Biochemical Journal最新文献_第5页

Roles of acidic residues in SpeG acetyltransferases-insights into importance for kinetic activity and polyamine binding in allosteric and acceptor sites. 酸性残基在SpeG乙酰转移酶中的作用——对变构和受体位点的动力学活性和多胺结合的重要性的见解。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-06-03 DOI: 10.1042/BCJ20260162

Hazel N Leiva Martel, Van Thi Bich Le, Ekaterina V Filippova, Aron W Fenton, Melissa Law, Martha Marquez-Ramirez, Misty L Kuhn

{"title":"Roles of acidic residues in SpeG acetyltransferases-insights into importance for kinetic activity and polyamine binding in allosteric and acceptor sites.","authors":"Hazel N Leiva Martel, Van Thi Bich Le, Ekaterina V Filippova, Aron W Fenton, Melissa Law, Martha Marquez-Ramirez, Misty L Kuhn","doi":"10.1042/BCJ20260162","DOIUrl":"10.1042/BCJ20260162","url":null,"abstract":"The Gcn5-related N-acetyltransferases belong to a massive superfamily of enzymes that perform a wide array of functions in different organisms. This family is comprised of smaller subfamilies, including one called the spermidine/spermine N-acetyltransferases (SSATs). SSATs acetylate positively charged long-chain polyamines to maintain their intracellular concentrations. In bacteria, one primary type of SSAT is the SpeG enzyme, which adopts a homododecameric assembly. In the present study, we sought to detail how polyamines bind to both the allosteric and active sites of SpeG and determine which conserved acidic and polar residues are critical for kinetic activity and polyamine binding. Therefore, we determined a crystal structure of the Vibrio cholerae (VcSpeG) enzyme in complex with spermine in the allosteric site and N1-acetylspermine in the active site. This result clearly defines two distinct and separate polyamine binding sites within the protein. Furthermore, it demonstrates that SpeG is indeed an allosteric enzyme: homotropic in that the ligands are identical and heterotropic in that the allosteric binding sites are distinct from the active sites. We also investigated the kinetic activity of substituted residues in both sites and found several residues are critical for enzyme activity, while some substitutions altered polyamine substrate specificity. These combined structural and functional results begin to illuminate how longer-chain polyamines with terminal aminopropyl groups are recognized and acetylated by SpeG. Finally, we present a hypothetical model for proposed roles of conserved acidic residues in both sites, which provides a framework for subsequent studies of SpeG's intricate allosteric network.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1075-1095"},"PeriodicalIF":3.9,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13212360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833095","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

Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia. 重新评估急性髓系白血病靶向氧化磷酸化的基本原理。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-05-27 DOI: 10.1042/BCJ20260185

Brett R Chrest, Kelsey H Fisher-Wellman

{"title":"Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.","authors":"Brett R Chrest, Kelsey H Fisher-Wellman","doi":"10.1042/BCJ20260185","DOIUrl":"10.1042/BCJ20260185","url":null,"abstract":"Targeting mitochondrial oxidative phosphorylation (OxPhos) has become a recurring strategy in the treatment of cancer, particularly in acute myeloid leukemia (AML). Early reports suggested that leukemic blasts, and especially leukemia stem cells, depend disproportionately on mitochondrial respiration, implying a therapeutic window for systemic inhibition of the electron transport system (ETS) and OxPhos. Yet, the clinical record of broad OxPhos inhibition has been disappointing. In the present review, we argue that the pivotal question is not whether mitochondria matter for cancer, but whether specific mitochondrial processes are disproportionately essential to malignant cells compared with the organism's most OxPhos-dependent organs. We clarify what OxPhos is (and is not), emphasizing why oxygen consumption rate (OCR) is an incomplete surrogate for ATP-producing OxPhos flux and why transcriptomic 'OxPhos signatures' often confound energetic demand with compensatory responses to mitochondrial damage. We then benchmark OxPhos capacity and flux across normal tissues versus tumors, highlighting that highly oxidative organs typically operate at far higher respiratory flux than most cancers. Using the Complex I inhibitor IACS-010759 as a case study, we discuss why systemic ETS inhibition predictably collided with dose-limiting toxicity. Finally, focusing on AML, we dissect how OxPhos 'dependency' was inferred from indirect assays, how the failure to normalize for mitochondrial content may invert conclusions, and how ATP synthase reversal can masquerade as 'ATP-linked respiration.' We conclude with practical criteria for identifying mitochondrial liabilities that are targetable rather than merely essential, and we outline alternative strategies, which may better align mitochondrial biology with a realistic therapeutic index.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"483 6","pages":"907-925"},"PeriodicalIF":3.9,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940034","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

Peeking behind the carbocation: identification of (alternative) catalytic bases in the class II active site of conifer resin acid diterpene synthases. 碳正离子背后的窥视：针叶树树脂酸二萜合成酶II类活性位点（替代）催化碱的鉴定。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250232

Ahmed M A A Raslan,Reuben J Peters

{"title":"Peeking behind the carbocation: identification of (alternative) catalytic bases in the class II active site of conifer resin acid diterpene synthases.","authors":"Ahmed M A A Raslan,Reuben J Peters","doi":"10.1042/bcj20250232","DOIUrl":"https://doi.org/10.1042/bcj20250232","url":null,"abstract":"Class II diterpene cyclases (DTCs) initiate biosynthesis of the labdane-related diterpenoids (LRDs), utilizing an acid-base mechanism to catalyze bicyclization of the general diterpenoid precursor (E,E,E)-geranylgeranyl pyrophosphate (1), most often producing the eponymous labdadienyl/copalyl pyrophosphate (CPP, 2). Prominent among the LRDs and terpenoids more generally are the conifer resin acids. The abietaenol synthase from Abies grandis (AgAS), due in part to crystallographic structural analysis, serves as a model for the DTCs initiating resin acid biosynthesis, with such activity having been conserved for over 300 million years. Previous work suggests that a hydrogen-bonded tyrosine-histidine pair in its DTC active site serves as the catalytic base, in part because the substitution of aspartate for the histidine or phenylalanine for the tyrosine leads to the incorporation/addition of water and the production of labda-13-en-8α-ol-15-yl pyrophosphate (LPP, 3). However, the exact identity of the catalytic base in the native reaction, as well as any alternative base(s) enabling the production of 3 and 7-endo-CPP (4) in the histidine to aspartate mutant, remains unknown. Here, the TerDockin computational approach, combining quantum chemical modeling with computational docking, was applied to the AgAS DTC active site. This not only indicated the Tyr hydroxyl group serves as the native catalytic base but also surprisingly found a serine capable of serving as an alternative base for the production of 3 and a tyrosine serving as the alternative base for the production of 4, as supported by mutational analysis in AgAS. This provides mechanistic insight and further validates the TerDockin approach to investigation of these important enzymes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"25 1","pages":"817-827"},"PeriodicalIF":4.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754698","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

Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass. 重新审视RAS家族GTPase信号：效应选择性和致癌旁路。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250142

Dhirendra K Simanshu,Frank McCormick

{"title":"Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass.","authors":"Dhirendra K Simanshu,Frank McCormick","doi":"10.1042/bcj20250142","DOIUrl":"https://doi.org/10.1042/bcj20250142","url":null,"abstract":"Distinct effector-binding preferences among RAS family GTPases challenge the longstanding view that canonical RAS proteins uniformly bind and activate RAF, PI3Kα, RalGDS, and other downstream effectors. Quantitative binding data, supported by structural insights into effector recognition, instead reveal a division of labor: the canonical RAS subfamily (KRAS, HRAS, NRAS) binds RAF kinases with high affinity, the RRAS subfamily (RRAS2 and MRAS) preferentially engages PI3Kα, and the RAP subfamily (RAP1A and RAP1B) shows the strongest binding to RalGDS. These intrinsic preferences, encoded in the switch regions and further shaped by isoform and effector expression, as well as subcellular localization, establish a hierarchy in which canonical RAS, RRAS2/MRAS, and RAP1A/B primarily activate RAF, PI3Kα, and RalGDS, respectively, in normal cells. Oncogenic mutations at codons G12, G13, or Q61 disrupt this hierarchy by driving sustained accumulation of GTP-bound canonical RAS, enabling engagement of lower-affinity effectors such as PI3Kα and RalGDS. In addition, certain mutations, including KRAS-G12D and -G12V, modestly enhance PI3Kα binding, representing a neomorphic expansion of effector engagement. Together, these effects bypass intrinsic effector selectivity, allowing canonical RAS to co-opt effectors normally associated with other RAS subfamilies and broaden downstream signaling. This framework explains how inherent effector preferences govern normal signaling and how oncogenic mutations override these constraints to expand effector engagement in RAS-driven cancers.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"6 1","pages":"761-775"},"PeriodicalIF":4.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731429","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

Histone modification cross-talk: analytical tools and molecular mechanisms. 组蛋白修饰串扰：分析工具和分子机制。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250115

Jennifer Jiang,Sarah DuBois-Coyne,Eunju Nam,Samuel D Whedon,Kwangwoon Lee,Philip A Cole

{"title":"Histone modification cross-talk: analytical tools and molecular mechanisms.","authors":"Jennifer Jiang,Sarah DuBois-Coyne,Eunju Nam,Samuel D Whedon,Kwangwoon Lee,Philip A Cole","doi":"10.1042/bcj20250115","DOIUrl":"https://doi.org/10.1042/bcj20250115","url":null,"abstract":"Chromatin function emerges from combinatorial patterns of histone post-translational modifications (PTMs) that are read, written, and erased by dedicated enzymes. Over the past 30 years, increasing evidence suggests that specific histone PTMs or combinations of PTMs influence one another, constituting epigenetic cross-talk that shapes chromatin structure, protein-protein interactions, and catalytic efficiency of nucleosome-targeting enzymes. Here, we summarize mechanistic and methodological advances that enable rigorous interrogation of histone PTM interplay. We highlight selected nucleosome engineering strategies that build precisely modified substrates to test in vitro, proteomic pipelines that preserve combinatorial information, and omics technology that can globally profile integrated chromatin regulatory events in cells and tissues. Furthermore, we survey multivalent reader modules and engineered biosensors that report combinatorial marks in nucleosomes and living cells. Representative case studies illustrate how defined PTMs modulate catalytic parameters of writer and eraser complexes, including lysine methyltransferases, demethylases, acetyltransferases, and deacetylases, focusing on cross-talk with histone H3 N-terminal tail marks. These include the role of H3K9me2/3 and K14ac in directing propagation of H3K9me3, the role of H3K4me1/2 and K14ac in slowing H3K4 demethylation, the role of H3K4me2/3 in directing H3K9 acetylation, and the role of H3K36 methylation in directing deacetylation of H3 and H4. The substrates for these case studies include both mononucleosomes and nucleosome arrays. These examples illustrate the principle of epigenetic cross-talk, namely, that specific combinatorial PTMs can affect enzymes and alter local biochemistry.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"68 1","pages":"713-740"},"PeriodicalIF":4.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695271","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 CRISPR ring nuclease Csx15 oligomerises on cyclic nucleotide binding to regulate antiviral defence. CRISPR环核酸酶Csx15寡聚在环核苷酸结合上调节抗病毒防御。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/BCJ20260019

Haotian Chi, Stephen A McMahon, Shirley Graham, Malcolm F White

引用次数: 0

Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology. 使用氢氘交换质谱法串联与现代结构生物学。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250131

Hunter G Nyvall,Alexandria L Shaw,Emma E Walsh,Hirsh Bhatti,John E Burke

{"title":"Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.","authors":"Hunter G Nyvall,Alexandria L Shaw,Emma E Walsh,Hirsh Bhatti,John E Burke","doi":"10.1042/bcj20250131","DOIUrl":"https://doi.org/10.1042/bcj20250131","url":null,"abstract":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS) is an established technique that measures the exchange rate of amide hydrogens, with this exchange rate being a surrogate for protein conformational dynamics. Advances in instrumentation, automation, and data analysis have transformed HDX-MS into a high-throughput and highly reproducible method capable of probing complex biological systems and addressing key questions that have been challenging to study by other structural biology approaches. By enabling measurement of amide exchange rates and mapping of differential exchange between distinct conformational states, HDX-MS provides insight into both allosteric transitions and protein interaction interfaces. Recent advances in the capabilities of artificial intelligence (AI) have been rapidly adopted by structural biology, leading to an unprecedented expansion in the quantity and accessibility of structural predictions, underscoring the need for experimental methods to validate these predicted models and provide insight into both epitopes and allosteric conformational changes. This is particularly critical for non-evolutionarily driven interactions such as antibodies, nanobodies, and artificially designed proteins, where AI technologies can yield false positives. This review highlights how HDX-MS can be integrated synergistically into modern structural biology workflows (cryo-EM, X-ray crystallography, and AI-enabled modeling) and how combining these approaches can be powerful to advance our mechanistic understanding of complex biological processes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"1 1","pages":"585-602"},"PeriodicalIF":4.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680561","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

Cutting edge: ESCRT-mediated phagophore closure in mammals. 前沿：escrt介导的哺乳动物噬细胞关闭。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250148

Yoshinori Takahashi,David M Opozda,Hong-Gang Wang

引用次数: 0

Protein kinase C theta: evolution, regulation, and function. 蛋白激酶C theta：进化、调控和功能。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/bcj20250280

Stefanie J Hodapp,Gerard Manning,Alexandra C Newton

引用次数: 0

Correction: Characterisation of RNA guanine-7 methyltransferase (RNMT) using a small molecule approach. 更正：使用小分子方法表征RNA鸟嘌呤-7甲基转移酶（RNMT）。

IF 4.3 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/BCJ20240608_COR

David W Gray, Lesley-Anne Pearson, Alain-Pierre Petit, Cesar Mendoza-Martinez, Fiona Bellany, De Lin, Sarah Niven, Rachel Swift, Thomas Eadsforth, Paul K Fyfe, Marilyn Paul, Vincent Postis, Xiao Hu, Victoria H Cowling

引用次数: 0