Advances in protein chemistry and structural biology最新文献

{"title":"Transcriptomic analysis reveals zinc-mediated virulence and pathogenicity in multidrug-resistant Acinetobacter baumannii.","authors":"Santhosh M E, Prasanna Kumar Selvam, Mohanraj Gopikrishnan, Karthick Vasudevan, Hatem Zayed, Magesh Ramasamy, Charles Emmanuel Jebaraj Walter, George Priya Doss C","doi":"10.1016/bs.apcsb.2023.12.018","DOIUrl":"10.1016/bs.apcsb.2023.12.018","url":null,"abstract":"<p><p>Acinetobacter baumannii is a gram-negative bacterium well known for its multidrug resistance and connection to nosocomial infections under ESKAPE pathogens. This opportunistic pathogen is ubiquitously associated with nosocomial infections, posing significant threats within healthcare environments. Its critical clinical symptoms, namely, meningitis, urinary tract infections, bloodstream infections, ventilator-associated pneumonia, and pneumonia, catalyze the imperative demand for innovative therapeutic interventions. The proposed research focuses on delineating the role of Zinc, a crucial metallo-binding protein and micronutrient integral to bacterial metabolism and virulence, to enhance understanding of the pathogenicity of A. baumannii. RNA sequencing and subsequent DESeq2 analytical methods were used to identify differential gene expressions influenced by zinc exposure. Exploiting the STRING database for functional enrichment analysis has demonstrated the complex molecular mechanisms underlying the enhancement of pathogenicity prompted by Zinc. Moreover, hub genes like gltB, ribD, AIL77834.1, sdhB, nuoI, acsA_1, acoC, accA, accD were predicted using the cytohubba tool in Cytoscape. This investigation underscores the pivotal role of Zinc in the virulence of A. baumannii elucidates the underlying molecular pathways responsible for its pathogenicity. The research further accentuates the need for innovative therapeutic strategies to combat A. baumannii infections, particularly those induced by multidrug-resistant strains.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496835","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 mechanistic insights into different aspects of promiscuity in metalloenzymes.","authors":"Ankita Tripathi, Kshatresh Dutta Dubey","doi":"10.1016/bs.apcsb.2023.12.022","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2023.12.022","url":null,"abstract":"<p><p>Enzymes are nature's ultimate machinery to catalyze complex reactions. Though enzymes are evolved to catalyze specific reactions, they also show significant promiscuity in reactions and substrate selection. Metalloenzymes contain a metal ion or metal cofactor in their active site, which is crucial in their catalytic activity. Depending on the metal and its coordination environment, the metal ion or cofactor may function as a Lewis acid or base and a redox center and thus can catalyze a plethora of natural reactions. In fact, the versatility in the oxidation state of the metal ions provides metalloenzymes with a high level of catalytic adaptability and promiscuity. In this chapter, we discuss different aspects of promiscuity in metalloenzymes by using several recent experimental and theoretical works as case studies. We start our discussion by introducing the concept of promiscuity and then we delve into the mechanistic insight into promiscuity at the molecular level.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"23-66"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496834","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":"Gut microbial metalloproteins and its role in xenobiotics degradation and ROS scavenging.","authors":"Shreya Vishwas Mohite, Krishna Kant Sharma","doi":"10.1016/bs.apcsb.2024.03.004","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.03.004","url":null,"abstract":"<p><p>The gut microbial metalloenzymes play an important role in maintaining the balance between gut microbial ecosystem, human physiologically processes and immune system. The metals coordinated into active site contribute in various detoxification and defense strategies to avoid unfavourable environment and ensure bacterial survival in human gut. Metallo-β-lactamase is a potent degrader of antibiotics present in periplasmic space of both commensals and pathogenic bacteria. The resistance to anti-microbial agents developed in this enzyme is one of the global threats for human health. The organophosphorus eliminator, organophosphorus hydrolases have evolved over a course of time to hydrolyze toxic organophosphorus compounds and decrease its effect on human health. Further, the redox stress responders namely superoxide dismutase and catalase are key metalloenzymes in reducing both endogenous and exogenous oxidative stress. They hold a great importance for pathogens as they contribute in pathogenesis in human gut along with reduction of oxidative stress. The in-silico study on these enzymes reveals the importance of point mutation for the evolution of these enzymes in order to enhance their enzyme activity and stability. Various mutation studies were conducted to investigate the catalytic activity of these enzymes. By using the \"directed evolution\" method, the enzymes involved in detoxification and defense system can be engineered to produce new variants with enhance catalytic features, which may be used to predict the severity due to multi-drug resistance and degradation pattern of organophosphorus compounds in human gut.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"495-538"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496758","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":"Single-cell transcriptomic analysis to identify endomembrane regulation of metalloproteins and motor proteins in autoimmunity.","authors":"Edoardo Abeni, Cinzia Cocola, Stefania Croci, Valentina Martino, Eleonora Piscitelli, Roberta Gualtierotti, Paride Pelucchi, Valeria Tria, Giovanni Porta, Fabian Troschel, Burkhard Greve, Giovanni Nano, Alexey Tomilin, James Kehler, Daniela Gerovska, Daniela Mazzaccaro, Martin Götte, Marcos J Arauzo-Bravo, Salvarani Carlo, Ileana Zucchi, Rolland Reinbold","doi":"10.1016/bs.apcsb.2024.03.007","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2024.03.007","url":null,"abstract":"<p><p>TMEM230 promotes antigen processing, trafficking, and presentation by regulating the endomembrane system of membrane bound organelles (lysosomes, proteosomes and mitochondria) and phagosomes. Activation of the immune system requires trafficking of various cargos between the endomembrane system and cell plasma membrane. The Golgi apparatus is the hub of the endomembrane system and essential for the generation, maintenance, recycling, and trafficking of the components of the endomembrane system itself and immune system. Intracellular trafficking and secretion of immune system components depend on mitochondrial metalloproteins for ATP synthesis that powers motor protein transport of endomembrane cargo. Glycan modifying enzyme genes and motor proteins are essential for the activation of the immune system and trafficking of antigens between the endomembrane system and the plasma membrane. Recently, TMEM230 was identified as co-regulated with RNASET2 in lysosomes and with metalloproteins in various cell types and organelles, including mitochondria in autoimmune diseases. Aberrant metalloproteinase secretion by motor proteins is a major contributor to tissue remodeling of synovial membrane and joint tissue destruction in rheumatoid arthritis (RA) by promoting infiltration of blood vessels, bone erosion, and loss of cartilage by phagocytes. In this study, we identified that specific glycan processing enzymes are upregulated in certain cell types (fibroblast or endothelial cells) that function in destructive tissue remodeling in rheumatoid arthritis compared to osteoarthritis (OA). TMEM230 was identified as a regulator in the secretion of metaloproteinases and heparanase necessary tissue remodeling in OA and RA. In dendritic (DC), natural killer and T cells, TMEM230 was expressed at low or no levels in RA compared to OA. TMEM230 expression in DC likely is necessary for regulatory or helper T cells to maintain tolerance to self-antigens and prevent susceptibility to autoimmune disease. To identify how TMEM230 and the endomembrane system contribute to autoimmunity we investigated, glycan modifying enzymes, metalloproteinases and motor protein genes co-regulated with or regulated by TMEM230 in synovial tissue by analyzing published single cell transcriptomic datasets from RA patient derived synovial tissue.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"141 ","pages":"299-329"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496832","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":"Unlocking estrogen receptor: Structural insights into agonists and antagonists for glioblastoma therapy.","authors":"Asokan Madeshwaran, Periyasamy Vijayalakshmi, Vidhya Rekha Umapathy, Rajeshkumar Shanmugam, Chandrabose Selvaraj","doi":"10.1016/bs.apcsb.2024.06.001","DOIUrl":"10.1016/bs.apcsb.2024.06.001","url":null,"abstract":"<p><p>Glioblastoma (GBM), a malignant brain tumor originating in glial cells, is one of the most common primary brain malignancies, affecting one in 100,000 people, typically in the frontal lobe. Estrogens, like estradiol-17 (E2), significantly influence GBM progression, metastasis, and angiogenesis. Estrogen receptors (ERs) are crucial in signal transduction and physiology, making them potential therapeutic targets. However, their roles in GBM pathogenesis remain unclear. This review explores ERs in GBM, focusing on their involvement in tumor immune evasion, modulation of the tumor microenvironment, and the mechanisms underlying GBM progression. Additionally, therapeutic opportunities targeting ERs for GBM treatment are discussed. Estrogen, synthesized primarily in ovaries and in smaller amounts by adrenal glands and fat tissues, regulates reproductive systems, bone density, skin health, and cardiovascular function. The invasive nature and heterogeneity of GBM complicate therapy development. Preclinical findings suggest that endocrine therapy with hormone receptor agonists or antagonists can extend patient survival and improve post-treatment quality of life. The ERβ pathway, in particular, shows tumor-suppressive potential, limiting glioma progression with fewer side effects. ERβ agonists could become a novel drug class for GBM treatment. Identifying biomarkers and specific therapeutic targets is crucial for early detection and improved prognosis. Estrogen and its receptors are advantageous for GBM treatment due to their regulation of numerous biological processes, ability to penetrate the blood-brain barrier, and genomic and non-genomic control of transcription, making them promising targets for GBM therapy.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"142 ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764737","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":"Cellular signals integrate cell cycle and metabolic control in cancer.","authors":"Chareeporn Akekawatchai,&nbsp;Sarawut Jitrapakdee","doi":"10.1016/bs.apcsb.2023.01.002","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2023.01.002","url":null,"abstract":"<p><p>Growth factors are the small peptides that can promote growth, differentiation, and survival of most living cells. However, aberrant activation of receptor tyrosine kinases by GFs can generate oncogenic signals, resulting in oncogenic transformation. Accumulating evidence support a link between GF/RTK signaling through the major signaling pathways, Ras/Erk and PI3K/Akt, and cell cycle progression. In response to GF signaling, the quiescent cells in the G₀ stage can re-enter the cell cycle and become the proliferative stage. While in the proliferative stage, tumor cells undergo profound changes in their metabolism to support biomass production and bioenergetic requirements. Accumulating data show that the cell cycle regulators, specifically cyclin D, cyclin B, Cdk2, Cdk4, and Cdk6, and anaphase-promoting complex/cyclosome (APC/C-Cdh1) play critical roles in modulating various metabolic pathways. These cell cycle regulators can regulate metabolic enzyme activities through post-translational mechanisms or the transcriptional factors that control the expression of the metabolic genes. This fine-tune control allows only the relevant metabolic pathways to be active in a particular phase of the cell cycle, thereby providing suitable amounts of biosynthetic precursors available during the proliferative stage. The imbalance of metabolites in each cell cycle phase can induce cell cycle arrest followed by p53-induced apoptosis.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"135 ","pages":"397-423"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9337448","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":"Computational screening and structural analysis of Gly201Arg and Gly201Asp missense mutations in human cyclin-dependent kinase 4 protein.","authors":"D Thirumal Kumar,&nbsp;Nishaat Shaikh,&nbsp;R Bithia,&nbsp;V Karthick,&nbsp;C George Priya Doss,&nbsp;R Magesh","doi":"10.1016/bs.apcsb.2023.02.002","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2023.02.002","url":null,"abstract":"<p><p>The regulatory proteins, cyclins, and cyclin-dependent kinases (CDKs) control the cell cycle progression. CDK4 gene mutations are associated with certain cancers such as melanoma, breast cancer, and rhabdomyosarcoma. Therefore, understanding the mechanisms of cell cycle control and cell proliferation is essential in developing cancer treatment regimens. In this study, we obtained cancer-causing CDK4 mutations from the COSMIC database and subjected them to a series of in silico analyses to identify the most significant mutations. An overall of 238 mutations (119 missense mutations) retrieved from the COSMIC database were investigated for the pathogenic and destabilizing properties using the PredictSNP and iStable algorithms. Further, the amino acid position of the most pathogenic and destabilizing mutations were analyzed to understand the nature of amino acid conservation across the species during the evolution. We observed that the missense mutations G201R and G201D were more significant and the Glycine at position 201 was found to highly conserved. These significant mutations were subjected to molecular dynamics simulation analysis to understand the protein's structural changes. The results from molecular dynamics simulations revealed that both G201R and G201D of CDK4 are capable of altering the protein's native form. On comparison among the most significant mutations, G201R disrupted the protein structure higher than the protein with G201D.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"135 ","pages":"57-96"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9337450","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":"Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.","authors":"Komal Sharma,&nbsp;Joyobrata Sarkar,&nbsp;Anchal Trisal,&nbsp;Rishika Ghosh,&nbsp;Anubhuti Dixit,&nbsp;Abhishek Kumar Singh","doi":"10.1016/bs.apcsb.2023.02.016","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2023.02.016","url":null,"abstract":"<p><p>Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"136 ","pages":"309-337"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10239511","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":"Molecular characterization of circadian gene expression and its correlation with survival percentage in colorectal cancer patients.","authors":"Ankur Datta,&nbsp;Hephzibah Cathryn R,&nbsp;S Udhaya Kumar,&nbsp;Karthick Vasudevan,&nbsp;D Thirumal Kumar,&nbsp;Hatem Zayed,&nbsp;C George Priya Doss","doi":"10.1016/bs.apcsb.2023.02.007","DOIUrl":"10.1016/bs.apcsb.2023.02.007","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a form of cancer characterized by many symptoms and readily metastasizes to different organs in the body. Circadian rhythm is one of the many processes that is observed to be dysregulated in CRC-affected patients. In this study, we aim to identify the dysregulated physiological processes in CRC-affected patients and correlate the expression profiles of the circadian clock genes with CRC-patients' survival rates. We performed an extensive microarray gene expression pipeline, whereby 471 differentially expressed genes (DEGs) were identified, following which, we streamlined our search to 43 circadian clock affecting DEGs. The Circadian Gene Database was accessed to retrieve the circadian rhythm-specific genes. The DEGs were then subjected to multi-level functional annotation, i.e., preliminary analysis using ClueGO/CluePedia and pathway enrichment using DAVID. The findings of our study were interesting, wherein we observed that the survival percentage of CRC-affected patients dropped significantly around the 100th-month mark. Furthermore, we identified hormonal activity, xenobiotic metabolism, and PI3K-Akt signaling pathway to be frequently dysregulated cellular functions. Additionally, we detected that the ZFYVE family of genes and the two genes, namely MYC and CDK4 were the significant DEGs that are linked to the pathogenesis and progression of CRC. This study sheds light on the importance of bioinformatics to simplify our understanding of the interactions of different genes that control different phenotypes.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"137 ","pages":"161-180"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10287727","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":"Mitochondria-derived peptides in healthy ageing and therapy of age-related diseases.","authors":"Siarhei A Dabravolski","doi":"10.1016/bs.apcsb.2023.02.015","DOIUrl":"https://doi.org/10.1016/bs.apcsb.2023.02.015","url":null,"abstract":"<p><p>Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by mitochondrial DNA and involved in various stress-protecting mechanisms. To date, eight mitochondrial-derived peptides have been identified: MOTS-c sequence is hidden in the 12 S rRNA gene (MT-RNR1), and the other 7 (humanin and small humanin-like peptides 1-6) are encoded by the 16 S rRNA (MT-RNR2) gene. While the anti-apoptotic, anti-inflammatory and cardioprotective activities of MDPs are well described, recent research suggests that MDPs are sensitive metabolic sensors, closely connected with mtDNA mutation-associated diseases and age-associated metabolic disorders. In this chapter, we focus on the recent progress in understanding the metabolo-protective properties of MDPs, their role in maintenance of the cellular and mitochondrial homeostasis associated with age-related diseases: Alzheimer's disease, cognitive decline, macular degeneration and cataracts. Also, we will discuss MDPs-based and MDPs-targeted interventions to treat age-related diseases and extend a healthy lifespan.</p>","PeriodicalId":7376,"journal":{"name":"Advances in protein chemistry and structural biology","volume":"136 ","pages":"197-215"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10239510","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}