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International Journal of Molecular... Dec 2016Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor... (Review)
Review
Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression.
Topics: Animals; Humans; Lipid Metabolism; Mutant Proteins; Neoplasm Proteins; Neoplasms; Tumor Suppressor Protein p53
PubMed: 27973397
DOI: 10.3390/ijms17122074 -
Journal of Physics. Condensed Matter :... Dec 2015Simple physical mechanisms are behind the flow of energy in all forms of life. Energy comes to living systems through electrons occupying high-energy states, either from... (Review)
Review
Simple physical mechanisms are behind the flow of energy in all forms of life. Energy comes to living systems through electrons occupying high-energy states, either from food (respiratory chains) or from light (photosynthesis). This energy is transformed into the cross-membrane proton-motive force that eventually drives all biochemistry of the cell. Life's ability to transfer electrons over large distances with nearly zero loss of free energy is puzzling and has not been accomplished in synthetic systems. The focus of this review is on how this energetic efficiency is realized. General physical mechanisms and interactions that allow proteins to fold into compact water-soluble structures are also responsible for a rugged landscape of energy states and a broad distribution of relaxation times. Specific to a protein as a fluctuating thermal bath is the protein-water interface, which is heterogeneous both dynamically and structurally. The spectrum of interfacial fluctuations is a consequence of protein's elastic flexibility combined with a high density of surface charges polarizing water dipoles into surface nanodomains. Electrostatics is critical to the protein function and the relevant questions are: (i) What is the spectrum of interfacial electrostatic fluctuations? (ii) Does the interfacial biological water produce electrostatic signatures specific to proteins? (iii) How is protein-mediated chemistry affected by electrostatics? These questions connect the fluctuation spectrum to the dynamical control of chemical reactivity, i.e. the dependence of the activation free energy of the reaction on the dynamics of the bath. Ergodicity is often broken in protein-driven reactions and thermodynamic free energies become irrelevant. Continuous ergodicity breaking in a dense spectrum of relaxation times requires using dynamically restricted ensembles to calculate statistical averages. When applied to the calculation of the rates, this formalism leads to the nonergodic activated kinetics, which extends the transition-state theory to dynamically dispersive media. Releasing the grip of thermodynamics in kinetic calculations through nonergodicity provides the mechanism for an efficient optimization between reaction rates and the spectrum of relaxation times of the protein-water thermal bath. Bath dynamics, it appears, play as important role as the free energy in optimizing biology's performance.
Topics: Electron Transport; Kinetics; Photosynthesis; Proteins; Temperature; Water
PubMed: 26558324
DOI: 10.1088/0953-8984/27/47/473001 -
International Journal of Molecular... Jan 2019Lipid modification is an important post-translational modification. S-acylation is unique among lipid modifications, as it is reversible and has thus attracted much... (Review)
Review
Lipid modification is an important post-translational modification. S-acylation is unique among lipid modifications, as it is reversible and has thus attracted much attention. We summarize some proteins that have been shown experimentally to be S-acylated in plants. Two of these S-acylated proteins have been matched to the S-acyl transferase. More importantly, the first protein thioesterase with de-S-acylation activity has been identified in plants. This review shows that S-acylation is important for a variety of different functions in plants and that there are many unexplored aspects of S-acylation in plants.
Topics: Acylation; Lipid Metabolism; Models, Biological; Monomeric GTP-Binding Proteins; Plant Proteins; Protein Processing, Post-Translational; Transcription Factors
PubMed: 30699892
DOI: 10.3390/ijms20030560 -
Methods in Molecular Biology (Clifton,... 2023Cysteine-SILAC enables the detection and quantification of protein S-palmitoylation, an important protein posttranslational modification. Here we describe the cell...
Cysteine-SILAC enables the detection and quantification of protein S-palmitoylation, an important protein posttranslational modification. Here we describe the cell culture, protein extraction, selective enrichment, mass spectrometry, and data analysis for palmitoylated proteins from cell samples by this method.
Topics: Cysteine; Lipoylation; Mass Spectrometry; Protein Processing, Post-Translational; Proteins
PubMed: 36370270
DOI: 10.1007/978-1-0716-2863-8_5 -
Biochemical Society Transactions Jun 2018In a diverse family of cellular cofactors, coenzyme A (CoA) has a unique design to function in various biochemical processes. The presence of a highly reactive thiol... (Review)
Review
In a diverse family of cellular cofactors, coenzyme A (CoA) has a unique design to function in various biochemical processes. The presence of a highly reactive thiol group and a nucleotide moiety offers a diversity of chemical reactions and regulatory interactions. CoA employs them to activate carbonyl-containing molecules and to produce various thioester derivatives (e.g. acetyl CoA, malonyl CoA and 3-hydroxy-3-methylglutaryl CoA), which have well-established roles in cellular metabolism, production of neurotransmitters and the regulation of gene expression. A novel unconventional function of CoA in redox regulation, involving covalent attachment of this coenzyme to cellular proteins in response to oxidative and metabolic stress, has been recently discovered and termed protein CoAlation (S-thiolation by CoA or CoAthiolation). A diverse range of proteins was found to be CoAlated in mammalian cells and tissues under various experimental conditions. Protein CoAlation alters the molecular mass, charge and activity of modified proteins, and prevents them from irreversible sulfhydryl overoxidation. This review highlights the role of a key metabolic integrator CoA in redox regulation in mammalian cells and provides a perspective of the current status and future directions of the emerging field of protein CoAlation.
Topics: Animals; Coenzyme A; Gene Expression Regulation; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Proteins
PubMed: 29802218
DOI: 10.1042/BST20170506 -
Vitamins and Hormones 2022A wide variety of organisms encode cobalamin-dependent enzymes catalyzing essential metabolic reactions, but the cofactor cobalamin (vitamin B12) is only synthesized by...
A wide variety of organisms encode cobalamin-dependent enzymes catalyzing essential metabolic reactions, but the cofactor cobalamin (vitamin B12) is only synthesized by a subset of bacteria and archaea. The biosynthesis of cobalamin is complex and energetically costly, making cobalamin variants and precursors metabolically valuable. Auxotrophs for these molecules have evolved uptake mechanisms to compensate for the lack of a synthesis pathway. Bacterial transport of cobalamin involves the passage over one or two lipidic membranes in Gram-positive and -negative bacteria, respectively. In higher eukaryotes, a complex system of carriers, receptors and transporters facilitates the delivery of the essential molecule to the tissues. Biochemical and genetic approaches have identified different transporter families involved in cobalamin transport. The majority of the characterized cobalamin transporters are active transport systems that belong to the ATP-binding cassette (ABC) superfamily of transporters. In this chapter, we describe the different cobalamin transport systems characterized to date that are present in bacteria and humans, as well as yet-to-be-identified transporters.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Vitamin B 12
PubMed: 35337617
DOI: 10.1016/bs.vh.2022.01.008 -
Methods in Enzymology 2022A protein's structure and function often depend not only on its primary sequence, but also the presence or absence of any number of non-coded posttranslational...
A protein's structure and function often depend not only on its primary sequence, but also the presence or absence of any number of non-coded posttranslational modifications. Complicating their study is the fact that the physiological consequences of these modifications are context-, protein-, and site-dependent, and there exist no purely biological techniques to unambiguously study their effects. To this end, protein semisynthesis has become an invaluable chemical biology tool to specifically install non-coded or non-native moieties onto proteins in vitro using synthetic and/or recombinant polypeptides. Here, we describe two facets of protein semisynthesis (solid-phase peptide synthesis and expressed protein ligation) and their use in generating site-specifically glycosylated small heat shock proteins for functional studies. The procedures herein require limited specialized equipment, employ mild reaction conditions, and can be extended to myriad other proteins, modifications, and contexts.
Topics: Heat-Shock Proteins, Small; Peptides; Protein Processing, Post-Translational; Proteins
PubMed: 36220281
DOI: 10.1016/bs.mie.2022.07.004 -
Molecules (Basel, Switzerland) Aug 2017Protein -sulfhydration is a newly discovered post-translational modification of specific cysteine residue(s) in target proteins, which is involved in a broad range of... (Review)
Review
Protein -sulfhydration is a newly discovered post-translational modification of specific cysteine residue(s) in target proteins, which is involved in a broad range of cellular functions and metabolic pathways. By changing local conformation and the final activity of target proteins, -sulfhydration is believed to mediate most cellular responses initiated by H₂S, a novel gasotransmitter. In comparison to protein -sulfhydration, nitric oxide-mediated protein -nitrosylation has been extensively investigated, including its formation, regulation, transfer and metabolism. Although the investigation on the regulatory mechanisms associated with protein -sulfhydration is still in its infancy, accumulated evidence suggested that protein -sulfhydration may share similar chemical features with protein -nitrosylation. Glutathione persulfide acts as a major donor for protein -sulfhydration. Here, we review the present knowledge on protein -sulfhydration, and also predict its formation and regulation mechanisms based on the knowledge from protein -nitrosylation.
Topics: Animals; Cysteine; Disulfides; Glutathione; Humans; Hydrogen Sulfide; Nitric Oxide; Protein Conformation; Protein Processing, Post-Translational; Proteins
PubMed: 28800080
DOI: 10.3390/molecules22081334 -
Advances in Experimental Medicine and... 2019The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess... (Review)
Review
The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?
Topics: Endoplasmic Reticulum; Lipid Metabolism; Lipoproteins; Signal Transduction; Unfolded Protein Response
PubMed: 31140172
DOI: 10.1007/978-3-030-11488-6_5 -
Frontiers in Immunology 2021Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian... (Review)
Review
Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.
Topics: Acyltransferases; Adaptive Immunity; Animals; Humans; Immune System; Immune System Diseases; Immunity, Innate; Lipoylation; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 34557182
DOI: 10.3389/fimmu.2021.661202