Biochimica et biophysica acta. Proteins and proteomics最新文献_第2页

Comparative proteomic profiling of advanced, injectable, and titanium-prepared platelet rich fibrins (PRF): Insights into functional divergence and clinical potential 晚期，可注射和钛制备的富血小板纤维蛋白（PRF）的比较蛋白质组学分析：功能差异和临床潜力的见解。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-12-17 DOI: 10.1016/j.bbapap.2025.141121

Sri Vidhya Marimuthu , Tamizhini Loganathan , Muthukumar Santhanakrishnan , C. George Priya Doss , Magesh Ramasamy

Platelet-rich fibrin (PRF) has emerged as a pivotal autologous biomaterial in regenerative medicine. Yet, comparative proteomic insights into its diverse formulations advanced PRF (A-PRF), injectable PRF (I-PRF), and titanium-prepared PRF (T-PRF) remain scarce. This study presents a comprehensive proteomic characterization of A-PRF, I-PRF, and T-PRF, employing imputed intensity data, principal component analysis (PCA), correlation matrices, and differential expression analysis. PCA identified distinct clustering patterns, reinforcing reproducible and formulation-specific proteomic signatures. Correlation and intensity distribution analyses demonstrated strong intra-group consistency, with A-PRF exhibiting the highest reproducibility, whereas T-PRF displayed greater variability. Differential expression analysis further delineated significant inter-group molecular variations, revealing unique proteomic compositions. Protein-protein interaction (PPI) network analysis identified key regulatory proteins such as fibrinogen alpha (FGA), fibrinogen beta (FGB), and fibronectin 1 (FN1), In contrast, enrichment analyses revealed biological processes related to coagulation, platelet activation, immune modulation, and extracellular matrix dynamics. Functional pathway mapping underscored divergent biological roles, A-PRF was enriched in coagulation-related pathways, while I-PRF linked to lipid metabolism and immune signaling. These findings validate the molecular distinctiveness of PRF variants and establish a proteomic framework for their precision-driven application in tissue engineering and regenerative therapy.

富血小板纤维蛋白（PRF）已成为再生医学中关键的自体生物材料，但对其不同配方的比较蛋白质组学见解-先进PRF (a -PRF)，可注射PRF （I-PRF）和钛制PRF （T-PRF）仍然很少。本研究采用输入强度数据、主成分分析（PCA）、相关矩阵和差异表达分析，对a - prf、I-PRF和T-PRF进行了全面的蛋白质组学表征。主成分分析确定了不同的聚类模式，加强了可重复性和配方特异性蛋白质组学特征。相关性和强度分布分析显示了很强的组内一致性，A-PRF具有最高的可重复性，而T-PRF具有更大的变异性。差异表达分析进一步描绘了显著的组间分子变异，揭示了独特的蛋白质组学组成。蛋白-蛋白相互作用（PPI）网络分析确定了关键的调节蛋白，如纤维蛋白原α (FGA)、纤维蛋白原β (FGB)和纤维连接蛋白1 (FN1)，而富集分析揭示了包括凝血、血小板活化、免疫调节和细胞外基质动力学在内的生物过程。功能途径图谱强调了不同的生物学作用，A-PRF富集于凝固相关途径，而I-PRF与脂质代谢和免疫信号传导有关。这些发现验证了PRF变体的分子独特性，并为其在组织工程和再生治疗中的精确应用建立了蛋白质组学框架。

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引用次数: 0

MetIoR: A meta predictor to predict intrinsic disorder in RNA binding proteins MetIoR：预测RNA结合蛋白内在紊乱的meta预测因子。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-12-17 DOI: 10.1016/j.bbapap.2025.141119

Swarnadip Mitra , Ranjit Prasad Bahadur

Intrinsic disorder in proteins is ubiquitous in nature across various proteomes. The association of intrinsically disordered proteins (IDP) with a large variety of biomolecules is essential in many cellular functions. Moreover, IDPs are involved in many macromolecular assemblies including ribosome and spliceosome. Intrinsic disorder has been reported in several RNA binding proteins (RBPs), which makes the study of disordered regions in RBPs crucial. Experimental difficulties in accurately determining the structure of proteins with disordered regions using biophysical techniques necessitates their computational prediction. A large number of available computational tools have been developed to predict disordered residues in proteins, but the majority of them are generic in nature. In this study, we have addressed the lack of specific intrinsic disorder predictors in RBPs. We have developed MetIoR, a prediction tool specifically trained on RBPs, to predict intrinsically disordered regions in RBP using a meta-approach. We have developed our meta predictor, which requires a protein sequence, using five individual disorder predictors. We have employed a number of machine learning classifiers with stratified ten-fold cross validation and selected the best method in terms of prediction metrics. We have also examined the most optimal combination of individual predictors. MetIoR developed using Random Forest is fast, accurate and outperforms all its individual component predictors achieving an accuracy of 93.87 %, and a high AUC value of 0.91. The developed meta predictor is deployed as the MetIoR webserver, which can be freely accessed at http://www.csb.iitkgp.ac.in/applications/MetIoR/index.php

蛋白质的内在紊乱在自然界中普遍存在于各种蛋白质组中。内在无序蛋白（IDP）与多种生物分子的结合在许多细胞功能中是必不可少的。此外，IDPs还参与许多大分子组装，包括核糖体和剪接体。一些RNA结合蛋白（rbp）存在内在紊乱，这使得对rbp紊乱区域的研究变得至关重要。使用生物物理技术精确测定具有无序区域的蛋白质结构的实验困难需要它们的计算预测。目前已经开发了大量可用的计算工具来预测蛋白质中的无序残基，但它们中的大多数本质上是通用的。在这项研究中，我们解决了rbp缺乏特定的内在障碍预测因子的问题。我们开发了MetIoR，这是一种专门针对RBP进行训练的预测工具，可以使用元方法预测RBP的内在无序区域。我们开发了我们的元预测器，它需要一个蛋白质序列，使用五种个体疾病预测因子。我们使用了许多具有分层十倍交叉验证的机器学习分类器，并选择了预测指标方面的最佳方法。我们还研究了个体预测因子的最优组合。使用Random Forest开发的MetIoR快速，准确，优于其所有单个成分预测器，准确率达到93.87 %，AUC值高达0.91。开发的元预测器作为MetIoR web服务器部署，可以在http://www.csb.iitkgp.ac.in/applications/MetIoR/index.php上免费访问。

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引用次数: 0

Nitrated products formed on α-synuclein are preferentially incorporated into oligomers but excluded from fibrils: A mechanism for accumulation of neurotoxic species 在α-突触核蛋白上形成的硝化产物优先被纳入低聚物，但被原纤维排除在外：神经毒性物质积累的机制

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-12-10 DOI: 10.1016/j.bbapap.2025.141118

Daniel E. Otzen , Luke F. Gamon , Per Hägglund , Janni Nielsen , Jannik N. Pedersen , Tina Nybo , Jan S. Nowak , Søren K. Amstrup , Mitra Pirhaghi , Michael J. Davies

Post-translational modifications (PTMs) such as nitration of Tyr (Y) residues and di-tyrosine (DT) formation are known to impact the aggregation behavior of α-synuclein (α-syn), a protein closely linked to Parkinson's disease. Using tetranitromethane (TNM) as a model nitrating agent, we systematically investigated the chemical modifications of α-syn and their consequences for aggregation. Mass spectrometry analysis revealed site-selective nitration of all four Tyr residues, with Y39 and Y125 being most susceptible. DT crosslinks were also observed, primarily involving Y39, but were disfavored at higher TNM concentrations, indicating competition between nitration and crosslinking pathways. Higher TNM concentrations favored nitration over crosslinking, consistent with common radical intermediates. Even sub-stoichiometric amounts of TNM-modified α-syn significantly inhibited fibril elongation, suggesting that nitration disrupts the templated addition of monomers into the ordered fibrillar structure. Consistent with this, TNM-modified α-syn was strongly excluded from fibrillar assemblies. In contrast, they were preferentially incorporated into soluble oligomers, underlining the promiscuous ability of oligomers to act as a sink for chemically modified α-syn monomers, with potential implications for neurotoxicity.

翻译后修饰（PTMs），如Tyr (Y)残基的硝化和二酪氨酸（DT）的形成，已知会影响α-突触核蛋白（α-syn）的聚集行为，α-突触核蛋白是一种与帕金森病密切相关的蛋白质。以四硝基甲烷（TNM）为模型硝化剂，系统研究了α-syn的化学修饰及其对其聚集的影响。质谱分析显示，4个Tyr残基均具有选择性硝化作用，其中Y39和Y125最敏感。还观察到DT交联，主要涉及Y39，但在较高的TNM浓度下不受欢迎，这表明硝化和交联途径之间存在竞争。较高的TNM浓度有利于硝化而不是交联，这与常见的自由基中间体一致。即使是亚化学计量量的tnm修饰α-syn也能显著抑制纤维伸长，这表明硝化破坏了单体在有序纤维结构中的模板添加。与此一致的是，tnm修饰的α-syn被强烈地排除在纤维组装中。相反，它们被优先结合到可溶性低聚物中，强调了低聚物作为化学修饰α-syn单体的汇的混杂能力，具有潜在的神经毒性。

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引用次数: 0

LncRNA CERS6 - AS1 mediates the IGF2BP1/LIN28B axis to promote proliferation, migration and invasion in ovarian cancer LncRNA CERS6 - AS1介导IGF2BP1/LIN28B轴促进卵巢癌的增殖、迁移和侵袭。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-23 DOI: 10.1016/j.bbapap.2025.141117

Jia Hang , Huiwen Sun , Chengzhen Gao, Yan Zhu, Lijuan Yang, Yan Li

Ovarian cancer remains a significant clinical challenge for women's health, making it imperative to elucidate its underlying molecular mechanisms. LncRNA CERS6-AS1 and LIN28B-binding proteins play a vital role in the development of ovarian cancer. The expression levels of CERS6-AS1 and LIN28B in ovarian cancer tissues and cell lines were evaluated using qPCR. Protein levels were analyzed through IHC. The survival rate was assessed using the Kaplan-Meier curve. LIN28B or CERS6-AS1 was silenced via RNA interference (shRNA), and the effects on proliferation, migration, and invasion were examined through cell cloning, scratch assays, and Transwell assays. RNA pull-down and RIP experiments confirmed the binding of CERS6-AS1 to IGF2BP1 and enhances on the stability of LIN28B mRNA. Finally, LIN28B overexpression was performed for functional recovery experiments. Elevated expression of CERS6-AS1 and LIN28B was observed in both clinical ovarian cancer specimens and derived cell lines. The knockdown of LIN28B suppressed ovarian cancer cell proliferation, migration and invasion. Molecular investigations revealed that CERS6-AS1 stabilized LIN28B through IGF2BP1 binding. Furthermore, CERS6-AS1 depletion similarly attenuated malignant phenotypes, effects that were rescued by LIN28B overexpression. Collectively, the CERS6-AS1-regulated IGF2BP1/LIN28B signaling axis promoted ovarian cancer progression by enhancing tumor cell proliferation, migration and invasion, highlighting this pathway as a promising therapeutic target.

卵巢癌仍然是妇女健康的重大临床挑战，阐明其潜在的分子机制势在必行。LncRNA CERS6-AS1和lin28b结合蛋白在卵巢癌的发展中起着至关重要的作用。采用qPCR技术检测卵巢癌组织和细胞系中CERS6-AS1和LIN28B的表达水平。通过免疫组化分析蛋白水平。采用Kaplan-Meier曲线评估生存率。通过RNA干扰（shRNA）沉默LIN28B或CERS6-AS1，并通过细胞克隆、scratch实验和Transwell实验检测其对增殖、迁移和侵袭的影响。RNA pull-down和RIP实验证实了CERS6-AS1与IGF2BP1的结合，增强了LIN28B mRNA的稳定性。最后，通过过表达LIN28B进行功能恢复实验。在临床卵巢癌标本和衍生细胞系中均观察到CERS6-AS1和LIN28B的表达升高。敲低LIN28B可抑制卵巢癌细胞的增殖、迁移和侵袭。分子研究表明，CERS6-AS1通过IGF2BP1结合稳定了LIN28B。此外，CERS6-AS1缺失类似地减弱了恶性表型，这种效应被LIN28B过表达所挽救。综上所述，cers6 - as1调控的IGF2BP1/LIN28B信号轴通过增强肿瘤细胞的增殖、迁移和侵袭来促进卵巢癌的进展，这表明该途径是一个有希望的治疗靶点。

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引用次数: 0

Flexibility in acidophilic thioredoxins: Insights from Asp43 substitutions in E. coli thioredoxin 嗜酸硫氧还蛋白的灵活性：来自大肠杆菌硫氧还蛋白Asp43取代的见解。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-19 DOI: 10.1016/j.bbapap.2025.141115

Oanh Mai Ho, Mohammed Shazaly A. Elhassan, Khang Nguyen, ChangWoo Lee

Thioredoxins (Trxs) are small, highly conserved oxidoreductases characterized by a redox-active CXXC motif. While the structural adaptation of modern Trxs such as Escherichia coli Trx (EcTrx) has been described, the mechanisms underlying Trx adaptation to acidic environments remain unclear. In EcTrx, Asp43 stabilizes the active-site region through a water-mediated hydrogen bond with Lys57, which modulates the protonation state of Cys32 in cooperation with Asp26. Comparative sequence analysis shows that small, nonpolar amino acids—such as Gly and Ala—are frequently found at position 43 in acidophilic Trxs, indicating that structural flexibility at this position may contribute to acidic adaptation. To test how substitutions at position 43 affect Trx stability and function, we generated EcTrx mutants (D43G, D43A, D43S, D43N, D43L, and D43E). Thermal shift and guanidinium chloride-induced unfolding assays revealed that D43A and D43S markedly reduced stability, while D43G retained moderate stability, likely due to tighter N-terminal packing as observed in the acidophilic Acetobacter aceti Trx. These three mutants also displayed increased conformational flexibility, whereas D43N and D43L conferred partial stabilization through polar or hydrophobic side chains. In contrast, D43E—mimicking ancestral Glu—restored hydrogen bonding and enhanced thermal stability, resulting in the most rigid structure. Most mutants retained catalytic activity in DTNB assays, except D43S, which showed 50% of wild-type activity. Overall, our results demonstrate that Asp43 is critical for maintaining EcTrx structural stability and suggest that enhanced, but not excessive, flexibility at this position facilitates Trx adaptation to acidic environments.

硫氧还毒素（Trxs）是一种小而高度保守的氧化还原酶，其特征是具有氧化还原活性的CXXC基序。虽然现代Trx如大肠杆菌Trx （EcTrx）的结构适应性已经被描述，但Trx适应酸性环境的机制尚不清楚。在EcTrx中，Asp43通过水介导的与Lys57的氢键稳定活性位点区域，与Asp26合作调节Cys32的质子化状态。比较序列分析显示，在亲酸Trxs的43号位置经常发现小的非极性残基，如Gly和ala，这表明该位点的结构灵活性可能有助于酸性适应。为了测试该位点的替换如何影响Trx的稳定性和功能，我们在43号位置生成了EcTrx突变体（D43G, D43A, D43S, D43N， D43L和D43E）。热移和氯化胍（GdmCl）诱导的展开实验显示，D43A和D43S的稳定性显著降低，而D43G保持中等稳定性，这可能是由于在嗜酸乙酰杆菌Trx中观察到的更紧密的n端包装。这三个突变体也表现出增加的构象灵活性，而D43N和D43L通过极性或疏水侧链赋予部分稳定性。相比之下，d43e -模拟祖先的glue恢复了氢键，增强了热稳定性，形成了最刚性的结构。除D43S外，大多数突变体在DTNB试验中保持催化活性，其活性为野生型的~ 50% %。总之，我们的研究结果表明，Asp43对于维持EcTrx的结构稳定性至关重要，并表明该位点增强但不是过度的灵活性有助于Trx适应酸性环境。

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引用次数: 0

Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases 薯蓣皂苷元在神经退行性疾病中预防蛋白质聚集作用的分子研究。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-19 DOI: 10.1016/j.bbapap.2025.141116

Nagma Parveen , Faizan Abul Qais , Mohammad Faheem

Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with −11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA₂₈₂_–₂₉₂ oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ₁₆_–₂₂) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.

神经退行性疾病（ND）如帕金森氏症和阿尔茨海默氏症逐渐损害神经系统，导致认知退化和运动功能障碍。这些疾病的一个主要因素是错误折叠的蛋白质聚集体的积累，它干扰细胞过程并最终导致神经元死亡。阻止这些有毒聚集体的形成有可能保护神经元并减缓疾病的进展。本研究以人血清白蛋白（HSA）为模型蛋白，研究了薯蓣皂苷元对蛋白质聚集的影响。薯蓣皂苷元使ThT荧光降低64.35 %，浊度降低62.61 %，表明对蛋白质聚集有明显的抑制作用。α-螺旋从57.68 %下降到8.82 %，薯蓣皂苷元处理后恢复到43.89 %。结合研究表明，薯蓣皂苷元与HSA相互作用的结合能为-11.0 kcal/mol，通过范德华、疏水和氢键相互作用，并通过分子模拟验证了HSA-薯蓣皂苷元配合物的稳定性。为了进一步阐明薯蓣皂苷元的聚集抑制机制，采用先进的分子动力学模拟方法。diogenin提高了HSA282-292低聚物的溶剂亲和性，减少了β-sheet的形成，并阻止了h -键相互作用，这是聚集体形成的关键因素。对Aβ低聚物（Aβ16-22）的分子模拟也表明薯蓣皂苷元可以抑制α β低聚和β-薄片的形成。我们发现薯蓣皂苷元由于其稳定蛋白质结构和抑制蛋白质聚集的能力而提供了一个很有希望的替代方案，使其成为nd的潜在治疗候选者。然而，进一步的动物模型实验验证是必要的，以确认薯蓣皂苷元的抗聚集作用，特别是淀粉样蛋白形成。

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引用次数: 0

Enhancement of the nucleotide incorporation activity of the terminal deoxynucleotidyl transferase by N-terminal truncation and DNA-binding protein modulation 通过n端截断和dna结合蛋白调节增强末端脱氧核苷酸转移酶的核苷酸结合活性。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-12 DOI: 10.1016/j.bbapap.2025.141114

Antos B. Sachanka, Stafaniya S. Douhaya, Veronika V. Shchur, Aliaksei V. Yantsevich

Terminal deoxynucleotidyl transferase (TdT) is a unique DNA polymerase that catalyzes the template-independent addition of nucleotides to the 3′ terminus of single-stranded DNA. Its distinctive catalytic properties have been exploited in aptasensor design, nanomaterial synthesis, DNA mutagenesis, innovative data storage based on single-nucleotide DNA sequences, and enzymatic de novo DNA synthesis. However, the application of the enzyme is limited by its low expression yield, poor thermostability, and reduced nucleotide incorporation efficiency with substrates prone to forming secondary structures. To overcome these limitations, we engineered a bovine TdT variant truncated at the N-terminus by 148 residues (148_TrTdT), which demonstrates a twofold increase in expression yield, a 5 °C improvement in thermostability, and over 30 % enhancement in nucleotide incorporation efficiency and processivity compared to the wild-type enzyme. Moreover, we demonstrated that DNA-binding proteins enhance the nucleotide incorporation activity of native TdT (10-fold) and 148_TrTdT (2-fold) when substrates are prone to forming secondary structures. Collectively, the methodologies implemented in this study exhibit significant potential for enhancing the efficiency of enzymatic de novo DNA synthesis, thereby enabling the development of new bioengineering and biomedical applications.

末端脱氧核苷酸转移酶（TdT）是一种独特的DNA聚合酶，它催化核苷酸在单链DNA 3'端独立于模板的添加。其独特的催化特性已被用于配体传感器设计、纳米材料合成、DNA诱变、基于单核苷酸DNA序列的创新数据存储和酶促从头合成DNA。然而，该酶的应用受到其表达量低、热稳定性差以及与底物形成二级结构的核苷酸结合效率降低的限制。为了克服这些限制，我们设计了一个在n端被148个残基截断的牛TdT变体（148_TrTdT），与野生型酶相比，其表达量增加了两倍，热稳定性提高了5 °C，核苷酸结合效率和加工效率提高了30 %以上。此外，我们还证明，当底物易于形成二级结构时，dna结合蛋白可增强天然TdT（10倍）和148_TrTdT（2倍）的核苷酸结合活性。总的来说，本研究中实施的方法在提高酶促从头DNA合成的效率方面表现出巨大的潜力，从而使新的生物工程和生物医学应用得以发展。

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引用次数: 0

Integrated computational and biological assays to identify and validate L. donovani homoserine dehydrogenase inhibitors 综合计算和生物测定鉴定和验证L. donovani高丝氨酸脱氢酶抑制剂。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-11 DOI: 10.1016/j.bbapap.2025.141112

Shalu Verma , Shaswat Sengar , Abdul Basit Khan , Anil Kumar Shakya , J. Venkatesh Pratap

The Neglected Tropical Disease (NTD) Leishmaniasis continues to pose a serious global health burden affecting millions globally. Visceral leishmaniasis, one of three clinical forms, can be fatal, if left untreated. Current treatment regimen relies mostly on re-purposed drugs and is limited by toxicity, high cost and the emergence of drug resistance, highlighting the need for safer, targeted therapies. In this study, we characterized Leishmania donovani homoserine dehydrogenase (LdHSD), a crucial enzyme in the aspartate pathway. As no human homolog exists, it represents a promising target for selective therapeutic intervention. LdHSD was purified to homogeneity, characterized biophysically and its activity biochemically assayed. Docking of the substrate (L-homoserine) and the cofactor (NADP⁺) to the LdHSD homology model identified adjacent but discrete binding pockets. Structure-based virtual screening of the Maybridge Compound Library was subsequently performed and the top 10 substrate-site bound compounds were taken for experimental validation. Two of the three piperidine/piperazine scaffold compounds inhibited LdHSD activity by ∼90 %. These findings highlight the therapeutic potential of targeting LdHSD for the development of novel, selective anti-leishmanial agents and establish a strong foundation for future optimization of these identified inhibitors.

被忽视的热带病利什曼病继续构成严重的全球健康负担，影响全球数百万人。内脏利什曼病是三种临床形式之一，如果不及时治疗，可能会致命。目前的治疗方案主要依赖于重新利用的药物，受到毒性、高成本和耐药性出现的限制，突出表明需要更安全的靶向治疗。在这项研究中，我们鉴定了利什曼原虫同型丝氨酸脱氢酶（LdHSD），这是天冬氨酸途径中的一个关键酶。由于没有人类同源物存在，它代表了选择性治疗干预的一个有希望的目标。对LdHSD进行纯化至均匀性，进行生物物理表征，并进行生物化学活性测定。底物（l -高丝氨酸）和辅因子（NADP）对接到LdHSD同源模型，确定了相邻但离散的结合口袋。随后对Maybridge化合物库进行基于结构的虚拟筛选，并选取前10个底物-位点结合化合物进行实验验证。三种哌啶/哌嗪支架化合物中的两种抑制LdHSD活性~90 %。这些发现突出了以LdHSD为靶点开发新型、选择性抗利什曼药物的治疗潜力，并为这些已确定的抑制剂的未来优化奠定了坚实的基础。

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引用次数: 0

Integrative multi-omics machine learning reveals novel driver genes associations in lung adenocarcinoma 综合多组学机器学习揭示了肺腺癌中新的驱动基因关联。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-08 DOI: 10.1016/j.bbapap.2025.141113

Fei Yuan , FeiMing Huang , Xiaoyu Cao , Yu-Hang Zhang , KaiYan Feng , YuSheng Bao , Tao Huang , Yu-Dong Cai

Lung adenocarcinoma remains a major challenge in cancer research due to its complex molecular underpinnings. In this study, we developed an integrated machine learning framework to identify novel driver genes associated with lung adenocarcinoma by leveraging multi-omics data. We curated gene candidates from methylation, RNAseq, mutation, and miRNA levels, and mapped them onto a protein–protein interaction network from STRING to generate informative feature vectors using a node2vec method. Furthermore, they were also represented by GO and KEGG enrichment features. All features were then refined through a multi-step process, beginning with the Boruta algorithm for filtering and followed by the minimum redundancy maximum relevance method for ranking. An incremental feature selection strategy was employed to determine the optimal feature subsets, which were used to build predictive models with random forest and support vector machine classifiers. To address class imbalance, synthetic sampling was applied, and ten-fold cross-validation ensured model robustness. Consequently, we predicted 428, 105, 1039, and 1748 potential lung adenocarcinoma driver genes for RNAseq, methylation, mutation, and miRNA levels, respectively. Integrated analysis of overlapping gene sets further highlighted key candidates, including PQLC3, FAM192A, FAM83D, SPRED1, SFTPB, and TM4SF5, with high composite probability scores. Some identified genes may be the driver genes of lung adenocarcinoma and have some druggable potential. These findings provide new insights into the molecular mechanisms of lung adenocarcinoma and suggest promising targets for future diagnostic and therapeutic strategies.

由于其复杂的分子基础，肺腺癌仍然是癌症研究的主要挑战。在这项研究中，我们开发了一个集成的机器学习框架，通过利用多组学数据来识别与肺腺癌相关的新驱动基因。我们筛选了来自甲基化、RNAseq、突变和miRNA水平的候选基因，并将它们映射到来自STRING的蛋白质-蛋白质相互作用网络上，使用node2vec方法生成信息丰富的特征向量。此外，它们还具有GO和KEGG富集特征。然后通过多步骤过程对所有特征进行细化，首先使用Boruta算法进行过滤，然后使用最小冗余最大相关性方法进行排序。采用增量特征选择策略确定最优特征子集，并结合随机森林和支持向量机分类器构建预测模型。为了解决类别不平衡问题，采用了合成抽样，并进行了十倍交叉验证，确保了模型的稳健性。因此，我们分别预测了428、105、1039和1748个潜在的肺腺癌驱动基因的RNAseq、甲基化、突变和miRNA水平。对重叠基因集的综合分析进一步突出了关键候选基因，包括PQLC3、FAM192A、FAM83D、SPRED1、SFTPB和TM4SF5，它们的复合概率得分很高。一些已鉴定的基因可能是肺腺癌的驱动基因，具有一定的药物潜力。这些发现为肺腺癌的分子机制提供了新的见解，并为未来的诊断和治疗策略提供了有希望的靶点。

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引用次数: 0

Novel interactions between FOXP2 and PAX6: Implications for neural development and autism spectrum disorders FOXP2和PAX6之间新的相互作用：对神经发育和自闭症谱系障碍的影响。

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Proteins and proteomics

Pub Date : 2025-11-08 DOI: 10.1016/j.bbapap.2025.141110

Jessica Brothwell , Olamide Jeje , Dineo Mashamaite , Sylvia Fanucchi

FOXP2 and PAX6 are transcription factors essential for neural development, with mutations in both linked to autism spectrum disorders (ASDs). Their DNA-binding domains include a forkhead domain (FHD) for FOXP2 and a paired domain (PD) plus homeodomain (HD) for PAX6. We investigated whether the FOXP2 FHD interacts directly with PAX6 PD or HD, and how such interactions influence DNA binding. Fluorescence anisotropy showed that all three domains bind specifically to their respective DNA targets with similar affinities. The FOXP2 FHD also interacts directly with both PAX6 PD and HD, with low micromolar binding affinities. Despite its stronger intrinsic DNA affinity, the FHD was displaced from its target DNA by both PAX6 domains, suggesting that protein–protein interactions can override DNA affinity under competitive conditions. In contrast, FOXP2 could not displace PD or HD from their DNA targets. Molecular docking supported these findings: DNA–protein interfaces were largely unchanged by the second protein, but protein–protein interfaces were strongly influenced by DNA occupancy. The H3 helix of FHD was identified as a central point for assembly, contributing to both DNA and protein interfaces. When FHD was bound to DNA, H3 was occupied, forcing PD or HD to dock at alternative, less optimal sites. HD maintained stronger contacts in these rearranged states, consistent with its greater competitive strength. This asymmetric interplay indicates competitive dominance by PAX6 and suggests mechanisms that could underlie transcriptional regulation in neurodevelopment.

FOXP2和PAX6是神经发育所必需的转录因子，两者的突变都与自闭症谱系障碍（asd）有关。它们的dna结合域包括FOXP2的叉头结构域（FHD）和PAX6的成对结构域（PD）加同源结构域（HD）。我们研究了FOXP2 FHD是否直接与PAX6 PD或HD相互作用，以及这种相互作用如何影响DNA结合。荧光各向异性表明，这三个结构域特异性结合各自的DNA目标具有相似的亲和力。FOXP2 FHD也直接与PAX6 PD和HD相互作用，具有低微摩尔结合亲和力。尽管FHD具有更强的内在DNA亲和力，但它被两个PAX6结构域从目标DNA中取代，这表明在竞争条件下，蛋白质-蛋白质相互作用可以覆盖DNA亲和力。相比之下，FOXP2不能将PD或HD从它们的DNA靶标上取代。分子对接支持这些发现：DNA-蛋白质界面在很大程度上不受第二个蛋白质的影响，但蛋白质-蛋白质界面受到DNA占用的强烈影响。FHD的H3螺旋被确定为组装的中心点，有助于DNA和蛋白质的界面。当FHD与DNA结合时，H3被占用，迫使PD或HD停靠在替代的、不太理想的位置。HD在这些重组后的州保持了更强的联系，这与它更强的竞争实力相一致。这种不对称的相互作用表明PAX6具有竞争性优势，并提示了神经发育中转录调节的机制。

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引用次数: 0