Biochimie最新文献

{"title":"Advanced profiling and structural analysis of anencephaly gangliosides by ion mobility tandem mass spectrometry","authors":"Maria Roxana Biricioiu ,&nbsp;Mirela Sarbu ,&nbsp;Raluca Ica ,&nbsp;Željka Vukelić ,&nbsp;David E. Clemmer ,&nbsp;Alina D. Zamfir","doi":"10.1016/j.biochi.2025.01.011","DOIUrl":"10.1016/j.biochi.2025.01.011","url":null,"abstract":"<div><div>Anencephaly, the most severe type of neural tube defects (NTDs) in humans, occurs between the third and fourth gestational weeks (GW), involves the cranial part of the NT and results in the absence of the forebrain and skull. Exposed to amniotic fluid toxicity, neural tissue is degraded and prevented from development. Currently, little is known about the molecular bases of the disease and the possible involvement of glycans. In this context, considering the role played by gangliosides (GGs) in fetal brain development and the previous achievements of ion mobility separation (IMS) mass spectrometry (MS) in biomarker discovery, we report here on the introduction of this advanced analytical technique in NTD research, and its optimization for a comprehensive determination of anencephaly gangliosidome. Three native GG extracts from residual brains of anencephalic fetuses in 28, 35 and 37 GW were comparatively profiled by IMS MS, structurally analyzed by IMS MS/MS, and finally assessed against a native GG mixture from normal fetal brain. IMS MS provided data on 343 anencephaly gangliosides <em>vs</em>. only 157 known before and revealed for the first time the incidence of the entire penta-to octasialylated series. The comparative assay disclosed variations in GG expression with fetal age and a correlation of the pattern with the developmental stage. In contrast to the normal fetal brain, the neural tissue in anencephaly was found to contain an elevated number of polysialogangliosides and a lower expression of <em>O</em>-Ac- and GalNAc-modified glycoforms. These species worth further detailed investigation as new potential anencephaly markers.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 91-104"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069674","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}

{"title":"Chalcogen dihydrobenzofuran compounds as potential neuroprotective agents: An in vitro and in silico biological investigation","authors":"Tácia Katiane Hall ,&nbsp;Larissa Sander Magalhães ,&nbsp;Mariana Parron Paim ,&nbsp;Taís da Silva Teixeira Rech ,&nbsp;Amanda Rebelo de Azevedo ,&nbsp;Vanessa Nascimento ,&nbsp;José Sebastião Santos Neto ,&nbsp;César Augusto Brüning ,&nbsp;Cristiani Folharini Bortolatto","doi":"10.1016/j.biochi.2025.01.006","DOIUrl":"10.1016/j.biochi.2025.01.006","url":null,"abstract":"<div><div>Oxidative stress arises from an imbalance between reactive species (RS) production and the antioxidant defense, increasing the brain susceptibility to neurodegenerative and psychiatric diseases. Besides, changes in the expression or activity of neurotransmitter metabolism enzymes, such as monoamine oxidases (MAO), are also associated with mental disorders, including depression. Considering this, antioxidant and MAO-A activity inhibitory potential of six 2,3-chalcogenodihydrobenzofurans (2,3-DHBF) was investigated through <em>in vitro</em> and <em>in silico</em> tests. Compounds <strong>1</strong> to <strong>5</strong> incorporate sulfur (S) as chalcogen, whereas compound <strong>6</strong> integrates tellurium (Te). A screening (compounds <strong>1</strong>–<strong>6</strong>) of cerebral MAO-A activity showed inhibitory activity for the compounds <strong>2</strong>, <strong>4</strong>, <strong>5</strong>, and <strong>6</strong>. Among sulfur compounds, compound <strong>2</strong> demonstrated superior scores in docking studies, yielding a value of - 9.9 kcal/mol. Selected for concentration-response curves, compounds <strong>2</strong> (with S) and <strong>6</strong> (with Te) inhibited MAO-A at concentrations equal to or higher than 25 μM. In a redox screening test, only compound <strong>6</strong> showed antioxidant effects. Concentration-response curves indicated that compound <strong>6</strong> reduced lipid peroxidation and protein carbonylation levels in mouse brain tissue (≥0.5 μM), as well as reduced RS levels (≥1 μM). Furthermore, the compound <strong>6</strong> (≥5 μM) was effective in reducing the ferric ion (FRAP). In radical scavenging tests such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), compound <strong>6</strong> showed significant results in concentrations from 50 μM and mimicked the enzyme glutathione S-transferase (GST) at 100 μM. In summary, this study demonstrated the cerebral antioxidant and/or MAO-A inhibition properties of 2,3-DHBF, presenting potential as neuroprotective candidates.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 54-65"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069711","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}

{"title":"Interaction and cleavage of cell and plasma proteins by the platelet-aggregating serine protease PA-BJ of Bothrops jararaca venom","authors":"Daniela Cajado-Carvalho,&nbsp;Mariana S.L.C. Morone,&nbsp;Nancy da Rós,&nbsp;Solange M.T. Serrano","doi":"10.1016/j.biochi.2025.01.007","DOIUrl":"10.1016/j.biochi.2025.01.007","url":null,"abstract":"<div><div>PA-BJ is a serine protease present in <em>Bothrops jararaca</em> venom that triggers platelet aggregation and granule secretion by activating the protease-activated receptors PAR-1 and PAR-4, without clotting fibrinogen. These receptors also have a relevant role in endothelial cells, however, the interaction of PA-BJ with other membrane-bound or soluble targets is not known. Here we explored the activity of PA-BJ on endothelial cell receptor, cytoskeleton, and coagulation proteins <em>in vitro</em>, and show the degradation of fibrinogen and protein C, and the limited proteolysis of actin, EPCR, PAR-1, and thrombomodulin. Antithrombin, factors XI and XIII and protein S were not cleaved by PA-BJ. Moreover, using surface plasmon resonance PA-BJ was demonstrated to bind to actin, EPCR, fibrinogen, PAR-1, and thrombomodulin, with dissociation constants (K_D) in the micromolar range. Considering that these proteins play critical roles in pathways of blood coagulation and maintenance of endothelium integrity, their binding and cleavage by PA-BJ could contribute to the alterations in hemostasis and cell permeability observed in <em>B. jararaca</em> envenomation process.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 127-132"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069804","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}

{"title":"The modulation of low molecular weight sulfur compounds levels in visceral adipose tissue of TLR2-deficient mice on a high-fat diet","authors":"Patrycja Bronowicka-Adamska ,&nbsp;Dominika Szlęzak ,&nbsp;Anna Bentke-Imiolek ,&nbsp;Kinga Kaszuba ,&nbsp;Monika Majewska-Szczepanik","doi":"10.1016/j.biochi.2025.01.008","DOIUrl":"10.1016/j.biochi.2025.01.008","url":null,"abstract":"<div><div>Obesity treatment requires an individualized approach, emphasizing the need to identify metabolic pathways of diagnostic relevance. Toll-like receptors (TLRs), particularly TLR2 and TLR4, play a crucial role in metabolic disorders, as receptor deficiencies improves insulin sensitivity and reduces obesity-related inflammation. Additionally, hydrogen sulfide (H₂S) influences lipolysis, adipogenesis, and adipose tissue browning through persulfidation.</div><div>This study investigates the impact of a high-fat diet (HFD) on low molecular weight sulfur compounds in the visceral adipose tissue (VAT) of C57BL/6 and TLR2-deficient mice. It focuses on key enzymes involved in H₂S metabolism: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CGL), 3-mercaptopyruvate sulfurtransferase (MPST), and thiosulfate sulfurtransferase (TST).</div><div>In C57BL/6 mice on HFD, MPST activity decreased, while CBS level increased, potentially compensating for H₂S production. In contrast, TLR2-deficient mice on HFD exhibited higher MPST activity but reduced level of CBS and CGL activity, suggesting that TLR2 deficiency mitigates HFD-induced changes in sulfur metabolism. TST activity was lower in TLR2-deficient mice, indicating an independent regulatory role of TLR2 in TST activity. Elevated oxidative stress, reflected by increased glutathione levels, was observed in wild-type mice. Interestingly, cysteine and cystine were detectable only in the VAT of the C57BL/6 ND group and were absent in all other groups. The capacity for hydrogen sulfide production in tissues from TLR2−/−B6 HFD group was significantly lower than in the C57BL/6 HFD group.</div><div>In conclusion, TLR2 modulates sulfur metabolism, oxidative stress, and inflammation in obesity. TLR2 deficiency disrupts H₂S production and redox balance, potentially contributing to metabolic dysfunction, highlighting TLR2 as a potential therapeutic target for obesity-related metabolic disorders.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 66-73"},"PeriodicalIF":3.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054506","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}

{"title":"Neutrophils and purinergic signaling: Partners in the crime against Leishmania parasites?","authors":"Mariana M. Chaves","doi":"10.1016/j.biochi.2025.01.004","DOIUrl":"10.1016/j.biochi.2025.01.004","url":null,"abstract":"<div><div>The parasite of the genus <em>Leishmania</em> is the causative agent of diseases that affect humans called leishmaniasis. These diseases affect millions of people worldwide and the currently existing drugs are either very toxic or the parasites acquire resistance. Therefore, new elimination mechanisms need to be elucidated so that new therapeutic strategies can be developed. Much has already been discussed about the role of neutrophils in <em>Leishmania</em> infection, and their participation is still controversial. A recent study showed that receptors present in the neutrophil membrane, the purinergic receptors, can control the infection when activated, but the triggering mechanism has not been elucidated. In this review, we will address the possible participation of purinergic receptors expressed in the neutrophil extracellular membrane that may be participating in the detection of <em>Leishmania</em> infection and their possible effects during parasitism.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 43-53"},"PeriodicalIF":3.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043750","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}

{"title":"Structure and function analysis of microcystin transport protein MlrD","authors":"Jiaqi Li ,&nbsp;Huanhuan Sun ,&nbsp;Huasheng Wang ,&nbsp;Fengqiu Zhou ,&nbsp;Wenyu Wu ,&nbsp;Dan Chen ,&nbsp;Zhenning Zhou ,&nbsp;Hai Yan","doi":"10.1016/j.biochi.2025.01.005","DOIUrl":"10.1016/j.biochi.2025.01.005","url":null,"abstract":"<div><div>Microorganisms play a crucial role in the degradation of microcystins (MCs), with most MC-degrading bacteria utilizing the <em>mlr</em> gene cluster (<em>mlrABCD</em>) mechanism. While previous studies have advanced our understanding of the structure, function, and degradation mechanisms of MlrA, MlrB, and MlrC, research on MlrD remains limited. Consequently, the molecular structure and specific catalytic processes of MlrD are still unclear. This study investigates MlrD from <em>Sphingopyxis</em> sp. USTB-05, utilizing bioinformatics tools for analysis and prediction, conducting homology analysis, and constructing the molecular structure of MlrD. Bioinformatics analysis suggests that MlrD is an alkaline, hydrophobic protein with good thermal stability and is likely located in the cell membrane as a membrane protein without a signal peptide. Homology analysis indicates that MlrD belongs to the PTR2 protein family and contains a PTR2 domain. Phylogenetic analysis reveals that MlrD follows both vertical and horizontal genetic transfer patterns during evolution. Homology modeling demonstrates that the three-dimensional structure of MlrD is primarily composed of 12 α-helices, with conserved residues between the <em>N</em>-terminal and <em>C</em>-terminal domains forming a large reaction cavity. This research broadens current knowledge of MC biodegradation and offers a promising foundation for future studies.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"231 ","pages":"Pages 155-162"},"PeriodicalIF":3.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026150","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}

{"title":"Macrolactin a is an inhibitor of protein biosynthesis in bacteria","authors":"Alexey S. Vasilchenko ,&nbsp;Dmitry A. Lukyanov ,&nbsp;Diana S. Dilbaryan ,&nbsp;Konstantin S. Usachev ,&nbsp;Darya V. Poshvina ,&nbsp;Amir Kh. Taldaev ,&nbsp;Arina A. Nikandrova ,&nbsp;Arina N. Imamutdinova ,&nbsp;Natalia S. Garaeva ,&nbsp;Aydar G. Bikmullin ,&nbsp;Evelina A. Klochkova ,&nbsp;Alexander L. Rusanov ,&nbsp;Daniil D. Romashin ,&nbsp;Natalia G. Luzgina ,&nbsp;Ilya A. Osterman ,&nbsp;Petr V. Sergiev ,&nbsp;Anastasia V. Teslya","doi":"10.1016/j.biochi.2025.01.003","DOIUrl":"10.1016/j.biochi.2025.01.003","url":null,"abstract":"<div><div>Macrolactin A (McA) is a secondary metabolite produced by <em>Bacillus</em> species. It has been known for its antimicrobial properties since the late 1980s, although the exact mechanism of its antibacterial activity remains unknown. In this study, we have found that McA is an inhibitor of protein synthesis in bacteria. Our conclusion is based on the results obtained by <em>in vivo</em> and <em>in vitro</em> bioreporter systems. We demonstrated that the inhibitory activity of McA is independent of bacterial species. However, the concentration of McA required to inhibit protein synthesis in the <em>E. coli</em> cell-free translational model was found to be 50 times lower than the concentration required in the <em>S. aureus</em> cell-free translational model. To investigate the mechanism of McA's inhibitory activity, we conducted a toe-printing assay, sequenced and annotated the genomes of McA-resistant <em>Bacillus pumilus</em> McA^R and its parental strain. The results showed that McA inhibits the initial step of the elongation phase of protein synthesis. We identified single and multiple nucleotide polymorphisms in the gene encoding the translation elongation factor Tu (EF-Tu). Molecular modeling showed that the McA molecule can form non-covalent bonds with amino acids at the interface of domains 1 and 2 of EF-Tu. A cross-resistance assay was conducted using kirromycin on <em>B. pumilus</em> McA^R. The results confirmed the assumption that McA has a mode of action similar to that of other elfamycin-like antibiotics (targeting EF-Tu). Overall, our study addresses a significant gap in our understanding of the mechanism of action of McA, a representative member of the macrolide antibiotics.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 25-34"},"PeriodicalIF":3.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018181","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}

{"title":"Redesigning methionine γ-lyase for improved stability and catalytic activity in the β-elimination reaction for the synthesis of thiosulfinates","authors":"Vitalia Kulikova,&nbsp;Natalya Anufrieva,&nbsp;Elena Morozova,&nbsp;Kseniya Levshina,&nbsp;Svetlana Revtovich,&nbsp;Pavel Solyev","doi":"10.1016/j.biochi.2025.01.002","DOIUrl":"10.1016/j.biochi.2025.01.002","url":null,"abstract":"<div><div>Pyridoxal 5′-phosphate (PLP)-dependent enzymes are involved in many cellular processes and possess unequalled catalytic versatility. Rational design through site-directed mutagenesis is a powerful strategy for creating tailor-made enzymes for a wide range of biocatalytic applications. PLP-dependent methionine γ-lyase (MGL), which degrades sulfur-containing amino acids, is an encouraging enzyme for many therapeutic purposes – from combating bacterial resistant strains and fungi to antitumor activity. A two-component biosystem MGL/<em>S</em>-alk(en)yl-<span>l</span>-cysteine sulfoxide (an uncommon substrate for this enzyme) produces antimicrobial thiosulfinates during the β-elimination reaction. SH-groups of the enzyme are modified by the products of this reaction, which leads to the inactivation of the enzyme. Successful and efficient rational stabilization of MGL from <em>Clostridium novyi</em> can be achieved using site-directed mutagenesis. We have managed to obtain an improved version of the enzyme better than the natural one regarding the β-elimination reaction. Cys118, Cys184 and Cys273 of MGL from <em>Clostridium novyi</em> were substituted by His and two Ala, respectively. The resulting Cys-del variant had 2-3-fold improved <em>k</em>_<em>cat</em><em>/K</em>_<em>m</em> value for conventional β-eliminating substrates and up to 10-fold increase in catalytic efficiency with <em>S</em>-substituted-<span>l</span>-cysteine sulfoxides compared to the wild-type MGL. The Cys-del MGL remained active under the thiosulfinates, which are products of β-elimination reaction of <em>S</em>-alk(en)yl-<span>l</span>-cysteine sulfoxides. Moreover, Cys-del variant proved to be more stable during shelf storage. Thus, we have created an effective enzyme component of the biocatalytic system that is capable of generating antimicrobial drugs – thiosulfinates.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 35-42"},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018183","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}

{"title":"Interaction of small heat shock proteins with BAG3","authors":"Maria A. Zamotina ,&nbsp;Lydia K. Muranova ,&nbsp;Arthur I. Zabolotskii ,&nbsp;Nikolai B. Gusev","doi":"10.1016/j.biochi.2025.01.001","DOIUrl":"10.1016/j.biochi.2025.01.001","url":null,"abstract":"<div><div>BAG3 is a universal adapter protein involved in various cellular processes, including the regulation of apoptosis, chaperone-assisted selective autophagy, and heat shock protein function. The interaction between small heat shock proteins (sHsps) and their α-crystallin domains (Acds) with full-length BAG3 protein and its IPV domain was analyzed using size-exclusion chromatography, native gel electrophoresis, and chemical cross-linking. HspB7 and the 3D mutant of HspB1 (which mimics phosphorylation) showed no interaction, HspB6 weakly interacted, and HspB8 strongly interacted with full-length BAG3. In contrast to the full-length sHsps, their α-crystallin domains (AcdB1, AcdB5, and AcdB6) were able to interact with BAG3, with AcdB8 again being the strongest interactor. Among all the full-length sHsps analyzed, only HspB8 bound to the IPV domain of BAG3. AcdB1, AcdB5, AcdB6, and AcdB8 interacted with the IPV domain of BAG3, with AcdB8 displaying the highest binding efficiency. The stoichiometry of crosslinked complexes formed by HspB8 (or its Acd) and the IPV domain of BAG3 was 2:1, whereas for the other sHsps and their Acds, it was 1:1. These findings suggest that while the IPV domain of BAG3 and the Acds of sHsps play an important role in binding, other structural regions significantly contribute to this interaction. The unique binding efficiency between BAG3 and HspB8 may be attributed to the intrinsic disorder and simple oligomeric structure of HspB8.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 15-24"},"PeriodicalIF":3.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018179","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}

{"title":"Elucidating on the quaternary structure of viper venom phospholipase A2 enzymes in aqueous solution","authors":"Joana R. da Silva,&nbsp;Maria João Ramos,&nbsp;Pedro A. Fernandes","doi":"10.1016/j.biochi.2024.12.015","DOIUrl":"10.1016/j.biochi.2024.12.015","url":null,"abstract":"<div><div>This study focuses on the quaternary structure of the viper-secreted phospholipase A₂ (PLA₂), a central toxin in viper envenomation. PLA₂ enzymes catalyze the hydrolysis of the sn-2 ester bond of membrane phospholipids. Small-molecule inhibitors that act as snakebite antidotes, such as varespladib, are currently in clinical trials. These inhibitors likely bind to the enzyme in the aqueous cytosol prior to membrane-binding. Thus, understanding its controversial solution structure is key for drug design.</div><div>Crystal structures of PLA₂ in the PDB show at least four different dimeric conformations, the most well-known being “extended” and “compact”. This variability among enzymes with &gt;50 % sequence identity raises questions about their transferability to aqueous solution. Therefore, we performed extensive molecular dynamics (MD) simulations of several PLA₂ enzymes in water to determine their quaternary structure under physiological conditions. The MD simulations strongly indicate that PLA₂ enzymes adopt a “semi-compact” conformation in cytosol, a hybrid between extended and compact conformations.</div><div>To our knowledge, this is the first study that determines the most favorable dimeric conformation of PLA₂ enzymes in solution, providing a basis for advancements in snakebite envenoming treatment. Recognizing snakebite envenoming as a neglected tropical disease has driven the search for efficient, affordable alternatives to the current antivenoms. Therefore, understanding the main drug targets within snake venom is crucial to this achievement.</div></div>","PeriodicalId":251,"journal":{"name":"Biochimie","volume":"232 ","pages":"Pages 1-14"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973797","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}