ACS Chemical Neuroscience最新文献

Light-Activatable, Cell-Type Specific Labeling of the Nascent Proteome. 对新生蛋白质组进行光激活、细胞类型特异性标记。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-22 DOI: 10.1021/acschemneuro.4c00274

H T Evans, T Ko, M M Oliveira, A Yu, S V Kalavai, E N Golhan, A Polavarapu, E Balamoti, V Wu, E Klann, D Trauner

{"title":"Light-Activatable, Cell-Type Specific Labeling of the Nascent Proteome.","authors":"H T Evans, T Ko, M M Oliveira, A Yu, S V Kalavai, E N Golhan, A Polavarapu, E Balamoti, V Wu, E Klann, D Trauner","doi":"10.1021/acschemneuro.4c00274","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00274","url":null,"abstract":"Elucidating the mechanisms by which protein synthesis contributes to complex biological processes has remained a challenging endeavor. This is particularly true in the field of neuroscience, where multiple, tightly regulated periods of new protein synthesis in different cell-types are thought to facilitate intricate neurological functions, such as memory formation. Current methods for labeling the de novo proteome have lacked the spatial and temporal resolution to accurately discriminate these overlapping and often competing windows of mRNA translation. To address this technological limitation, here we describe a novel, light-inducible specific method for labeling newly synthesized proteins within a targeted cell-type.By developing Opto-ANL, a photocaged version of the nonendogenous amino acid azidonorleucine (ANL), we can selectively label newly synthesized proteins in specific cell-types through the targeted expression of a mutant methionyl-tRNA synthetase (L274G-MetRS). We demonstrate that Opto-ANL can be rapidly uncaged by UV light treatment in both cell culture and mouse brain slices, with Opto-ANL labeled proteins being able to be visualized via fluorescent noncanonical amino acid tagging. We also reveal that pretreatment with Opto-ANL not only allows for the period of de novo proteomic labeling to be tightly controlled, but also improves labeling efficiency compared to regular ANL. To demonstrate the potential applications of this novel technique, we use Opto-ANL to detect insulin-induced increases in protein synthesis and to label the excitatory neuronal de novo proteome in mouse brain slices. We believe that this application of photopharmacology will allow researchers to generate novel insights into how the translational landscape is altered across cell-types during complex neurological phenomena such as memory formation.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry 肌痛性脑脊髓炎患者和健康志愿者体内色氨酸代谢物的非靶向代谢组学和定量分析：使用高分辨率质谱法进行比较研究

IF 5 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-20 DOI: 10.1021/acschemneuro.4c00444

Sandy Abujrais, Theodosia Vallianatou, Jonas Bergquist

{"title":"Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry","authors":"Sandy Abujrais, Theodosia Vallianatou, Jonas Bergquist","doi":"10.1021/acschemneuro.4c00444","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00444","url":null,"abstract":"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide. To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry. We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group. These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alzheimer's Disease Immunotherapy and Mimetic Peptide Design for Drug Development: Mutation Screening, Molecular Dynamics, and a Quantum Biochemistry Approach Focusing on Aducanumab::Aβ2-7 Binding Affinity. 阿尔茨海默病免疫疗法和药物开发中的仿生肽设计：突变筛选、分子动力学和量子生物化学方法，聚焦 Aducanumab::Aβ2-7 结合亲和力。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-20 DOI: 10.1021/acschemneuro.4c00453

Victor L B França, Eveline M Bezerra, Roner F da Costa, Hernandes F Carvalho, Valder N Freire, Geanne Matos

{"title":"Alzheimer's Disease Immunotherapy and Mimetic Peptide Design for Drug Development: Mutation Screening, Molecular Dynamics, and a Quantum Biochemistry Approach Focusing on Aducanumab::Aβ2-7 Binding Affinity.","authors":"Victor L B França, Eveline M Bezerra, Roner F da Costa, Hernandes F Carvalho, Valder N Freire, Geanne Matos","doi":"10.1021/acschemneuro.4c00453","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00453","url":null,"abstract":"Seven treatments are approved for Alzheimer's disease, but five of them only relieve symptoms and do not alter the course of the disease. Aducanumab (Adu) and lecanemab are novel disease-modifying antiamyloid-β (Aβ) human monoclonal antibodies that specifically target the pathophysiology of Alzheimer's disease (AD) and were recently approved for its treatment. However, their administration is associated with serious side effects, and their use is limited to early stages of the disease. Therefore, drug discovery remains of great importance in AD research. To gain new insights into the development of novel drugs for Alzheimer's disease, a combination of techniques was employed, including mutation screening, molecular dynamics, and quantum biochemistry. These were used to outline the interfacial interactions of the Aducanumab::Aβ2-7 complex. Our analysis identified critical stabilizing contacts, revealing up to 40% variation in the affinity of the Adu chains for Aβ2-7 depending on the conformation outlined. Remarkably, two complementarity determining regions (CDRs) of the Adu heavy chain (HCDR3 and HCDR2) and one CDR of the Adu light chain (LCDR3) accounted for approximately 77% of the affinity of Adu for Aβ2-7, confirming their critical role in epitope recognition. A single mutation, originally reported to have the potential to increase the affinity of Adu for Aβ2-7, was shown to decrease its structural stability without increasing the overall binding affinity. Mimetic peptides that have the potential to inhibit Aβ aggregation were designed by using computational outcomes. Our results support the use of these peptides as promising drugs with great potential as inhibitors of Aβ aggregation.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional Characterization of an Arylsulfonamide-Based Small-Molecule Inhibitor of the NLRP3 Inflammasome 基于芳基磺酰胺的 NLRP3 炎症体小分子抑制剂的功能表征

IF 5 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-19 DOI: 10.1021/acschemneuro.4c00512

Savannah Biby, Prasenjit Mondal, Yiming Xu, Ashley Gomm, Baljit Kaur, Jannatun N. Namme, Changning Wang, Rudolph E. Tanzi, Shijun Zhang, Can Zhang

{"title":"Functional Characterization of an Arylsulfonamide-Based Small-Molecule Inhibitor of the NLRP3 Inflammasome","authors":"Savannah Biby, Prasenjit Mondal, Yiming Xu, Ashley Gomm, Baljit Kaur, Jannatun N. Namme, Changning Wang, Rudolph E. Tanzi, Shijun Zhang, Can Zhang","doi":"10.1021/acschemneuro.4c00512","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00512","url":null,"abstract":"Considerable evidence indicates that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays key roles in human pathophysiology, suggesting it as a potential drug target. Currently, studies have yet to develop compounds that are promising therapeutics in the clinic by targeting the NLRP3 inflammasome. Herein, we aim to further biologically characterize a previously identified small-molecule inhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm its functional activities. We showed that YM-I-26 is highly selective toward the NLRP3 inflammasome and binds to NLRP3 directly. A systemic analysis revealed YM-I-26 with inflammation-related and immunomodulatory activities by the Eurofins BioMAP Diversity PLUS panel. In addition, studies using the mouse microglia BV2 cell model demonstrated that YM-I-26 is not cytotoxic, improved the phagocytotic functions of BV2 cells toward beta-amyloid, and suppressed the production of cytokines of IL-1β and IL-10 upon the activation of the NLRP3 inflammasome. Collectively, our studies support the functional activities of YM-I-26 as a NLRP3 inhibitor in physiologically relevant cell models, and warrant future studies of YM-I-26 and its analogs to advance the drug development as potential therapeutics.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids. 在脂肪酸存在下生长的淀粉样β 1-42 寡聚体和纤维的纳米级结构特征。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 Epub Date: 2024-09-02 DOI: 10.1021/acschemneuro.4c00275

Kiryl Zhaliazka, Dmitry Kurouski

{"title":"Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.","authors":"Kiryl Zhaliazka, Dmitry Kurouski","doi":"10.1021/acschemneuro.4c00275","DOIUrl":"10.1021/acschemneuro.4c00275","url":null,"abstract":"Mono- and polyunsaturated fatty acids (FAs) are broadly used as food supplements. However, their effect on the aggregation of amyloidogenic proteins remains unclear. In this study, we investigated the effect of a large number of mono- and polyunsaturated, as well as fully saturated FAs on the aggregation of amyloid β1-42 (Aβ1-42) peptide. A progressive aggregation of this peptide is the expected molecular cause of Alzheimer's disease (AD), one of the most common neurodegenerative pathologies in the world. We found that arachidonic and stearic acids delayed the aggregation of Aβ1-42. Using Nano-Infrared spectroscopy, we found that FAs caused very little if any changes in the secondary structure of Aβ1-42 oligomers and fibrils formed at different stages of protein aggregation. However, the analyzed mono- and polyunsaturated, as well as fully saturated FAs uniquely altered the toxicity of Aβ1-42 fibrils. We found a direct relationship between the degree of FAs unsaturation and toxicity of Aβ1-42 fibrils formed in their presence. Specifically, with an increase in the degree of unsaturation, the toxicity Aβ1-42/FA fibrils increased. These results indicate that fully saturated or monounsaturated FAs could be used to decrease the toxicity of amyloid aggregates and, consequently, decelerate the development of AD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of New Highly Potent Histamine H₃ Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors. 发现新型强效组胺 H3 受体拮抗剂、钙通道阻滞剂和乙酰胆碱酯酶抑制剂。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 Epub Date: 2024-08-29 DOI: 10.1021/acschemneuro.4c00341

Rim Malek, Kinga Sałat, Perle Totoson, Tadeusz Karcz, Bernard Refouvelet, Anna Skrzypczak-Wiercioch, Maciej Maj, Alexey Simakov, Helene Martin, Agata Siwek, Natalia Szałaj, Justyna Godyń, Dawid Panek, Anna Więckowska, Krzysztof Jozwiak, Celine Demougeot, Katarzyna Kieć-Kononowicz, Fakher Chabchoub, Isabel Iriepa, José Marco-Contelles, Lhassane Ismaili

{"title":"Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.","authors":"Rim Malek, Kinga Sałat, Perle Totoson, Tadeusz Karcz, Bernard Refouvelet, Anna Skrzypczak-Wiercioch, Maciej Maj, Alexey Simakov, Helene Martin, Agata Siwek, Natalia Szałaj, Justyna Godyń, Dawid Panek, Anna Więckowska, Krzysztof Jozwiak, Celine Demougeot, Katarzyna Kieć-Kononowicz, Fakher Chabchoub, Isabel Iriepa, José Marco-Contelles, Lhassane Ismaili","doi":"10.1021/acschemneuro.4c00341","DOIUrl":"10.1021/acschemneuro.4c00341","url":null,"abstract":"At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Structure–Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents” 对 "芬太尼支架的结构-活性关系：确定作为潜在阿片类药物过量逆转剂的拮抗剂 "的更正

IF 5 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 DOI: 10.1021/acschemneuro.4c00579

Jessica P. Anand, Sierra C. Moore, Emma E. Dixon, Carmelita M. Perrien Naccarato, Joshua L. West, Lennon J. Delong, Emily Burgess, Jack J. Twarozynski, John R. Traynor

引用次数: 0

Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light. 用可见光可逆地控制原生含 GluN2B 的 NMDA 受体

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 Epub Date: 2024-09-06 DOI: 10.1021/acschemneuro.4c00247

Chloé Geoffroy, Romain Berraud-Pache, Nicolas Chéron, Isabelle McCort-Tranchepain, Julia Doria, Pierre Paoletti, Laetitia Mony

{"title":"Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light.","authors":"Chloé Geoffroy, Romain Berraud-Pache, Nicolas Chéron, Isabelle McCort-Tranchepain, Julia Doria, Pierre Paoletti, Laetitia Mony","doi":"10.1021/acschemneuro.4c00247","DOIUrl":"10.1021/acschemneuro.4c00247","url":null,"abstract":"NMDA receptors (NMDARs) are glutamate-gated ion channels playing a central role in synaptic transmission and plasticity. NMDAR dysregulation is linked to various neuropsychiatric disorders. This is particularly true for GluN2B-containing NMDARs (GluN2B-NMDARs), which have major pro-cognitive, but also pro-excitotoxic roles, although their exact involvement in these processes remains debated. Traditional GluN2B-selective antagonists suffer from slow and irreversible effects, limiting their use in native tissues. We therefore developed OptoNAM-3, a photoswitchable negative allosteric modulator selective for GluN2B-NMDARs. OptoNAM-3 provided light-induced reversible inhibition of GluN2B-NMDAR activity with precise temporal control both in vitro and in vivo on the behavior of freely moving Xenopus tadpoles. When bound to GluN2B-NMDARs, OptoNAM-3 displayed remarkable red-shifting of its photoswitching properties allowing the use of blue light instead of UV light to turn-off its activity, which we attributed to geometric constraints imposed by the binding site onto the azobenzene moiety of the ligand. This study therefore highlights the importance of the binding site in shaping the photochemical properties of azobenzene-based photoswitches. In addition, by enabling selective, fast, and reversible photocontrol of native GluN2B-NMDARs with in vivo compatible photochemical properties (visible light), OptoNAM-3 should be a useful tool for the investigation of the GluN2B-NMDAR physiology in native tissues.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation. 将 Anakinra 重新用于阿尔茨海默病：Anakinra对LPS和AC诱导的神经炎症的体外和体内影响

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 Epub Date: 2024-08-30 DOI: 10.1021/acschemneuro.4c00205

Thaarvena Retinasamy, Amber Lot Yee Lee, Hsien Siang Lee, Vanessa Lin Lin Lee, Mohd Farooq Shaikh, Keng Yoon Yeong

{"title":"Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation.","authors":"Thaarvena Retinasamy, Amber Lot Yee Lee, Hsien Siang Lee, Vanessa Lin Lin Lee, Mohd Farooq Shaikh, Keng Yoon Yeong","doi":"10.1021/acschemneuro.4c00205","DOIUrl":"10.1021/acschemneuro.4c00205","url":null,"abstract":"Alzheimer's disease is a significant global health issue, and studies suggest that neuroinflammation plays a vital role in the advancement of this disease. In this study, anakinra has been shown to display a time- and concentration-dependent antineuroinflammatory effect. In the in vitro studies, it diminished the gene expressions of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) synthase 2 stimulated by lipopolysaccharide (LPS). Anakinra also reduced the LPS-induced production of NO and reactive oxygen species. Thus, the hypertrophic state of LPS-activated BV2 microglial cells was reversed by anakinra. Furthermore, acrylamide (ACR)-induced activation of nuclear transcription factor-κB, TNF-α, and interleukin-1β was downregulated, while cAMP response element binding protein and brain-derived neurotrophic factor expression levels were markedly enhanced in ACR-treated zebrafish larvae. It was also observed that anakinra improved the uncoordinated swimming behaviors in ACR-exposed zebrafish larvae. Overall, anakinra demonstrated potential antineuroinflammatory and antioxidative effects.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kinetic Properties of Glutamate Carboxypeptidase II Partially Purified from Leukodystrophy Patient's Serum. 从白质营养不良症患者血清中部分纯化的谷氨酸羧肽酶 II 的动力学特性

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-09-18 Epub Date: 2024-09-06 DOI: 10.1021/acschemneuro.4c00366

Aws Z Abdulmajeed, Wasan Nazhan

{"title":"Kinetic Properties of Glutamate Carboxypeptidase II Partially Purified from Leukodystrophy Patient's Serum.","authors":"Aws Z Abdulmajeed, Wasan Nazhan","doi":"10.1021/acschemneuro.4c00366","DOIUrl":"10.1021/acschemneuro.4c00366","url":null,"abstract":"Glutamate carboxypeptidase II (GCPII), a metallopeptidase, is a recently identified pharmacologically targeted protein that is predominantly expressed in the human central nervous system, where it degrades the most abundant neuropeptide in the brain, N-acetyl aspartate glutamate, releasing free glutamate. Dysregulated glutamate release is associated with numerous neurological disorders and brain inflammation. The present study was designed to evaluate the activity of GCPII in 60 serum samples from patients with leukodystrophy and 30 samples from a control group with an age of less than 10 years. Subsequently, the enzyme was purified from the serum of leukodystrophy patients for experimental studies using ion exchange and gel filtration techniques to enhance the enzyme purity and reduce impurities. Finally, the kinetic properties of the purified enzyme were measured. The results of the present study demonstrated a reduction in the efficacy of the enzyme in comparison to the control group at a significance level of P ≤ 0.00003. Additionally, the kinetic study of the purified enzyme revealed a Michaelis-Menten constant value of 0.012 μM and a maximum velocity of 1.1318 μmol min-1. As demonstrated by the Lineweaver-Burk plot, using folate as the substrate, the Km value indicates the high affinity of the enzyme for folate, which is a crucial consideration in the development of therapies for neurological diseases. Additionally, the enzyme exhibited optimal activity at 37 °C and pH 7.4, with an incubation time of 5 min. The significance of GCPII in patients with leukodystrophy is 2-fold: first, it may serve as an early diagnostic marker for leukodystrophy, and second, it could represent a potential therapeutic target for neurological disorders.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0