Biochemical Society transactions最新文献_第9页

Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations. 蛋白酪氨酸磷酸酶的循环动力学、变构和功能：来自分子模拟的见解。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2026-01-21 DOI: 10.1042/BST20250018

Colin L Welsh, Shina Caroline Lynn Kamerlin

{"title":"Loop dynamics, allostery, and function in protein tyrosine phosphatases: insights from molecular simulations.","authors":"Colin L Welsh, Shina Caroline Lynn Kamerlin","doi":"10.1042/BST20250018","DOIUrl":"10.1042/BST20250018","url":null,"abstract":"Enzymes are dynamic entities, and their conformational dynamics are intimately linked to their function and evolvability. In this context, protein tyrosine phosphatases (PTPs) are an excellent model system to probe the role of conformational dynamics in enzyme function and evolution. They are a genetically diverse family of enzymes, with a highly conserved catalytic domain, identical catalytic mechanisms, and turnover numbers that vary by orders of magnitude, with their activity being determined by the mobility of a catalytic loop that closes over the active site and places a key catalytic residue in place for efficient catalysis. From a biological perspective, PTPs are important regulators of a host of cellular processes, including cellular signaling, which has made them in particular important anticancer drug targets, among other diseases of interest. The high structural conservation of their active sites renders them therapeutically elusive, but there exist allosteric inhibitors that exploit the allosteric regulation of these enzymes to impede the motion of their catalytic WPD-loops, thus inactivating them. Conformational dynamics and allostery are problems that are ideal for computational investigation, and indeed, advances in computational methodologies have resulted in a range of exciting studies illuminating the molecular details of structure-function-dynamics-allostery links in these enzymes. This review provides both a brief history of computational work in this space, as well as discussing in detail recent advances, illustrating how molecular simulations have been successfully exploited to enhance our fundamental understanding of these biomedically important enzymes, and of the function and regulation of 'loopy' enzymes more broadly.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008735","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

Regulation of renal aquaporins: implications in tubular epithelial integrity. 肾水通道蛋白的调控：对小管上皮完整性的影响。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2026-01-12 DOI: 10.1042/BST20253114

Vishalini Venkatesan, Charlotte M Sørensen, Emma Tina B Olesen

{"title":"Regulation of renal aquaporins: implications in tubular epithelial integrity.","authors":"Vishalini Venkatesan, Charlotte M Sørensen, Emma Tina B Olesen","doi":"10.1042/BST20253114","DOIUrl":"10.1042/BST20253114","url":null,"abstract":"Aquaporins (AQPs) are crucial membrane proteins that primarily facilitate water transport across cell membranes. In the kidneys, AQP1, AQP7, AQP8, and AQP11 are expressed in the proximal tubules. AQP1 is also localized to the thin descending limb of the loop of Henle. AQP2, AQP3, AQP4, AQP5, and AQP6 are expressed in the collecting ducts. Specific AQPs, such as aquaglyceroporins and peroxiporins, also transport solutes like glycerol and hydrogen peroxide, indicating their broader physiological roles beyond water permeability. Renal AQPs play a fundamental role in urine concentration and maintaining water balance. However, some studies using AQP knockout mouse models have reported structural abnormalities in the renal tubules, along with defective water handling. These findings highlight the involvement of AQPs in regulating cell proliferation, migration, and apoptosis, which are essential processes for maintaining tubular integrity. Furthermore, aquaglyceroporins and peroxiporins are implicated in modulating cellular redox balance and contributing to oxidative stress responses that are also associated with tubular damage. This review explores how AQPs are regulated under physiological conditions and how they become dysregulated in kidney diseases such as acute kidney injury, diabetic kidney disease, and polycystic kidney disease. Understanding these mechanisms may help in identifying new therapeutic strategies targeting AQPs in renal pathologies.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958525","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

Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review. 嘧啶生物合成途径在结核分枝杆菌中的靶向机会：简要综述。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2026-01-12 DOI: 10.1042/BST20253113

Marta Alberti, Riccardo Miggiano

{"title":"Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review.","authors":"Marta Alberti, Riccardo Miggiano","doi":"10.1042/BST20253113","DOIUrl":"10.1042/BST20253113","url":null,"abstract":"Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB) in humans, an infectious disease that continues to be a significant global health concern. The long-term use of multiple anti-tubercular agents may result in patient non-compliance and increased drug toxicity, which could contribute to the emergence of drug-resistant MTB strains that are not susceptible even to second-line available drugs. It is therefore imperative that new antitubercular drugs and vaccines are developed. The peculiar traits of MTB, such as the biochemical and structural features of vital metabolic pathways, can be assessed to identify possible targets for drug development. Enzymes involved in pyrimidine metabolism may be suitable drug targets for TB, given that this pathway is essential for mycobacteria and comprises enzymes that differ from those found in humans. Here, we focused on reviewing the state of the art concerning the therapeutic opportunities presented by the pyrimidine biosynthetic pathway (PBP) as a potential source of enzymes that could be targeted for the treatment of TB. We selected essential enzymes belonging to the PBP for which we identified the existence of a drug discovery pipeline at both the preclinical and clinical levels. Moreover, we emphasize the biochemical and structural characteristics that are pertinent to the development of pharmaceutical agents. These include the molecular details that can ensure selectivity towards the pathogen's proteins.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958537","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

Regulation and activity of the phosphatase SHP2: SH2 domains, dephosphorylation activity, and beyond. 磷酸酶SHP2的调控和活性：SH2结构域、去磷酸化活性等。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2026-01-09 DOI: 10.1042/BST20253102

Catia L Pierotti, Maja Köhn

{"title":"Regulation and activity of the phosphatase SHP2: SH2 domains, dephosphorylation activity, and beyond.","authors":"Catia L Pierotti, Maja Köhn","doi":"10.1042/BST20253102","DOIUrl":"10.1042/BST20253102","url":null,"abstract":"Src homology 2 (SH2) domain-containing phosphatase-2 (SHP2, PTPN11) is implicated in diseases such as cancer and RASopathies, where it is often mutated. It has gained strong attention due to promising new drug development strategies, with drug candidates currently in clinical trials. SHP2 is activated downstream of cell surface receptors to promote signaling pathways involved in cell growth and to inhibit immune cell activation. The phosphatase has two SH2 domains and a protein tyrosine phosphatase (PTP) domain, is post-translationally modified, and can function as an active phosphatase or as an adaptor/scaffold protein. It is subject to tight regulation in its cellular environment, for which novel insights have recently emerged. In this focused review, we first summarize the roles of the two SH2 domains and phosphorylation on the regulation of wildtype SHP2. We then describe new developments concerning catalytic and non-catalytic functions of SHP2, as well as recent progress in the understanding of SHP2 regulation, including it being subjected to SUMOylation, activated independently of cell surface receptors, and regulated by substrate phosphorylation. These new insights not only demonstrate the complexity of SHP2 regulation but also guide future studies, contributing important insights that could aid in targeting SHP2 in different disease contexts in the future.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"54 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931923","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

Leveraging AI for cell biology discovery. 利用人工智能进行细胞生物学发现。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2026-01-08 DOI: 10.1042/BST20253023

Adriana Simizo, Mauro de Morais, Matheus Vesco, Helder Nakaya

引用次数: 0

A busy BOD1-y: the diverse functions of an intracellular signaling regulatory protein family. 繁忙的BOD1-y：细胞内信号调节蛋白家族的多种功能。

IF 4.3 3区生物学

Biochemical Society transactions Pub Date : 2025-12-24 DOI: 10.1042/BST20253107

Thomas J Kucharski, Martin R Higgs, Duane A Compton, Susanne Bechstedt

{"title":"A busy BOD1-y: the diverse functions of an intracellular signaling regulatory protein family.","authors":"Thomas J Kucharski, Martin R Higgs, Duane A Compton, Susanne Bechstedt","doi":"10.1042/BST20253107","DOIUrl":"10.1042/BST20253107","url":null,"abstract":"The biorientation-defective (BOD) protein family, comprising BOD1, BOD1L1 (BOD1-like 1), and BOD1L2, plays critical and diverse roles in fundamental cellular processes, including mitosis, DNA repair, neurological function, and metabolism. BOD1 and BOD1L2 are small proteins of less than 200 amino acids, whereas BOD1L1 contains a long C-terminal extension, totaling 3042 amino acids. BOD1 was originally identified in Xenopus laevis oocyte chromatin extracts. Subsequent work in mitotic human cells demonstrated that BOD1 is an outer kinetochore protein that regulates PP2A-B56 phosphatase function and consequently is vital for chromosome biorientation and segregation fidelity, hence the name. BOD1 also has important roles in neurological function and lipid metabolism as a component of the COMPASS (complex of proteins associated with SET1)-SETD1B complex. In contrast, BOD1L1 was first identified as a phosphorylated target of the ATM kinase and then highlighted in a screen for DNA replication fork components. Further work demonstrated a role for BOD1L1 in DNA double-stranded break repair, where BOD1L1 is required to recruit the protein RIF1 to damaged chromatin to enable efficient DNA repair and control sensitivity to radio/chemotherapeutics. Consistently, BOD1L1 binds known DNA damage/repair/replication proteins, including FANCD2, RIF1, and BRCA2. Loss of BOD1L1 causes catastrophic genome instability through misrepair and/or overprocessing of damaged DNA. Recently, BOD1L1 has also been shown to regulate the PP2A-B56 phosphatase at kinetochores in mitotic human cells. In contrast, little is known about BOD1L2, which is only expressed in sperm cells and precursors. In this review, we describe recent progress in understanding the functions of this protein family and discuss future avenues of research.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":" ","pages":"1479-1491"},"PeriodicalIF":4.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793140","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

Tuft cell-mediated pathogen sensing and inflammation resolution. 簇毛细胞介导的病原体感知和炎症消退。

IF 4.3 3区生物学

Biochemical Society transactions Pub Date : 2025-12-24 DOI: 10.1042/BST20253057

Liquan Huang, Yuan-Yuan Peng, Defu Yu

{"title":"Tuft cell-mediated pathogen sensing and inflammation resolution.","authors":"Liquan Huang, Yuan-Yuan Peng, Defu Yu","doi":"10.1042/BST20253057","DOIUrl":"10.1042/BST20253057","url":null,"abstract":"Tuft cells are a rare type of epithelial cells characterized not only by their tuft-like structure but also by the expression of specific genes, including those encoding the transcription factor Pou2f3 and canonical gustatory signaling proteins. However, tuft cells can be heterogeneous in various features, both across different tissues and within the same tissue. Homeostatic tuft cells are generated from stem/progenitor cells; however, their formation and gene expression profiles are regulated epigenetically and in response to changes in their microenvironments. Ectopic formation of tuft cells, their transdifferentiation into other cell types, and dedifferentiation to stem/progenitor cells have also been found in some tissues upon severe injuries. Tuft cells function as chemosensory sentinels and can detect a variety of pathogens such as bacteria, protists, and helminths with their cell surface receptors. Activation of these receptors in turn activates intracellular signaling cascades, leading to the release of output effectors: the cytokine IL-25, the eicosanoids, and the transmitters acetyl choline and ATP, some of which act on group 2 innate lymphoid cells, triggering innate immune responses, or on neighboring epithelial cells to accelerate cilia beating and increase mucus secretion, or on the nerve terminals to initiate neuroimmune responses. Some tuft cells are also critical to inflammation resolution and tissue repair-an important part of the healing and recovery process. Further elucidation of tuft cells' ligands, respective receptors and downstream signaling pathways, and output effectors can provide more insights into these cells' pivotal roles in health and disease.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":" ","pages":"1445-1455"},"PeriodicalIF":4.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601971","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

eIF3: a critical player in mRNA recruitment to the ribosome with emerging roles across translation. eIF3: mRNA向核糖体募集的关键参与者，在翻译过程中发挥着新的作用。

IF 4.4 3区生物学

Biochemical Society transactions Pub Date : 2025-12-24 DOI: 10.1042/BST20253069

Nicholas A Ide, Sufana Noorwez, Christine Xu, Colin Echeverría Aitken

引用次数: 0

Catalytic-independent roles of chromatin modifiers in mammalian development and the implications for treating human disease. 染色质修饰剂在哺乳动物发育中的催化独立作用及其对治疗人类疾病的影响。

IF 4.3 3区生物学

Biochemical Society transactions Pub Date : 2025-12-24 DOI: 10.1042/BST20253098

Hannah K Vanyai, Marnie E Blewitt

{"title":"Catalytic-independent roles of chromatin modifiers in mammalian development and the implications for treating human disease.","authors":"Hannah K Vanyai, Marnie E Blewitt","doi":"10.1042/BST20253098","DOIUrl":"10.1042/BST20253098","url":null,"abstract":"The molecular function of chromatin modifiers is canonically assumed to be directly related to their enzymatic activities and these activities are typically measured when investigating the molecular consequences of manipulation in model systems. However, it is increasingly apparent that chromatin modifiers exhibit various functions beyond purely their enzymatic roles and, surprisingly, this is true across many classes of so-called 'writers' and 'erasers', including histone acetylases and methylases, and histone deacetylases and demethylases. Some of the most striking examples of the catalytic-independent roles of chromatin modifiers can be demonstrated in mouse models, where catalytic-inactive-encoding mutant alleles, in contrast with null alleles, can prolong survival during embryogenesis or, even more profoundly, allow otherwise embryonic lethal mutants to be born and live into adulthood. A deep understanding of the enzymatic and non-enzymatic roles of chromatin regulators is of clear relevance to understanding how they contribute to normal biology and becomes even more relevant given that many of these factors are also now therapeutic targets in the context of disease. Since therapeutic options have expanded beyond small molecule enzymatic inhibitors to include degraders and interaction blocking modalities, the time is ripe to consider these questions. In this review, we explore the catalytic-independent functions of members of four classes of chromatin modifiers, through the lens of mouse embryogenesis where much of the limited in vivo data have been reported to date. In addition, we examine how existing mouse models can be assessed to tease apart enzymatic versus non-enzymatic requirements of chromatin modifiers.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":" ","pages":"1507-1516"},"PeriodicalIF":4.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793162","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

Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate. 硫酸肝素与神经发育：星形胶质细胞表达硫酸肝素的解剖作用。

IF 4.3 3区生物学

Biochemical Society transactions Pub Date : 2025-12-24 DOI: 10.1042/BST20253088

Martina Gyimesi, Rachel K Okolicsanyi, Larissa M Haupt

{"title":"Heparan sulphate and neural development: dissecting the roles of astrocyte-expressed heparan sulphate.","authors":"Martina Gyimesi, Rachel K Okolicsanyi, Larissa M Haupt","doi":"10.1042/BST20253088","DOIUrl":"10.1042/BST20253088","url":null,"abstract":"Astrocytes are key regulators of neurogenesis, synaptogenesis, synaptic transmission and the clearance of pathological factors within the brain, while maintaining homeostasis throughout life. They also aid in the establishment and maintenance of a neurogenic niche enriched with precisely balanced growth factors, morphogens and extracellular matrix proteoglycans (PGs) to support neuronal development and function. Membrane-bound heparan sulphate (HS) PGs consist of core proteins decorated with HS glycosaminoglycan side chains, whose highly variable sulphation patterns regulate cellular signalling pathways such as Wnt and fibroblast growth factor. However, the specific contributions of astrocyte-derived and/or neuronal HSPGs within this microenvironment remain unclear. This mini-review examined our current understanding of the regulatory role of astrocyte-expressed HSPGs and their associated HS side chain structural variability. In particular, their influence on prenatal brain development, ageing and the changes occurring that contribute to neurodegeneration. We focused on the emerging concept that HS aggregation and impaired neurogenesis may serve as important preclinical contributors to Alzheimer's disease pathology. Alterations in astrocyteexpressed HS and their HSPG landscape are discussed as potential precursors to pathological HS aggregation and reactivity, shifting the focus of disease initiation to the potential compromise of the supportive astrocytic environment. We suggest that neuronal dysfunction cannot be solely attributed to neurodegeneration but must also be considered in the context of a deteriorating support system, where cells that once nurtured neurogenesis and synaptic integrity become dysfunctional contributors to disease pathology.","PeriodicalId":8841,"journal":{"name":"Biochemical Society transactions","volume":"53 6","pages":"1543-1554"},"PeriodicalIF":4.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817774","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