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Antioxidants & Redox Signaling Mar 2012Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling...
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling pathways, and they are known also as deleterious mediators of cellular stress and cell death. ROS and RNS, and their cross products like peroxynitrite, react primarily with cysteine residues whose oxidative modification leads to functional alterations in the proteins. In this Forum, the collection of six review articles presents a perspective on the broad biological impact of cysteine modifications in health and disease from the molecular to the cellular and organismal levels, focusing in particular on reversible protein-S-glutathionylation and its central role in transducing redox signals as well as protecting proteins from irreversible cysteine oxidation. The Forum review articles consider the role of S-glutationylation in regulation of the peroxiredoxin enzymes, the special redox environment of the mitochondria, redox regulation pertinent to the function of the cardiovascular system, mechanisms of redox-activated apoptosis in the pulmonary system, and the role of glutathionylation in the initiation, propagation, and treatment of neurodegenerative diseases. Several common themes emerge from these reviews; notably, the probability of crosstalk between signaling/regulation mechanisms involving protein-S-nitrosylation and protein-S-glutathionylation, and the need for quantitative analysis of the relationship between specific cysteine modifications and corresponding functional changes in various cellular contexts.
Topics: Cysteine; Glutathione; Humans; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 22136616
DOI: 10.1089/ars.2011.4454 -
Trends in Endocrinology and Metabolism:... Sep 2016G protein-coupled receptors (GPCRs) regulate virtually all metabolic processes, including glucose and energy homeostasis. Recently, the use of designer GPCRs referred to... (Review)
Review
G protein-coupled receptors (GPCRs) regulate virtually all metabolic processes, including glucose and energy homeostasis. Recently, the use of designer GPCRs referred to as designer receptors exclusively activated by designer drug (DREADDs) has made it possible to dissect metabolically relevant GPCR signaling pathways in a temporally and spatially controlled fashion in vivo.
Topics: Animals; Humans; Metabolic Networks and Pathways; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 27381463
DOI: 10.1016/j.tem.2016.04.001 -
Trends in Microbiology Jan 2004The yiaQRS genes of Escherichia coli K-12 are involved in carbohydrate metabolism. Clustering of homologous genes was found throughout several unrelated bacteria.... (Review)
Review
The yiaQRS genes of Escherichia coli K-12 are involved in carbohydrate metabolism. Clustering of homologous genes was found throughout several unrelated bacteria. Strikingly, all four bacterial transport protein classes were found, conserving transport function but not mechanism. It appears that during evolution the ability to transport, phosphorylate and metabolize substrates of unknown identity have been conserved. However, the transporter classes have been swapped. This probably demonstrates the subtlety of transport-protein evolution.
Topics: Bacteria; Bacterial Proteins; Biological Transport; Carbohydrate Metabolism; Evolution, Molecular; Membrane Transport Proteins; Multigene Family
PubMed: 14700544
DOI: 10.1016/j.tim.2003.11.001 -
PloS One 2014During long distance endurance races, horses undergo high physiological and metabolic stresses. The adaptation processes involve the modulation of the energetic pathways...
During long distance endurance races, horses undergo high physiological and metabolic stresses. The adaptation processes involve the modulation of the energetic pathways in order to meet the energy demand. The aims were to evaluate the effects of long endurance exercise on the plasma metabolomic profiles and to investigate the relationships with the individual horse performances. The metabolomic profiles of the horses were analyzed using the non-dedicated methodology, NMR spectroscopy and statistical multivariate analysis. The advantage of this method is to investigate several metabolomic pathways at the same time in a single sample. The plasmas were obtained before exercise (BE) and post exercise (PE) from 69 horses competing in three endurance races at national level (130-160 km). Biochemical assays were also performed on the samples taken at PE. The proton NMR spectra were compared using the supervised orthogonal projection on latent structure method according to several factors. Among these factors, the race location was not significant whereas the effect of the race exercise (sample BE vs PE of same horse) was highly discriminating. This result was confirmed by the projection of unpaired samples (only BE or PE sample of different horses). The metabolomic profiles proved that protein, energetic and lipid metabolisms as well as glycoproteins content are highly affected by the long endurance exercise. The BE samples from finisher horses could be discriminated according to the racing speed based on their metabolomic lipid content. The PE samples could be discriminated according to the horse ranking position at the end of the race with lactate as unique correlated metabolite. As a conclusion, the metabolomic profiles of plasmas taken before and after the race provided a better understanding of the high energy demand and protein catabolism pathway that could expose the horses to metabolic disorders.
Topics: Animals; Energy Metabolism; Horses; Lipid Metabolism; Metabolomics; Nuclear Magnetic Resonance, Biomolecular; Physical Conditioning, Animal; Physical Endurance; Proteins
PubMed: 24658361
DOI: 10.1371/journal.pone.0090730 -
Trends in Molecular Medicine Sep 2009Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates... (Review)
Review
Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates important roles for S-nitrosylation both in normal physiology and in a broad spectrum of human diseases. Here we review recent findings that implicate S-nitrosylation in cardiovascular, pulmonary, musculoskeletal and neurological (dys)function, as well as in cancer. The emerging picture shows that, in many cases, pathophysiology correlates with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to loss of or enhanced nitric oxide synthase activity. In addition, it is increasingly evident that dysregulated S-nitrosylation can not only result from alterations in the expression, compartmentalization and/or activity of nitric oxide synthases, but can also reflect a contribution from denitrosylases, including prominently the S-nitrosoglutathione (GSNO)-metabolizing enzyme GSNO reductase. Finally, because exogenous mediators of protein S-nitrosylation or denitrosylation can substantially affect the development or progression of disease, potential therapeutic agents that modulate S-nitrosylation could well have broad clinical utility.
Topics: Animals; Disease; Health; Humans; Nitrates; Nitric Oxide; Nitrosation; Proteins; Signal Transduction
PubMed: 19726230
DOI: 10.1016/j.molmed.2009.06.007 -
Methods in Molecular Biology (Clifton,... 2022Cell polarity is a common feature of many living cells, especially epithelial cells, and plays important roles in development, tissue homeostasis, and diseases....
Cell polarity is a common feature of many living cells, especially epithelial cells, and plays important roles in development, tissue homeostasis, and diseases. Therefore, the signaling pathways involved in establishing and maintaining cell polarity are tightly controlled. Protein S-palmitoylation has been recently recognized as an important posttranslational modification involved in cell polarity, via dynamic covalent attachment of fatty acyl groups to the cysteine residues of cell polarity proteins. Here, we describe the methods to study the function and regulation of S-palmitoylation of cell polarity proteins.
Topics: Cell Polarity; Cysteine; Lipoylation; Protein Processing, Post-Translational; Proteins
PubMed: 35147938
DOI: 10.1007/978-1-0716-2035-9_7 -
PloS One 2016The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or...
The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.
Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Gene Expression Regulation; Liver; Male; Mice; Oxidative Stress; Protoporphyrins; Pyridines; Retinoblastoma Protein; Tumor Suppressor Protein p53
PubMed: 26967735
DOI: 10.1371/journal.pone.0150064 -
Cellular and Molecular Life Sciences :... Jun 2009Cullin-RING E3 ubiquitin-Ligases (CRLs) are the most prominent class of ubiquitin-ligases. By controlling the stability of a cohort of key regulators, CRLs impinge on... (Review)
Review
Cullin-RING E3 ubiquitin-Ligases (CRLs) are the most prominent class of ubiquitin-ligases. By controlling the stability of a cohort of key regulators, CRLs impinge on many cellular and biological processes such as immunity, development, transcription, cell signalling and cell cycle progression. CRLs are multi-subunit complexes composed of a catalytic site and a substrate recognition module nucleated around a cullin scaffold protein. Most eukaryotic genomes encode at least five distinct cullins, and each of these cullins recruits a specific substrate-recognition module such that CRL complexes are modular. Despite their considerable diversity, CRLs are regulated by similar mechanisms. In particular, recent observations indicate that conformational variability induced by CRL dimerization and by conjugation of the ubiquitin-like protein NEDD8 on the cullin subunit stimulates substrate polyubiquitination. In this review, we discuss the composition of CRL complexes and the various molecular mechanisms controlling their activity.
Topics: Animals; Arabidopsis Proteins; Cullin Proteins; Drosophila Proteins; Enzyme Activation; NEDD8 Protein; Phosphorylation; Protein Binding; Protein Multimerization; Saccharomyces cerevisiae Proteins; Substrate Specificity; Ubiquitination; Ubiquitins
PubMed: 19194658
DOI: 10.1007/s00018-009-8712-7 -
BMC Bioinformatics Feb 2023Protein S-nitrosylation (SNO) plays a key role in transferring nitric oxide-mediated signals in both animals and plants and has emerged as an important mechanism for...
pLMSNOSite: an ensemble-based approach for predicting protein S-nitrosylation sites by integrating supervised word embedding and embedding from pre-trained protein language model.
BACKGROUND
Protein S-nitrosylation (SNO) plays a key role in transferring nitric oxide-mediated signals in both animals and plants and has emerged as an important mechanism for regulating protein functions and cell signaling of all main classes of protein. It is involved in several biological processes including immune response, protein stability, transcription regulation, post translational regulation, DNA damage repair, redox regulation, and is an emerging paradigm of redox signaling for protection against oxidative stress. The development of robust computational tools to predict protein SNO sites would contribute to further interpretation of the pathological and physiological mechanisms of SNO.
RESULTS
Using an intermediate fusion-based stacked generalization approach, we integrated embeddings from supervised embedding layer and contextualized protein language model (ProtT5) and developed a tool called pLMSNOSite (protein language model-based SNO site predictor). On an independent test set of experimentally identified SNO sites, pLMSNOSite achieved values of 0.340, 0.735 and 0.773 for MCC, sensitivity and specificity respectively. These results show that pLMSNOSite performs better than the compared approaches for the prediction of S-nitrosylation sites.
CONCLUSION
Together, the experimental results suggest that pLMSNOSite achieves significant improvement in the prediction performance of S-nitrosylation sites and represents a robust computational approach for predicting protein S-nitrosylation sites. pLMSNOSite could be a useful resource for further elucidation of SNO and is publicly available at https://github.com/KCLabMTU/pLMSNOSite .
Topics: Animals; Proteins; Nitric Oxide; Oxidation-Reduction; Protein Processing, Post-Translational; Signal Transduction
PubMed: 36755242
DOI: 10.1186/s12859-023-05164-9 -
Nature Communications Jul 2023Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general...
Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to metabolic functions, e.g. the synthesis of biomass building blocks. FDM allowed for a detailed quantification of the energy and biosynthesis budget for growing Escherichia coli cells. Surprisingly, the ATP generated during the biosynthesis of building blocks from glucose almost balances the demand from protein synthesis, the largest energy expenditure known for growing cells. This leaves the bulk of the energy generated by fermentation and respiration unaccounted for, thus challenging the common notion that energy is a key growth-limiting resource. Moreover, FDM together with proteomics enables the quantification of enzymes contributing towards each metabolic function, allowing for a first-principle formulation of a coarse-grained model of global protein allocation based on the structure of the metabolic network.
Topics: Energy Metabolism; Fermentation; Proteins; Metabolic Networks and Pathways; Escherichia coli
PubMed: 37443156
DOI: 10.1038/s41467-023-39724-7