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Ageing Research Reviews May 2016The damage to cellular components by reactive oxygen species, termed oxidative stress, both increases with age and likely contributes to age-related diseases including... (Review)
Review
The damage to cellular components by reactive oxygen species, termed oxidative stress, both increases with age and likely contributes to age-related diseases including Alzheimer's disease, atherosclerosis, diabetes, and cataract formation. In the setting of oxidative stress, hydroxyl radicals can oxidize the benzyl ring of the amino acid phenylalanine, which then produces the abnormal tyrosine isomers meta-tyrosine or ortho-tyrosine. While elevations in m-tyrosine and o-tyrosine concentrations have been used as a biological marker of oxidative stress, there is emerging evidence from bacterial, plant, and mammalian studies demonstrating that these isomers, particularly m-tyrosine, directly produce adverse effects to cells and tissues. These new findings suggest that the abnormal tyrosine isomers could in fact represent mediators of the effects of oxidative stress. Consequently the accumulation of m- and o-tyrosine may disrupt cellular homeostasis and contribute to disease pathogenesis, and as result, effective defenses against oxidative stress can encompass not only the elimination of reactive oxygen species but also the metabolism and ultimately the removal of the abnormal tyrosine isomers from the cellular amino acid pool. Future research in this area is needed to clarify the biologic mechanisms by which the tyrosine isomers damage cells and disrupt the function of tissues and organs and to identify the metabolic pathways involved in removing the accumulated isomers after exposure to oxidative stress.
Topics: Aging; Animals; Biomarkers; Isomerism; Oxidative Stress; Tyrosine
PubMed: 27039887
DOI: 10.1016/j.arr.2016.03.005 -
Annual Review of Biophysics May 2022Some oxidoreductase enzymes use redox-active tyrosine, tryptophan, cysteine, and/or glycine residues as one-electron, high-potential redox (radical) cofactors.... (Review)
Review
Some oxidoreductase enzymes use redox-active tyrosine, tryptophan, cysteine, and/or glycine residues as one-electron, high-potential redox (radical) cofactors. Amino-acid radical cofactors typically perform one of four tasks-they work in concert with a metallocofactor to carry out a multielectron redox process, serve as storage sites for oxidizing equivalents, activate the substrate molecules, or move oxidizing equivalents over long distances. It is challenging to experimentally resolve the thermodynamic and kinetic redox properties of a single-amino-acid residue. The inherently reactive and highly oxidizing properties of amino-acid radicals increase the experimental barriers further still. This review describes a family of stable and well-structured model proteins that was made specifically to study tyrosine and tryptophan oxidation-reduction. The so-called αX model protein system was combined with very-high-potential protein film voltammetry, transient absorption spectroscopy, and theoretical methods to gain a comprehensive description of the thermodynamic and kinetic properties of protein tyrosine and tryptophan radicals.
Topics: Amino Acids; Free Radicals; Kinetics; Proteins; Thermodynamics; Tryptophan; Tyrosine
PubMed: 35133854
DOI: 10.1146/annurev-biophys-100521-103031 -
Experimental Eye Research Apr 2015The extracellular matrix (ECM) plays a significant role in cellular and retinal health. The study of retinal tyrosine-sulfated proteins is an important first step toward... (Review)
Review
The extracellular matrix (ECM) plays a significant role in cellular and retinal health. The study of retinal tyrosine-sulfated proteins is an important first step toward understanding the role of ECM in retinal health and diseases. These secreted proteins are members of the retinal ECM. Tyrosine sulfation was shown to be necessary for the development of proper retinal structure and function. The importance of tyrosine sulfation is further demonstrated by the evolutionary presence of tyrosylprotein sulfotransferases, enzymes that catalyze proteins' tyrosine sulfation, and the compensatory abilities of these enzymes. Research has identified four tyrosine-sulfated retinal proteins: fibulin 2, vitronectin, complement factor H (CFH), and opticin. Vitronectin and CFH regulate the activation of the complement system and are involved in the etiology of some cases of age-related macular degeneration. Analysis of the role of tyrosine sulfation in fibulin function showed that sulfation influences the protein's ability to regulate growth and migration. Although opticin was recently shown to exhibit anti-angiogenic properties, it is not yet determined what role sulfation plays in that function. Future studies focusing on identifying all of the tyrosine-sulfated retinal proteins would be instrumental in determining the impact of sulfation on retinal protein function in retinal homeostasis and diseases.
Topics: Animals; Humans; Molecular Structure; Protein Processing, Post-Translational; Retina; Tyrosine
PubMed: 25819460
DOI: 10.1016/j.exer.2014.07.007 -
Scientific Reports Mar 2024The amino acids tryptophan, tyrosine, and phenylalanine have been extensively used for different label-free protein studies, based on the intensity, lifetime, wavelength...
The amino acids tryptophan, tyrosine, and phenylalanine have been extensively used for different label-free protein studies, based on the intensity, lifetime, wavelength and/or polarization of their emitted fluorescence. Similar to most fluorescent organic molecules, these amino acids can undergo transitions into dark meta-stable states, such as triplet and photo-radical states. On the one hand, these transitions limit the fluorescence signal, but they are also highly environment-sensitive and can offer an additional set of parameters, reflecting interactions, folding states, and immediate environments around the proteins. In this work, by analyzing the average intensity of tyrosine emission under different excitation modulations with the transient state monitoring (TRAST) technique, we explored the photo physics of tyrosine as a basis for such environment-sensitive readouts. From how the dark state transitions of tyrosine varied with excitation intensity and solvent conditions we first established a photophysical model for tyrosine. Next, we studied Calmodulin (containing two tyrosines), and how its conformation is changed upon calcium binding. From these TRAST experiments, performed with 280 nm time-modulated excitation, we show that tyrosine dark state transitions clearly change with the calmodulin conformation, and may thus represent a useful source of information for (label-free) analyses of protein conformations and interactions.
Topics: Tyrosine; Calmodulin; Spectrometry, Fluorescence; Protein Conformation; Tryptophan; Coloring Agents
PubMed: 38499633
DOI: 10.1038/s41598-024-57054-6 -
Biochimica Et Biophysica Acta.... May 2021A suite of adaptations allows insects to survive in hostile terrestrial environments for long periods of time. Temperature represents a key environmental factor for most... (Review)
Review
A suite of adaptations allows insects to survive in hostile terrestrial environments for long periods of time. Temperature represents a key environmental factor for most ectothermic insects, and they rapidly acclimate to high and low temperatures. Vast amounts of data in this research field support the idea that an insect's ability to tolerate fluctuating temperatures can be regarded as a biphasic hormetic dose response. Observation indicates that their thermal hormetic response represents a conservative estimate of their intrinsic capacity for rapid adaptation to environmental changes in nature because they naturally experience diel or seasonal temperature fluctuations. It is therefore reasonable to suppose that the hormetic response in insects reflects a surplus physiological capacity to deal with temperature changes that they would experience naturally. Although it has been unknown how thermal acclimation is induced, a stress-dependent increase in N-acetyltyrosine (NAT) was recently found to occur in insect larvae who had endured high temperatures. NAT treatment was demonstrated to induce thermotolerance in several tested insect species. NAT was also identified in the serum of humans as well as mice, and its concentration in mice was shown to be increased by heat and restraint stress, with NAT pretreatment lowering the concentrations of corticosterone and peroxidized lipids in stressed mice. These recent findings may give us some hints about how long a hormetic response lasts. Here, I will discuss recent findings underlying hormetic responses induced by an intrinsic factor, NAT, and how the hormetic response may begin and end.
Topics: Animals; Hormesis; Humans; Insecta; Mice; Oxidation-Reduction; Seasons; Signal Transduction; Thermotolerance; Tyrosine
PubMed: 33617888
DOI: 10.1016/j.bbamcr.2021.118990 -
Deutsches Arzteblatt International Apr 2018
Topics: Eye Diseases; Humans; Male; Middle Aged; Ochronosis; Tyrosine
PubMed: 29739500
DOI: 10.3238/arztebl.2018.0286a -
The Biochemical Journal Oct 2018Sulfation is a common modification of extracelluar glycans and tyrosine residues on proteins, which is important in many signalling pathways and interactions. Existing... (Review)
Review
Sulfation is a common modification of extracelluar glycans and tyrosine residues on proteins, which is important in many signalling pathways and interactions. Existing methods for studying sulfotransferases, the enzymes that catalyse sulfation, are cumbersome and low-throughput. Recent studies published in the have repurposed established biochemical assays from the kinase field and applied them to the characterisation of sulfotransferases. Biochemical screening of a library of kinase inhibitors revealed that compounds that target RAF kinases may also be repurposed to inhibit sulfotransferases. Together with the available structures of sulfotransferases, these studies open the door to the development of chemical tools to probe the biological functions of these important enzymes.
Topics: Animals; Carbohydrates; Humans; Nuclear Magnetic Resonance, Biomolecular; Sulfotransferases; Tyrosine
PubMed: 30291171
DOI: 10.1042/BCJ20180480 -
ELife Jul 2023The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural...
The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural constraints on the kinase domain holding it in a catalytically non-permissive state. The transition between inactive and active conformation is known to be largely regulated by the phosphorylation state of key tyrosines 416 and 527. Here, we identified that phosphorylation of tyrosine 90 reduces binding affinity of the SH3 domain to its interacting partners, opens the Src structure, and renders Src catalytically active. This is accompanied by an increased affinity to the plasma membrane, decreased membrane motility, and slower diffusion from focal adhesions. Phosphorylation of tyrosine 90 controlling SH3-medited intramolecular inhibitory interaction, analogical to tyrosine 527 regulating SH2-C-terminus bond, enables SH3 and SH2 domains to serve as cooperative but independent regulatory elements. This mechanism allows Src to adopt several distinct conformations of varying catalytic activities and interacting properties, enabling it to operate not as a simple switch but as a tunable regulator functioning as a signalling hub in a variety of cellular processes.
Topics: src-Family Kinases; Phosphorylation; src Homology Domains; Tyrosine; Protein-Tyrosine Kinases
PubMed: 37428018
DOI: 10.7554/eLife.82428 -
The Journal of Biological Chemistry Aug 2022Tyrosine sulfation, a post-translational modification, can determine and often enhance protein-protein interaction specificity. Sulfotyrosyl residues (sTyrs) are formed... (Review)
Review
Tyrosine sulfation, a post-translational modification, can determine and often enhance protein-protein interaction specificity. Sulfotyrosyl residues (sTyrs) are formed by the enzyme tyrosyl-protein sulfotransferase during protein maturation in the Golgi apparatus and most often occur singly or as a cluster within a six-residue span. With both negative charge and aromatic character, sTyr facilitates numerous atomic contacts as visualized in binding interface structural models, thus there is no discernible binding site consensus. Found exclusively in secreted proteins, in this review, we discuss the four broad sequence contexts in which sTyr has been observed: first, a solitary sTyr has been shown to be critical for diverse high-affinity interactions, such as between peptide hormones and their receptors, in both plants and animals. Second, sTyr clusters within structurally flexible anionic segments are essential for a variety of cellular processes, including coreceptor binding to the HIV-1 envelope spike protein during virus entry, chemokine interactions with receptors, and leukocyte rolling cell adhesion. Third, a subcategory of sTyr clusters is found in conserved acidic sequences termed hirudin-like motifs that enable proteins to interact with thrombin; consequently, many proven and potential therapeutic proteins derived from blood-consuming invertebrates depend on sTyrs for their activity. Finally, several proteins that interact with collagen or similar proteins contain one or more sTyrs within an acidic residue array. Refined methods to direct sTyr incorporation in peptides synthesized both in vitro and in vivo, together with continued advances in mass spectrometry and affinity detection, promise to accelerate discoveries of sTyr occurrence and function.
Topics: Animals; Peptides; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Proteins; Tyrosine
PubMed: 35798140
DOI: 10.1016/j.jbc.2022.102232 -
Nature Feb 2020Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone...
Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis. Tyrosine proximity within TG is thought to enable the coupling reaction but hormonogenic tyrosines have not been clearly identified, and the lack of a three-dimensional structure of TG has prevented mechanistic understanding. Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 Å, determined by cryo-electron microscopy. We identified all of the hormonogenic tyrosine pairs in the structure, and verified them using site-directed mutagenesis and in vitro hormone-production assays using human TG expressed in HEK293T cells. Our analysis revealed that the proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. We transferred the reaction sites from TG to an engineered tyrosine donor-acceptor pair in the unrelated bacterial maltose-binding protein (MBP), which yielded hormone production with an efficiency comparable to that of TG. Our study provides a framework to further understand the production and regulation of thyroid hormones.
Topics: Bacterial Proteins; Cryoelectron Microscopy; HEK293 Cells; Humans; Maltose-Binding Proteins; Models, Molecular; Mutation; Reproducibility of Results; Solvents; Thyroglobulin; Thyroid Hormones; Tyrosine
PubMed: 32025030
DOI: 10.1038/s41586-020-1995-4