug amantadine and further designed amantadine-responsive heterodimers and heterotrimers. Biophysical characterization confirmed their amantadine-dependent assembly, and their crystal structures closely matched the design models. We demonstrated their broad applicability in controlling protein localization, membraneless condensate formation, and gene expression. Our approach opens new avenues for designing small molecule–responsive proteins and expands the chemogenetic toolkit for manipulating complex biological processes.
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Cell Chemical Biology
·
2026
·Vol. 33
·期 1
·102-116
·
IF 7.2
Yucheng Guo,Zhenlin Ouyang,Wenbo He,Qian Qin,Jiaxin Zhang,Ting Yu,Min Jiao,Peter M. Hwang,Fang Zheng,Serge Muyldermans,Yurong Wen
Enterotoxigenic Bacteroides fragilis (ETBF) promotes colonic inflammation by secreting metalloenzyme toxins (BFTs). Understanding BFT mechanisms and developing neutralization strategies is critical. Here, we have solved the structures of BFT-1 and BFT-2, revealing that residue 357 in the active site of the catalytic domain explains the diversity of function observed in BFT subtypes. We demonstrate that BFTs can directly cleave human epithelial-cadherin at extracellular domain 4, with BFT-2 possessing the highest activity. Using an alpaca antibody library, we identified a single-domain antibody, Nb2.43, targeting the BFTs. Nb2.43 can neutralize all three subtypes of BFT by directly binding the metalloenzyme catalytic zinc ion with its CDR3 antigen-binding loop. Furthermore, Nb2.43 blocks cleavage of E-cadherin by BFT and prevents the damage caused by ETBF in vitro and in a mouse colitis model. This work provides structural insights into BFT diversity and delivers a therapeutic nanobody against ETBF-mediated inflammation.
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JOURNAL OF HAZARDOUS MATERIALS
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2026
·
IF 11.3
Quanfu Wang,Xingshun Li,Yatong Wang,Yanhua Hou
The persistent accumulation of poly(butylene adipate-co-terephthalate) (PBAT) in the environment poses severe ecological threats. While enzymatic degradation offers promise, most reported enzymes require elevated reaction temperatures. Furthermore, free enzymes often suffer from limitations such as poor stability and high production costs. This study identified and characterized an innovative cold-adapted arylesterase (CsAE). CsAE exhibited optimum activity at 20℃ while retaining 48.77 % residual activity at 0℃, demonstrating characteristics of a cold-adapted enzyme. The engineered bacterium BL21/pET-INPN-CsAE, constructed via INPN surface display technology, exhibited normal growth while maintaining outer membrane integrity. Compared to the free CsAE, the whole-cell catalyst exhibited markedly enhanced thermal stability, reusability, and long-term operational stability. Notably, the observed features on the PBAT film—including the appearance of pores and cracks, a decrease in the water contact angle, cleavage of ester bonds, a reduction in the amorphous phase, and the emergence of the degradation monomer terephthalic acid—collectively indicate that both CsAE and the engineered strain facilitated the degradation of PBAT. Bioremediation experiments confirmed that the engineered strain mediated a 20.46 % degradation of PBAT over 21 days at 15℃, demonstrating its efficacy under low-temperature conditions. Collectively, this work establishes INPN-mediated surface display of the cold-adapted CsAE as a sustainable biocatalytic strategy for PBAT remediation in cold environments.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
·
IF 6.1
Ye Wang,Heshi Tian,Qiannan Li,Zhenhua Ma,Yunna Jia,Xiaojun Liang,Xiuzhen Yu,Xiuyun Jiang,Yunhang Gao
Tylosin (TYL), a widely used macrolide antibiotic in livestock and poultry production, has attracted considerable attention owing to its strong adsorption capacity, persistence, and ecological risks in aquatic and soil environments. Because of their high efficiency and substrate specificity, microbial degradation enzymes are among the most promising agents for removing TYL from the environment. In this study, α/β hydrolase (Rcmd-2829) was expressed and purified from Kurthia gibsonii TYL-A1. The results showed that the optimum reaction conditions for Rcmd-2829 were pH 9.0 and 30°C. Molecular docking analyses, molecular dynamics simulations, and site-directed mutagenesis confirmed the key role of the Ser-102 residue in the catalytic degradation of TYL by Rcmd-2829. Rcmd-2829 retained its high catalytic activity in aquaculture wastewater, removing 83 % of 150 mg/L of TYL within 5 d. This study is the first to elucidate the Ser-102-dependent molecular mechanism underlying TYL degradation by the α/β hydrolase Rcmd-2829, providing a foundation for the development of efficient enzymatic-remediation technologies.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
·
IF 6.2
Xiaoxiao Li,Ying Chen,Zhengyu Jin,Yuxiang Bai
The GH70 family 4,3/6-α-glucanotransferase efficiently converted readily digestible (α1→4) glycosidic bonds into (α1→3) or (α1→6) glycosidic bonds, thus serving as an effective enzymatic tool for preparing starch-based dietary fiber. Amino acid residues, including V1409, Q1397, T1366, K1362, H1369, and N1418 of Limosilactobacillus fermentum NCC 2970 GtfB 4,3-α-glucanotransferase (Lf2970 GtfB), were found via sequence conservation analysis and tunnel engineering for further analysis. Mutants from K1362, T1366, H1369, and N1418 at the tunnel entrance showed increased enzyme activity and catalytic efficiency but reduced molecular weight of products. The mutant Q1397P within the tunnel increased the proportion of (α1→6) bonds in the products to 7.9% and (α1→3) bonds to 26.3%, from the wild-type of 1.2% and 21.9%, respectively. These results indicated that amino acid residues located at the tunnel entrance regulated the enzyme activity and product size of Lf2970GtfB, while the Q1397 site within the tunnel regulated the type and proportion of glycosidic bonds.
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