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Journal of Proteome Research Jan 2020Redox proteomics is a field of proteomics that is concerned with the characterization of the oxidation state of proteins to gain information about their modulated... (Review)
Review
Redox proteomics is a field of proteomics that is concerned with the characterization of the oxidation state of proteins to gain information about their modulated structure, function, activity, and involvement in different physiological pathways. Oxidative modifications of proteins have been shown to be implicated in normal physiological processes of cells as well as in pathomechanisms leading to the development of cancer, diabetes, neurodegenerative diseases, and some rare hereditary metabolic diseases, like classic galactosemia. Reactive oxygen species generate a variety of reversible and irreversible modifications in amino acid residue side chains and within the protein backbone. These oxidative post-translational modifications (Ox-PTMs) can participate in the activation of signal transduction pathways and mediate the toxicity of harmful oxidants. Thus the application of advanced redox proteomics technologies is important for gaining insights into molecular mechanisms of diseases. Mass-spectrometry-based proteomics is one of the most powerful methods that can be used to give detailed qualitative and quantitative information on protein modifications and allows us to characterize redox proteomes associated with diseases. This Review illustrates the role and biological consequences of Ox-PTMs under basal and oxidative stress conditions by focusing on protein carbonylation and S-glutathionylation, two abundant modifications with an impact on cellular pathways that have been intensively studied during the past decade.
Topics: Humans; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Protein Processing, Post-Translational; Proteome; Proteomics; Reactive Oxygen Species
PubMed: 31647248
DOI: 10.1021/acs.jproteome.9b00586 -
Science (New York, N.Y.) May 2010The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase...
The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses.
Topics: Binding Sites; Carbon; Cell Cycle Proteins; DNA Damage; MAP Kinase Signaling System; Mass Spectrometry; Metabolic Networks and Pathways; Models, Biological; Nitrogen; Phosphoprotein Phosphatases; Phosphorylation; Protein Interaction Mapping; Protein Kinases; Protein Serine-Threonine Kinases; Protein Subunits; Protein Tyrosine Phosphatases; Proteome; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 20489023
DOI: 10.1126/science.1176495 -
Current Pharmaceutical Biotechnology May 2011It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or... (Review)
Review
It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.
Topics: Biological Transport; Female; Humans; Membrane Transport Proteins; Pharmaceutical Preparations; Pharmacokinetics; Placenta; Pregnancy
PubMed: 21342126
DOI: 10.2174/138920111795470877 -
Antioxidants & Redox Signaling Mar 2012In photosynthetic organisms, besides the well-established disulfide/dithiol exchange reactions specifically controlled by thioredoxins (TRXs), protein... (Review)
Review
SIGNIFICANCE
In photosynthetic organisms, besides the well-established disulfide/dithiol exchange reactions specifically controlled by thioredoxins (TRXs), protein S-glutathionylation is emerging as an alternative redox modification occurring under stress conditions. This modification, consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue, can not only protect specific cysteines from irreversible oxidation but also modulate protein activities and appears to be specifically controlled by small disulfide oxidoreductases of the TRX superfamily named glutaredoxins (GRXs).
RECENT STUDIES
In recent times, several studies allowed significant progress in this area, mostly due to the identification of several plant proteins undergoing S-glutathionylation and to the characterization of the molecular mechanisms and the proteins involved in the control of this modification.
CRITICAL ISSUES
This article provides a global overview of protein glutathionylation in photosynthetic organisms with particular emphasis on the mechanisms of protein glutathionylation and deglutathionylation and a focus on the role of GRXs. Then, we describe the methods employed for identification of glutathionylated proteins in photosynthetic organisms and review the targets and the possible physiological functions of protein glutathionylation.
FUTURE DIRECTIONS
In order to establish the importance of protein S-glutathionylation in photosynthetic organisms, future studies should be aimed at delineating more accurately the molecular mechanisms of glutathionylation and deglutathionylation reactions, at identifying proteins undergoing S-glutathionylation in vivo under diverse conditions, and at investigating the importance of redoxins, GRX, and TRX, in the control of this redox modification in vivo.
Topics: Animals; Glutathione; Humans; Oxidation-Reduction; Photosynthesis; Proteins
PubMed: 22053845
DOI: 10.1089/ars.2011.4255 -
Metabolic Engineering Jan 2002The understanding of the control of metabolic flux in plants requires integrated mathematical formulations of gene and protein expression, enzyme kinetics, and... (Review)
Review
The understanding of the control of metabolic flux in plants requires integrated mathematical formulations of gene and protein expression, enzyme kinetics, and developmental biology. Plants have a large number of metabolically active compartments, and non-steady-state conditions are frequently encountered. Consequently steady-state metabolic flux balance and isotopic flux balance modeling approaches have limited utility in probing plant metabolic systems. Transient isotopic flux analysis and kinetic modeling are powerful proven techniques for the quantification of metabolic fluxes in compartmentalized, dynamic metabolic systems. These tools are now widely used to address metabolic flux responses to environmental and genetic perturbations in plant metabolism. Continued developments in isotopic and kinetic modeling, quantifying metabolite exchange between compartments, and transcriptional and posttranscriptional regulatory mechanisms governing enzyme level and activity will enable simulation of large sections of plant metabolism under non-steady-state conditions. Metabolic control analysis will continue to make substantial contributions to the understanding of quantitative distribution of control of flux. From the synergy between mathematical models and experiments, creative methods for controlling the distribution of flux by genetic or environmental means will be discovered and rationally implemented.
Topics: Forecasting; Gene Expression Regulation, Plant; Kinetics; Models, Theoretical; Plant Proteins; Plants; Protein Processing, Post-Translational; Transcription, Genetic
PubMed: 11800577
DOI: 10.1006/mben.2001.0211 -
Chembiochem : a European Journal of... May 2004Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of... (Review)
Review
Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.
Topics: Fluorine; Ligands; Models, Molecular; Molecular Conformation; Pharmaceutical Preparations; Protein Binding; Proteins; Structure-Activity Relationship
PubMed: 15122635
DOI: 10.1002/cbic.200301023 -
Frontiers in Immunology 2023
Topics: Humans; Neoplasms; Proteins; Immunotherapy; Protein Processing, Post-Translational
PubMed: 37822939
DOI: 10.3389/fimmu.2023.1289016 -
Ageing Research Reviews Mar 2024Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially... (Review)
Review
Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially in elderly patients. The brain, which is one of the body's most metabolically dynamic organs, lacks fuel stores and therefore requires a continuous supply of energy substrates. Metabolic abnormalities are closely associated with the pathogenesis of CNS disorders. Post-translational modifications (PTMs) are essential regulatory mechanisms that affect the functions of almost all proteins. Succinylation, a broad-spectrum dynamic PTM, primarily occurs in mitochondria and plays a crucial regulatory role in various diseases. In addition to directly affecting various metabolic cycle pathways, succinylation serves as an efficient and rapid biological regulatory mechanism that establishes a connection between metabolism and proteins, thereby influencing cellular functions in CNS diseases. This review offers a comprehensive analysis of succinylation and its implications in the pathological mechanisms of CNS diseases. The objective is to outline novel strategies and targets for the prevention and treatment of CNS conditions.
Topics: Humans; Aged; Lysine; Proteins; Protein Processing, Post-Translational; Central Nervous System Diseases; Metabolic Networks and Pathways
PubMed: 38387517
DOI: 10.1016/j.arr.2024.102242 -
Archives of Toxicology Jan 2021Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze the metabolic conversion of foreign compounds,... (Comparative Study)
Comparative Study
Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze the metabolic conversion of foreign compounds, and various transport proteins are engaged in the excretion of metabolites from the hepatocytes. Inter-species and inter-individual differences in the hepatic levels and activities of drug-metabolizing enzymes and transporters result from genetic as well as from environmental factors, and play a decisive role in determining the pharmacokinetic properties of a compound in a given test system. To allow for a meaningful comparison of results from metabolism studies, it is, therefore, of utmost importance to know about the specific metabolic properties of the test systems, especially about the levels of metabolic enzymes such as the CYPs. Using a targeted proteomics approach, we, therefore, compared the hepatic levels of important CYP enzymes and transporters in different experimental systems in vivo and in vitro, namely Wistar rats, C57/Bl6 mice, mice humanized for the two xeno-sensing receptors PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor), mice with human hepatocyte-repopulated livers, human HepaRG hepatocarcinoma cells, primary human hepatocytes, and human liver biopsies. In addition, the effects of xenobiotic inducers of drug metabolism on CYP enzymes and transporters were analyzed in selected systems. This study for the first time presents a comprehensive overview of similarities and differences in important drug metabolism-related proteins among the different experimental models.
Topics: Animals; Biological Transport; Biotransformation; Cell Line; Constitutive Androstane Receptor; Cytochrome P-450 Enzyme System; Humans; Isoenzymes; Liver; Membrane Transport Proteins; Mice, Inbred C57BL; Pharmaceutical Preparations; Pregnane X Receptor; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Species Specificity; Substrate Specificity; Xenobiotics; Mice; Rats
PubMed: 33150952
DOI: 10.1007/s00204-020-02939-4 -
Methods in Molecular Biology (Clifton,... 2018Thiol-redox proteomics methods are rapidly developing tools in redox biology. These are applied to identify and quantify proteins with reversible thiol oxidations that...
Thiol-redox proteomics methods are rapidly developing tools in redox biology. These are applied to identify and quantify proteins with reversible thiol oxidations that are formed under normal growth and oxidative stress conditions inside cells. The proteins with reversible thiol oxidations are usually prepared by alkylation of reduced thiols, subsequent reduction of disulfide bonds followed by a second differential alkylation of newly released thiols. Here, we describe two methods for detection of protein S-thiolations in Gram-positive bacteria using the direct shotgun approach and the fluorescent-label thiol-redox proteomics method that have been successfully applied in our previous work.
Topics: Bacteria; Bacterial Proteins; Fluorescent Dyes; Mass Spectrometry; Oxidation-Reduction; Oxidative Stress; Proteolysis; Proteome; Proteomics; Reactive Oxygen Species; Staining and Labeling; Sulfhydryl Compounds; Workflow
PubMed: 30259492
DOI: 10.1007/978-1-4939-8695-8_18