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Pharmaco-nutraceutical improvement of the response to obeticholic acid with omega-3 polyunsaturated fatty acids. omega-3多不饱和脂肪酸对欧比胆酸反应的药物营养改善。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-07-22 DOI: 10.1042/bcj20253113
Audrey-Anne Lavoie,Ariane Thérien,Anisia Silva,Emanuel Paré,Anna Ciešlak,William Gagnon,Clémence Desjardins,Mélanie Verreault,Jocelyn Trottier,Marie-Claude Vohl,Jean-Philippe Drouin-Chartier,Jacques Corbeil,Alexandre Caron,Olivier Barbier
{"title":"Pharmaco-nutraceutical improvement of the response to obeticholic acid with omega-3 polyunsaturated fatty acids.","authors":"Audrey-Anne Lavoie,Ariane Thérien,Anisia Silva,Emanuel Paré,Anna Ciešlak,William Gagnon,Clémence Desjardins,Mélanie Verreault,Jocelyn Trottier,Marie-Claude Vohl,Jean-Philippe Drouin-Chartier,Jacques Corbeil,Alexandre Caron,Olivier Barbier","doi":"10.1042/bcj20253113","DOIUrl":"https://doi.org/10.1042/bcj20253113","url":null,"abstract":"Obeticholic acid (OCA) is the second line therapy for primary biliary cholangitis. While efficient in promoting BA detoxification and limiting liver fibrosis, its clinical use is restricted by severe dose-dependent side effects. We tested the hypothesis that adding n-3 polyunsaturated fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids to OCA may improve the therapeutic effect of the low drug dosage. Several liver cell lines were exposed to vehicle, low or high OCA dose (1-20μM) in the presence or absence of EPA/DHA for 24H. To induce ER stress, apoptosis, and fibrosis, HepG2 cells were exposed to a 400μM BA mixture or to 2ng/mL TGF-β. For inflammation analyses, THP-1 cells were activated with 100ng/mL LPS. The impact OCA+EPA/DHA was assessed using transcriptomic (qRT-PCR), proteomic (ELISA, caspase-3), and metabolomic (LC-MS/MS) approaches. The addition of EPA/DHA reinforced the ability of low OCA dose to down-regulate the expression of genes involved in BA synthesis (CYP7A1, CYP8B1) and uptake (NTCP) and to up-regulate MRP2 & 3 genes expression. EPA/DHA also enhanced the anti-inflammatory response of the drug by reducing the expression of the LPS-induced cytokines: TNFα, IL-6, IL-1β and MCP-1 in THP-1 macrophages. OCA+EPA/DHA decreased the expression of BIP, CHOP and COL1A1 genes and the caspase-3 activity. EPA+DHA potentiate the response to low OCA doses on BA toxicity, and provide additional benefits on ER stress, apoptosis, inflammation and fibrosis. These observations support the idea that adding n-3 polyunsaturated fatty acids to the drug may reduce the risk of dose-related side effects in patients treated with OCA.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"17 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Proteomic analysis reveals inhibition of mevalonate and Glycolysis pathways in hepatocytes by 27-hydroxycholesterol. 蛋白质组学分析显示27-羟基胆固醇抑制肝细胞的甲羟戊酸和糖酵解途径。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-07-22 DOI: 10.1042/bcj20253035
Wan-Seog Shim,Seulah Lee,Bakhovuddin Azamov,Chanhee Lee,Yeowon Kang,Kwang Min Lee,Changwan Hong,Sang-Mo Kwon,Koanhoi Kim,Dongjun Lee,Jong Hyuk Yoon,Parkyong Song
{"title":"Proteomic analysis reveals inhibition of mevalonate and Glycolysis pathways in hepatocytes by 27-hydroxycholesterol.","authors":"Wan-Seog Shim,Seulah Lee,Bakhovuddin Azamov,Chanhee Lee,Yeowon Kang,Kwang Min Lee,Changwan Hong,Sang-Mo Kwon,Koanhoi Kim,Dongjun Lee,Jong Hyuk Yoon,Parkyong Song","doi":"10.1042/bcj20253035","DOIUrl":"https://doi.org/10.1042/bcj20253035","url":null,"abstract":"27-Hydroxycholesterol (27OHC), an endogenous oxysterol, has been implicated in various physiological processes, including regulation of estrogen receptor activity and lipid metabolism. However, studies on how 27OHC affects the metabolic changes associated with lipogenesis inhibition in the liver remain limited. This study aimed to investigate the systemic effects of 27OHC on hepatocytes through a comparative proteomic analysis of the proteomes in the 27OHC-treated AML12 cells. Ingenuity Pathway Analysis revealed significant downregulation of certain metabolic pathways, such as cholesterol biosynthesis and glycolysis, which are highly associated with lipid metabolism, following 27OHC treatment. Furthermore, in vitro biochemical analysis revealed significant inhibition of the expression of genes associated with the mevalonate pathway and a decrease in the total cellular cholesterol levels in AML12 cells and primary hepatocytes following 27OHC treatment. In addition, it was observed that 27OHC significantly reduced the transcripts levels of critical glycolytic enzymes such as aldolase, phosphofructokinase, and pyruvate kinase. This inhibition resulted in decreased lactate production and extracellular acidification (ECAR), indicating suppression of glycolytic flux. Concurrently, we proved that downregulation of reactive oxygen species generation and HIF-1α expression following 27OHC treatment partially contributed to glycolysis inhibition. Overall, we demonstrated the inhibitory effects of 27OHC on the hepatic mevalonate pathway and glycolysis, revealing a novel mechanism by which 27OHC regulates lipid metabolism. As the accumulation of cholesterol and lipids promotes hepatic fatty liver disease and increased glycolysis contributes to triacylglycerol maturation, the suppressive effects of 27OHC on hepatic lipid and glucose metabolism may contribute to protect against fatty liver development.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"707 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structure and activity of the essential UCH family deubiquitinase DUB16 from Leishmania donovani. 多诺瓦利什曼原虫UCH家族去泛素酶DUB16的结构和活性。
IF 4.3 3区 生物学
Biochemical Journal Pub Date : 2025-07-09 DOI: 10.1042/BCJ20253107
James A Brannigan, Mohd Kamran, Nathaniel G Jones, Elisa M Nightingale, Eleanor J Dodson, Sarfaraz A Ejazi, Jeremy C Mottram, Nahid Ali, Anthony J Wilkinson
{"title":"Structure and activity of the essential UCH family deubiquitinase DUB16 from Leishmania donovani.","authors":"James A Brannigan, Mohd Kamran, Nathaniel G Jones, Elisa M Nightingale, Eleanor J Dodson, Sarfaraz A Ejazi, Jeremy C Mottram, Nahid Ali, Anthony J Wilkinson","doi":"10.1042/BCJ20253107","DOIUrl":"10.1042/BCJ20253107","url":null,"abstract":"<p><p>In Leishmania parasites, as for their hosts, the ubiquitin (Ub) proteasome system is important for cell viability. As part of a systematic gene deletion study, it was discovered that four cysteine protease-type deubiquitinases (DUBs) are essential for parasite survival in the promastigote stage, including DUB16. Here, we have purified and characterised recombinant DUB16 from Leishmania donovani, which belongs to the Ub C-terminal hydrolase (UCH) family. DUB16 efficiently hydrolyses C-terminal aminocoumarin and rhodamine conjugates of Ub consistent with proposed cellular roles of UCH-type DUBs in regenerating free monomeric Ub from small molecule Ub adducts arising from adventitious metabolic processes. The crystal structure of DUB16 reveals a typical UCH-type DUB fold, and a relatively short and disordered cross-over loop that appears to restrict access to the catalytic cysteine. At close to stoichiometric enzyme to substrate ratios, DUB16 exhibits DUB activity towards diubiquitins linked through isopeptide bonds between Lys11, Lys48 or Lys63 residues of the proximal Ub and the C-terminus of the distal Ub. With 100-1000-fold higher turnover rates, DUB16 cleaves the ubiquitin-ribosomal L40 fusion protein to give the mature products. A DUB-targeting cysteine-reactive cyanopyrrolidine compound, IMP-1710, inhibits DUB16 activity. IMP-1710 was shown in promastigote cell viability assays to have parasite killing activity with EC50 values of 1-2 μM, comparable with the anti-leishmanial drug, miltefosine. L. mexicana parasites engineered to overproduce DUB16 showed a modest increase in resistance to IMP-1710, providing evidence that IMP-1710 inhibits DUB16 in vivo. While it is highly likely that IMP-1710 has additional targets, these results suggest that DUB16 is a potential target for the development of new anti-leishmanial compounds.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Pseudomonas aeruginosa Type VI secretion system toxin Tse8 evolved from a novel N-carbamoylputrescine amidohydrolase. 铜绿假单胞菌VI型分泌系统毒素Tse8是由一种新型n -氨甲酰腐胺水解酶进化而来的。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-07-09 DOI: 10.1042/bcj20253210
Bin Li,Hamid R Baniasadi,Margaret A Phillips,Anthony J Michael
{"title":"The Pseudomonas aeruginosa Type VI secretion system toxin Tse8 evolved from a novel N-carbamoylputrescine amidohydrolase.","authors":"Bin Li,Hamid R Baniasadi,Margaret A Phillips,Anthony J Michael","doi":"10.1042/bcj20253210","DOIUrl":"https://doi.org/10.1042/bcj20253210","url":null,"abstract":"The polyamine putrescine is synthesized primarily from L-arginine via agmatine in bacteria. There are currently three known routes from agmatine to putrescine, including direct conversion by agmatinase. The other two routes use agmatine deiminase to produce N-carbamoylputrescine from agmatine, then one of two nonhomologous enzymes, putrescine transcarbamylase or N-carbamoylputrescine amidohydrolase (NCPAH) convert N-carbamoylputrescine to putrescine. Here, we functionally identify enzymes from phylogenetically distant bacteria, the gamma-proteobacterium Shewanella oneidensis, and the actinomycetota species Microterricola gilva, that are novel alternative, nonhomologous, noncanonical NCPAHs that we term AguY, which have emerged by convergent evolution. Kinetic analysis indicates that the AguY enzymes are as efficient as the canonical NCPAH from Pseudomonas aeruginosa, in converting N-carbamoylputrescine to putrescine. Genomic evidence suggests that the AguY enzymes may participate in putrescine biosynthetic or agmatine catabolic pathways, and are occasionally encoded in genomes that also encode agmatinase. We show that the Type VI secretion system toxin Tse8 from Pseudomonas aeruginosa has evolved from AguY. It is formally possible that AguY evolved directly or indirectly from the ancient glutamine amidohydrolase GatA, a component of the transamidosome, an RNA/protein complex required for production of glutamine-charged tRNA. Our study provides a further example of the prevalence of convergent evolution and horizontal gene transfer in polyamine biosynthesis, suggesting pervasive selective pressure to evolve polyamine metabolism in bacteria.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"37 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cyanobacterial redox carriers support photosynthesis in a purple phototrophic bacterium. 蓝藻氧化还原载体支持紫色光养细菌的光合作用。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-07-08 DOI: 10.1042/bcj20253114
Adam Bowie,Andrew Hitchcock,Matthew Proctor,Elizabeth Martin,David Swainsbury,C Hunter
{"title":"Cyanobacterial redox carriers support photosynthesis in a purple phototrophic bacterium.","authors":"Adam Bowie,Andrew Hitchcock,Matthew Proctor,Elizabeth Martin,David Swainsbury,C Hunter","doi":"10.1042/bcj20253114","DOIUrl":"https://doi.org/10.1042/bcj20253114","url":null,"abstract":"In oxygenic and anoxygenic photosynthesis, excitation energy migrates from a surrounding antenna to specialised chlorophyll (Chl) or bacteriochlorophyll (BChl) pigments housed within a reaction centre (RC) complex. Here, a charge-separated state is formed within a few picoseconds, and an electron moves along a series of cofactors until it arrives at a quinone or iron-sulfur centre acceptor. Further photochemical cycles rely on rapid re-reduction of the photo-oxidised RC, usually by small, soluble metalloproteins which vary considerably between different phototrophic clades. In the purple phototrophic bacterium Rhodobacter (Rba.) sphaeroides, the electron carrier cytochrome c2 (cyt c2) shuttles between the periplasmic faces of the cytochrome bc1 complex and the reaction centre-light harvesting 1 (RC-LH1) core complex, the location of the BChl special pair (P865865). By contrast, in the model cyanobacterium Synechocystis sp. PCC 6803, electrons are transferred from cytochrome b6f to photosystem I (PSI) via two isofunctional redox carrier proteins, cytochrome c6 (cyt c6) and plastocyanin (Pc). In this paper, we demonstrate that both cyt c6 and Pc can substitute for cyt c2 in silico, in vitro and in vivo, even though their electrostatic properties may be counter-productive for binding the RC-LH1 complex. Interestingly, whilst P865865++ reduction was highest with cyt c2 and the full physiological RC-LH1 complex, both Synechocystis proteins were more compatible with the RC-only complex lacking the surrounding LH1 antenna. Taken together, this suggests the subunits that constitute the LH1 ring improve both the donor side activity and selectivity of the Rba. sphaeroides RC complex.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"74 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Activity-based probes for dynamic characterisation of polysaccharide-degrading enzymes. 基于活性的多糖降解酶动态表征探针。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-07-01 DOI: 10.1042/bcj20253060
Isabelle B Pickles,Thamy L R Corrêa,Herman S Overkleeft,Gideon J Davies
{"title":"Activity-based probes for dynamic characterisation of polysaccharide-degrading enzymes.","authors":"Isabelle B Pickles,Thamy L R Corrêa,Herman S Overkleeft,Gideon J Davies","doi":"10.1042/bcj20253060","DOIUrl":"https://doi.org/10.1042/bcj20253060","url":null,"abstract":"Carbohydrate-active enzymes play essential roles in polysaccharide degradation, yet their biochemical characterisation remains challenging - especially in the face of rapidly expanding genomic and structural data. Standard annotations often overlook critical properties such as expression patterns, enzyme stability and substrate specificity, which are key to understanding function in biological and industrial contexts. Activity-based probes (ABPs) offer a direct solution by enabling selective detection of active enzymes within complex systems. This review focuses on ABPs for retaining glycosidases, tracing their development from early applications in medical diagnostics to emerging uses in biomass degradation. We examine recent advances in scaffold design - including fluorosugars, epoxides, aziridines and cyclic sulphates - and their utility in enzyme profiling, inhibitor discovery and biotechnology. Current ABPs remain limited: they cannot yet target inverting enzymes and other classes lacking nucleophilic residues, a gap that may be bridged through computational modelling and AI-guided probe development. Looking forward, integration of ABPs with enzyme engineering and design holds promise for unlocking new classes of biocatalysts tailored for industrial and biomedical use.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"6 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characterisation of an Influenza B virus-derived peptide presented by HLA-B*18:01. HLA-B*18:01表达的乙型流感病毒衍生肽的特征
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-06-26 DOI: 10.1042/bcj20240739
Lawton D Murdolo,Samuel Liwei Leong,Janesha C Maddumage,Nicole Mifsud,Demetra Sm Chatzileontiadou,Emma J Grant,Stephanie Gras
{"title":"Characterisation of an Influenza B virus-derived peptide presented by HLA-B*18:01.","authors":"Lawton D Murdolo,Samuel Liwei Leong,Janesha C Maddumage,Nicole Mifsud,Demetra Sm Chatzileontiadou,Emma J Grant,Stephanie Gras","doi":"10.1042/bcj20240739","DOIUrl":"https://doi.org/10.1042/bcj20240739","url":null,"abstract":"The Influenza B virus (IBV) can pose a significant threat to global health. Despite this, IBV is understudied compared to Influenza A virus (IAV). CD8+ T cells have proven highly effective in reducing influenza disease severity. In addition, pre-existing immune responses towards IAV epitopes may provide protection against homologous IBV-derived peptides due to T cell cross-reactivity. To exploit the advantages of T cells for future vaccine developments, a better understanding of the IBV-derived peptide presentation by the highly polymorphic Human Leukocyte Antigen (HLA) is required. We previously determined that the IAV-derived PB1177-A peptide was presented by the HLA-B*18:01 molecule and induced CD8+ T cell responses. Here we assessed the PB1177-A IBV homologue (PB1177-B). Intracellular cytokine staining assays showed that PB1177-B was unable to activate CD8+ T cells from several HLA-B*18:01+ samples tested. We determined that the IAV- and IBV-derived PB1177 adopted different stability and conformation in the cleft of HLA-B*18:01. Molecular dynamics analysis on the crystal structure showed that PB1177-B had a central flexible region with a large hydrophobic patch formed by two phenylalanine residues, not present in PB1177-A. The flexibility and the lower stability of the HLA-B*18:01-PB1177-B complex may hinder CD8+ T cell receptor binding, underpinning the lack of CD8+ T cell activation observed. This provides additional insights into the differences between IAV- and IBV-specific CD8+ T cell responses.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"49 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of LRRK2 in axonal transport and Parkinson's disease. LRRK2在轴突转运和帕金森病中的作用。
IF 4.3 3区 生物学
Biochemical Journal Pub Date : 2025-06-25 DOI: 10.1042/BCJ20253133
Björn Twellsieck, C Alexander Boecker
{"title":"Role of LRRK2 in axonal transport and Parkinson's disease.","authors":"Björn Twellsieck, C Alexander Boecker","doi":"10.1042/BCJ20253133","DOIUrl":"10.1042/BCJ20253133","url":null,"abstract":"<p><p>Axonal transport is crucial for neuronal health and function, facilitating the delivery of newly synthesized material from the soma via anterograde transport and the removal of aged proteins and damaged organelles for degradation via retrograde transport. Emerging evidence links Parkinson's disease (PD)-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene to dysfunctional axonal transport. Pathogenic LRRK2 mutations induce increased LRRK2 kinase activity, leading to the hyperphosphorylation of RAB proteins, which are key regulators of intracellular trafficking and transport. Here, we review the current literature on how LRRK2 affects the axonal transport of different cargoes, focusing on synaptic vesicle precursors, mitochondria, and autophagosomes. We further discuss how LRRK2 influences cytoskeletal dynamics and how it affects vesicle trafficking at the Golgi, which may indirectly contribute to its effect on axonal transport. This review summarizes our current understanding of how pathogenic LRRK2 hyperactivation disrupts axonal transport and how this may be linked to the neurodegeneration of PD.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 13","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Methods to accelerate PROTAC drug discovery. 加速PROTAC药物发现的方法。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-06-25 DOI: 10.1042/bcj20243018
Jeyan Osman,Philip E Thompson,Manuela Jörg,Martin J Scanlon
{"title":"Methods to accelerate PROTAC drug discovery.","authors":"Jeyan Osman,Philip E Thompson,Manuela Jörg,Martin J Scanlon","doi":"10.1042/bcj20243018","DOIUrl":"https://doi.org/10.1042/bcj20243018","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) represent a novel and promising modality for probing biological systems, elucidating pharmacological mechanisms, and identifying potential therapeutic leads. The field has made significant strides, as demonstrated by the growing number of PROTACs advancing to clinical trials. Despite this progress, the development of PROTACs faces significant challenges, which is partially due to the heterobivalent nature of this class of molecules. PROTACs must simultaneously bind to a protein of interest and an E3 ubiquitin ligase. This means PROTACs are significantly larger and more complex than conventional small molecules. This complexity impacts their design and synthesis, requiring strategic approaches to create libraries of PROTACs with various combinations of target ligands, linkers, and E3 ligase-recruiting elements. To fully realise the potential of this innovative technology, there is a need for novel approaches to accelerate the development of PROTACs. This review focuses on three critical areas to accelerate PROTAC development: appropriate target selection, modular chemical synthesis, and high-throughput biological evaluation. By appropriate selection of target proteins for degradation, optimizing synthesis methods to handle the complexity of PROTAC molecules, and employing robust high-throughput biological assays to evaluate PROTAC activity, researchers in academia and industry have streamlined the development and increased the success rate of PROTAC-based discovery programmes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"18 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of LRRK2 in axonal transport and Parkinson's disease. LRRK2在轴突转运和帕金森病中的作用。
IF 4.1 3区 生物学
Biochemical Journal Pub Date : 2025-06-25 DOI: 10.1042/bcj20253133
Björn Twellsieck,C Alexander Boecker
{"title":"Role of LRRK2 in axonal transport and Parkinson's disease.","authors":"Björn Twellsieck,C Alexander Boecker","doi":"10.1042/bcj20253133","DOIUrl":"https://doi.org/10.1042/bcj20253133","url":null,"abstract":"Axonal transport is crucial for neuronal health and function, facilitating the delivery of newly synthesized material from the soma via anterograde transport and the removal of aged proteins and damaged organelles for degradation via retrograde transport. Emerging evidence links Parkinson's disease (PD)-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene to dysfunctional axonal transport. Pathogenic LRRK2 mutations induce increased LRRK2 kinase activity, leading to the hyperphosphorylation of RAB proteins, which are key regulators of intracellular trafficking and transport. Here, we review the current literature on how LRRK2 affects the axonal transport of different cargoes, focusing on synaptic vesicle precursors, mitochondria, and autophagosomes. We further discuss how LRRK2 influences cytoskeletal dynamics and how it affects vesicle trafficking at the Golgi, which may indirectly contribute to its effect on axonal transport. This review summarizes our current understanding of how pathogenic LRRK2 hyperactivation disrupts axonal transport and how this may be linked to the neurodegeneration of PD.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"91 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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