Biochemical Journal最新文献_第10页

Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome. 线粒体解偶联在心脏代谢综合征中的生化基础和治疗潜力。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240005

Bernardo Gindri Dos Santos, Niki F Brisnovali, Leigh Goedeke

{"title":"Biochemical basis and therapeutic potential of mitochondrial uncoupling in cardiometabolic syndrome.","authors":"Bernardo Gindri Dos Santos, Niki F Brisnovali, Leigh Goedeke","doi":"10.1042/BCJ20240005","DOIUrl":"10.1042/BCJ20240005","url":null,"abstract":"Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria, allowing for adjustments in cellular energy metabolism to maintain metabolic homeostasis. Small molecule uncouplers have been extensively studied for their potential to increase metabolic rate, and recent research has focused on developing safe and effective mitochondrial uncoupling agents for the treatment of obesity and cardiometabolic syndrome (CMS). Here, we provide a brief overview of CMS and cover the recent mechanisms by which chemical uncouplers regulate CMS-associated risk-factors and comorbidities, including dyslipidemia, insulin resistance, steatotic liver disease, type 2 diabetes, and atherosclerosis. Additionally, we review the current landscape of uncoupling agents, focusing on repurposed FDA-approved drugs and compounds in advanced preclinical or early-stage clinical development. Lastly, we discuss recent molecular insights by which chemical uncouplers enhance cellular energy expenditure, highlighting their potential as a new addition to the current CMS drug landscape, and outline several limitations that need to be addressed before these agents can successfully be introduced into clinical practice.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 23","pages":"1831-1854"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765735","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

Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase. 大分子拥挤和碳酸氢盐会增强过氧化氢诱导的甘油醛-3-磷酸脱氢酶失活。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240597

Rebecca H J Bloemen, Rafael Radi, Michael J Davies, Eduardo Fuentes-Lemus

{"title":"Macromolecular crowding and bicarbonate enhance the hydrogen peroxide-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase.","authors":"Rebecca H J Bloemen, Rafael Radi, Michael J Davies, Eduardo Fuentes-Lemus","doi":"10.1042/BCJ20240597","DOIUrl":"10.1042/BCJ20240597","url":null,"abstract":"The active site Cys residue in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to oxidation by hydrogen peroxide (H2O2), with this resulting in enzyme inactivation. This re-routes the carbon flux from glycolysis to the pentose phosphate pathway favoring the formation of NADPH and synthetic intermediates required for antioxidant defense and repair systems. Consequently, GAPDH inactivation serves as a redox switch for metabolic adaptation under conditions of oxidative stress. However, there is a major knowledge gap as to how GAPDH is efficiently oxidized and inactivated, when the increase in intracellular H2O2 is modest, and there is a high concentration of alternative (non-signaling) thiols and efficient peroxide removing systems. We have therefore explored whether GAPDH inactivation is enhanced by two factors of in vivo relevance: macromolecular crowding, an inherent property of biological environments, and the presence of bicarbonate, an abundant biological buffer. Bicarbonate is already known to modulate H2O2 metabolism via formation of peroxymonocarbonate. GAPDH activity was assessed in experiments with low doses of H2O2 under both dilute and crowded conditions (induced by inert high molecular mass polymers and small molecules), in both the absence and presence of 25 mM sodium bicarbonate. H2O2-induced inactivation of GAPDH was observed to be significantly enhanced under macromolecular crowding conditions, with bicarbonate having an additional effect. These data strongly suggest that these two factors are of major importance in redox switch mechanisms involving GAPDH (and possibly other thiol-dependent systems) within the cellular environment.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1855-1866"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646879","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

Editorial Note: Camelid single-domain antibodies raised by DNA immunization are potent inhibitors of EGFR signaling. 编辑注：DNA免疫引起的骆驼单域抗体是EGFR信号传导的有效抑制剂。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20180795_EDN

引用次数: 0

Investigating the differential structural organization and gene expression regulatory networks of lamin A Ig fold domain mutants of muscular dystrophy. 研究肌肉萎缩症的层粘连A Ig折叠结构域突变体的不同结构组织和基因表达调控网络。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240474

Subarna Dutta, Vikas Kumar, Arnab Barua, Madavan Vasudevan

{"title":"Investigating the differential structural organization and gene expression regulatory networks of lamin A Ig fold domain mutants of muscular dystrophy.","authors":"Subarna Dutta, Vikas Kumar, Arnab Barua, Madavan Vasudevan","doi":"10.1042/BCJ20240474","DOIUrl":"10.1042/BCJ20240474","url":null,"abstract":"Lamins form a proteinaceous meshwork as a major structural component of the nucleus. Lamins, along with their interactors, act as determinants for chromatin organization throughout the nucleus. The major dominant missense mutations responsible for autosomal dominant forms of muscular dystrophies reside in the Ig fold domain of lamin A. However, how lamin A contributes to the distribution of heterochromatin and balances euchromatin, and how it relocates epigenetic marks to shape chromatin states, remains poorly defined, making it difficult to draw conclusions about the prognosis of lamin A-mediated muscular dystrophies. In the first part of this report, we identified the in vitro organization of full-length lamin A proteins due to two well-documented Ig LMNA mutations, R453W and W514R. We further demonstrated that both lamin A/C mutant cells predominantly expressed nucleoplasmic aggregates. Labeling specific markers of epigenetics allowed correlation of lamin A mutations with epigenetic mechanisms. In addition to manipulating epigenetic mechanisms, our proteomic studies traced diverse expressions of transcription regulators, RNA synthesis and processing proteins, protein translation components, and posttranslational modifications. These data suggest severe perturbations in targeting other proteins to the nucleus.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1803-1827"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602290","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

Mitigating methylglyoxal-induced glycation stress: the protective role of iron, copper, and manganese coordination compounds in Saccharomyces cerevisiae. 减轻甲基乙二醛诱导的糖化应激：铁、铜和锰配位化合物在酿酒酵母中的保护作用

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240390

Maria Eduarda S F do Espírito Santo, Bárbara F Frascino, Larissa M M Mattos, Daniele C Pires, Simone S C de Oliveira, Lucas B Menezes, Bernardo F Braz, Ricardo E Santeli, André L S Santos, Adolfo Horn, Christiane Fernandes, Marcos D Pereira

{"title":"Mitigating methylglyoxal-induced glycation stress: the protective role of iron, copper, and manganese coordination compounds in Saccharomyces cerevisiae.","authors":"Maria Eduarda S F do Espírito Santo, Bárbara F Frascino, Larissa M M Mattos, Daniele C Pires, Simone S C de Oliveira, Lucas B Menezes, Bernardo F Braz, Ricardo E Santeli, André L S Santos, Adolfo Horn, Christiane Fernandes, Marcos D Pereira","doi":"10.1042/BCJ20240390","DOIUrl":"10.1042/BCJ20240390","url":null,"abstract":"Glycation-induced stress (G-iS) is a physiological phenomenon that leads to the formation of advanced glycation end-products, triggering detrimental effects such as oxidative stress, inflammation, and damage to intracellular structures, tissues, and organs. This process is particularly relevant because it has been associated with various human pathologies, including cancer, neurodegenerative diseases, and diabetes. As therapeutic alternatives, coordination compounds with antioxidant activity show promising potential due to their versatility in attenuating oxidative stress and inflammation. Herein, we investigated the antioxidant-related protective potential of a series of complexes: [Cu(II)(BMPA)Cl2] (1), [Fe(III)(BMPA)Cl3] (2), and [Cl(BMPA)MnII-(μ-Cl)2-MnII(BMPA)-(μ-Cl)- MnII(BMPA)(Cl)2]•5H2O (3), all synthesized with the ligand bis-(2-pyridylmethyl)amine (BMPA) in Saccharomyces cerevisiae exposed to G-iS caused by methylglyoxal (MG). Pre- treatment with complexes 1-3 proved highly effective, increasing yeast tolerance to G-iS and attenuating mitochondrial dysfunction. This observed phenotype appears to result from a reduction in intracellular oxidation, lipid peroxidation levels, and glycation. Additionally, an increase in the activity of the antioxidant enzymes superoxide dismutase and catalase was observed following treatment with complexes 1-3. Notably, although complexes 1-3 provided significant protection against oxidative stress induced by H2O2 and menadione, their protective role was more effective against MG-induced glycation stress. Our results indicate that these complexes possess both antiglycation and antioxidant properties, warranting further investigation as potential interventions for mitigating glycation and oxidative stress-related pathologies.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1771-1786"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614044","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

ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding. PI3K 酶的 ATP 竞争性抑制剂通过控制膜结合，显示出同工酶选择性的双重作用。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240479

Grace Q Gong, Glenn R Masson, Woo-Jeong Lee, James M J Dickson, Jackie D Kendall, Manoj K Rathinaswamy, Christina M Buchanan, Martin Middleditch, Brady M Owen, Julie A Spicer, Gordon W Rewcastle, William A Denny, John E Burke, Peter R Shepherd, Roger L Williams, Jack U Flanagan

{"title":"ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.","authors":"Grace Q Gong, Glenn R Masson, Woo-Jeong Lee, James M J Dickson, Jackie D Kendall, Manoj K Rathinaswamy, Christina M Buchanan, Martin Middleditch, Brady M Owen, Julie A Spicer, Gordon W Rewcastle, William A Denny, John E Burke, Peter R Shepherd, Roger L Williams, Jack U Flanagan","doi":"10.1042/BCJ20240479","DOIUrl":"10.1042/BCJ20240479","url":null,"abstract":"PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown. Using FRET and biolayer interferometry assays, we show that a class of ATP-site directed inhibitors represented by GSK2126458 block the growth factor activated PI3KαWT membrane interaction, an activity dependent on the ligand forming specific ATP-site interactions. The membrane interaction for hot spot oncogenic mutations that bypass normal p85α regulatory mechanisms was insensitive to GSK2126458, while GSK2126458 could regulate mutations found outside of these hot spot regions. Our data show that the effect of GSK126458 on the membrane interaction requires the enzyme to revert from its growth factor activated state to a basal state. We find that an ATP substrate analogue can increase the wild type PI3Kα membrane interaction, uncovering a substrate based regulatory event that can be mimicked by different inhibitor chemotypes. Our findings, together with the discovery of small molecule allosteric activators of PI3Kα illustrate that PI3Kα membrane interactions can be modulated by factors related to ligand binding both within the ATP site and at allosteric sites.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1787-1802"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557052","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

Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor. DRY 和 NPxxY 基序在选择性激活芹菜素受体下游信号中的不同作用。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240320

Subhashree Murali, Gopala Krishna Aradhyam

{"title":"Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor.","authors":"Subhashree Murali, Gopala Krishna Aradhyam","doi":"10.1042/BCJ20240320","DOIUrl":"10.1042/BCJ20240320","url":null,"abstract":"G protein-coupled receptors (GPCRs) serve as critical communication hubs, translating a wide range of extracellular signals into intracellular responses that govern numerous physiological processes. In class-A GPCRs, conserved motifs mediate conformational changes of the active states of the receptor, and signal transduction is achieved by selectively binding to Gα proteins and/or adapter protein, arrestin. Apelin receptor (APJR) is a class-A GPCR that regulates a wide range of intracellular signalling cascades in response to apelin and elabela peptide ligands. Understanding how conserved motifs within APJR mediate activation and signal specificity remains unexplored. This study focuses on the functional roles of the DRY and NPxxY motifs within APJR by analyzing their impact on downstream signaling pathways across the receptor's conformational ensembles. Our findings provide compelling evidence that mutations within the conserved DRY and NPxxY motifs of APJR significantly alter its conformational preferences where modification of DRY motif leads to abrogation of G-protein coupling and mutation of NPxxY motif causing abolition of β-arrestin-2 recruitment. These observations shed light on the importance of these motifs in APJR activation and its potential for functional selectivity, highlighting the role of DRY/NPxxY as conformational switches of APJR signalling.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1707-1722"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602283","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

The uncharacterized protein ZNF200 interacts with PRMT3 and aids its stability and nuclear translocation. 未定性蛋白质 ZNF200 与 PRMT3 相互作用，有助于其稳定性和核转位。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240476

Somlee Gupta, Mamta Verma, Rajashekar Varma Kadumuri, Namita Chutani, Mohd Imran K Khan, Sreenivas Chavali, Arunkumar Dhayalan

{"title":"The uncharacterized protein ZNF200 interacts with PRMT3 and aids its stability and nuclear translocation.","authors":"Somlee Gupta, Mamta Verma, Rajashekar Varma Kadumuri, Namita Chutani, Mohd Imran K Khan, Sreenivas Chavali, Arunkumar Dhayalan","doi":"10.1042/BCJ20240476","DOIUrl":"10.1042/BCJ20240476","url":null,"abstract":"Protein arginine methyltransferase 3 (PRMT3), a type I arginine methyltransferase is localized predominantly in the cytoplasm and regulates different cellular functions. Nevertheless, PRMT3 also exhibits regulatory functions in the nucleus by interacting with the liver X receptor alpha (LXRα) and catalyzes asymmetric dimethylation modifications at arginine 3 of histone 4 (H4R3me2a). However, very little is known about the regulation of the versatile global regulator PRMT3 and how PRMT3 is translocated to the nucleus. In this study, we identified ZNF200, a hitherto uncharacterized protein, as a potential binding partner of PRMT3 through yeast two-hybrid screening. We confirmed the interaction of PRMT3 with ZNF200 using immunoprecipitation and in vitro pull-down experiments. GST pull-down experiments and molecular docking studies revealed that the N-terminal zinc finger domain of PRMT3 binds to the C-terminal zinc finger regions of ZNF200. Furthermore, the evolutionary conservation of the Znf domain of PRMT3 correlates with the emergence of ZNF200 in mammals. We found that ZNF200 stabilizes PRMT3 by inhibiting its proteasomal degradation. ZNF200, a nuclear-predominant protein, promotes the nuclear translocation of PRMT3, leading to the global increase of H4R3me2a modifications. These findings imply that ZNF200 is a critical regulator of the steady-state levels and nuclear and epigenetic functions of PRMT3.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1723-1740"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602686","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

A prescription for engineering PFAS biodegradation. 全氟辛烷磺酸生物降解工程的处方。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240283

Lawrence P Wackett, Serina L Robinson

引用次数: 0

Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions. 在进化过程中，MCR 蛋白活性位点的序列变异是通过结构域间的相互作用来实现的。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-12-04 DOI: 10.1042/BCJ20240373

Avani Joshi, Nishad Matange

{"title":"Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions.","authors":"Avani Joshi, Nishad Matange","doi":"10.1042/BCJ20240373","DOIUrl":"10.1042/BCJ20240373","url":null,"abstract":"Sequence variation among homologous proteins can shed light on their function and ancestry. In this study, we analyze variation at catalytic residues among MCR (mobile colistin resistance) proteins, which confer resistance to the last resort antibiotic, colistin, in gram-negative bacteria. We show that not all naturally occurring variants at a lipid A-binding residue, Ser284, are tolerated in MCR-1. In particular, the substitution of Ser284 with Asp, found naturally in MCR-5, resulted in diminished colistin resistance. Using phylogenetic analyses and structure predictions we trace back variation at this site among MCRs to their ancestors, i.e. EptA phosphoethanolamine transferases that are encoded by diverse bacterial genomes. Mutational studies and AlphaFold-based structural modeling revealed that the functional importance of position 284 varies between phylogenetically distant MCRs, i.e. MCR-1 and MCR-5. Despite a high degree of similarity among their catalytic domains, inter-domain interactions were not conserved between MCR-1 and MCR-5 due to their different ancestries, providing a mechanistic basis behind the different phenotypes of similar mutations at position 284. Our study thus uncovers subtle differences in the organization of domains among MCR proteins that can lead to substantial differences in their catalytic properties and mutational tolerances.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1741-1755"},"PeriodicalIF":4.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602589","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