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Science (New York, N.Y.) Jun 2019The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the...
The human gut microbiota metabolizes the Parkinson's disease medication Levodopa (l-dopa), potentially reducing drug availability and causing side effects. However, the organisms, genes, and enzymes responsible for this activity in patients and their susceptibility to inhibition by host-targeted drugs are unknown. Here, we describe an interspecies pathway for gut bacterial l-dopa metabolism. Conversion of l-dopa to dopamine by a pyridoxal phosphate-dependent tyrosine decarboxylase from is followed by transformation of dopamine to -tyramine by a molybdenum-dependent dehydroxylase from These enzymes predict drug metabolism in complex human gut microbiotas. Although a drug that targets host aromatic amino acid decarboxylase does not prevent gut microbial l-dopa decarboxylation, we identified a compound that inhibits this activity in Parkinson's patient microbiotas and increases l-dopa bioavailability in mice.
Topics: Actinobacteria; Animals; Antiparkinson Agents; Bacterial Proteins; Decarboxylation; Dopamine; Enterococcus faecalis; Gastrointestinal Microbiome; Genome, Bacterial; HeLa Cells; Humans; Levodopa; Male; Metabolic Networks and Pathways; Mice, Inbred BALB C; Tyrosine; Tyrosine Decarboxylase
PubMed: 31196984
DOI: 10.1126/science.aau6323 -
Signal Transduction and Targeted Therapy Sep 2022Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways.... (Review)
Review
Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Tumor Microenvironment; Tyrosine
PubMed: 36115852
DOI: 10.1038/s41392-022-01168-8 -
Science (New York, N.Y.) Dec 2022Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal proteins are imported from the cytosol in a folded state by the...
Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal proteins are imported from the cytosol in a folded state by the soluble receptor PEX5. How folded cargo crosses the membrane is unknown. Here, we show that peroxisomal import is similar to nuclear transport. The peroxisomal membrane protein PEX13 contains a conserved tyrosine (Y)- and glycine (G)-rich YG domain, which forms a selective phase resembling that formed by phenylalanine-glycine (FG) repeats within nuclear pores. PEX13 resides in the membrane in two orientations that oligomerize and suspend the YG meshwork within the lipid bilayer. Purified YG domains form hydrogels into which PEX5 selectively partitions, by using conserved aromatic amino acid motifs, bringing cargo along. The YG meshwork thus forms an aqueous conduit through which PEX5 delivers folded proteins into peroxisomes.
Topics: Humans; Glycine; Nuclear Pore; Peroxisomes; Protein Transport; Membrane Proteins; Conserved Sequence; Protein Domains; Tyrosine
PubMed: 36520918
DOI: 10.1126/science.adf3971 -
FEMS Microbiology Reviews Aug 2021The integration of mobile genetic elements into their host chromosome influences the immediate fate of cellular organisms and gradually shapes their evolution.... (Review)
Review
The integration of mobile genetic elements into their host chromosome influences the immediate fate of cellular organisms and gradually shapes their evolution. Site-specific recombinases catalyzing this integration have been extensively characterized both in bacteria and eukarya. More recently, a number of reports provided the in-depth characterization of archaeal tyrosine recombinases and highlighted new particular features not observed in the other two domains. In addition to being active in extreme environments, archaeal integrases catalyze reactions beyond site-specific recombination. Some of these integrases can catalyze low-sequence specificity recombination reactions with the same outcome as homologous recombination events generating deep rearrangements of their host genome. A large proportion of archaeal integrases are termed suicidal due to the presence of a specific recombination target within their own gene. The paradoxical maintenance of integrases that disrupt their gene upon integration implies novel mechanisms for their evolution. In this review, we assess the diversity of the archaeal tyrosine recombinases using a phylogenomic analysis based on an exhaustive similarity network. We outline the biochemical, ecological and evolutionary properties of these enzymes in the context of the families we identified and emphasize similarities and differences between archaeal recombinases and their bacterial and eukaryal counterparts.
Topics: Archaea; Eukaryota; Integrases; Recombinases; Tyrosine
PubMed: 33524101
DOI: 10.1093/femsre/fuab004 -
Current Opinion in Allergy and Clinical... Dec 2022The purpose of this article is to provide an overview of the literature pertaining to the use of MicroCrystalline Tyrosine (MCT) in the immunotherapy with an emphasis on... (Review)
Review
PURPOSE OF REVIEW
The purpose of this article is to provide an overview of the literature pertaining to the use of MicroCrystalline Tyrosine (MCT) in the immunotherapy with an emphasis on recent developments.
RECENT FINDINGS
In addition to significant effectiveness and safety profiles, additional aspects of interest such as booster immunotherapy concepts, sustained clinical effects, long-term efficacy and disease-modifying effects are being focused on in the recently published studies. The depot adjuvant MCT also shows potential in promising disease-challenge models such as for malaria and melanoma.
SUMMARY
MCT-adsorbed immunotherapy products have been shown to provide convincing overall safety, tolerability and efficacy outcomes, as well in vulnerable groups such as children and asthmatic patients.
Topics: Child; Humans; Tyrosine; Immunotherapy; Adjuvants, Immunologic; Immunologic Factors; Asthma
PubMed: 36254926
DOI: 10.1097/ACI.0000000000000859 -
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 -
Antioxidants & Redox Signaling Mar 2017"Nitroproteomic" is under active development, as 3-nitrotyrosine in proteins constitutes a footprint left by the reactions of nitric oxide-derived oxidants that are... (Review)
Review
SIGNIFICANCE
"Nitroproteomic" is under active development, as 3-nitrotyrosine in proteins constitutes a footprint left by the reactions of nitric oxide-derived oxidants that are usually associated to oxidative stress conditions. Moreover, protein tyrosine nitration can cause structural and functional changes, which may be of pathophysiological relevance for human disease conditions. Biological protein tyrosine nitration is a free radical process involving the intermediacy of tyrosyl radicals; in spite of being a nonenzymatic process, nitration is selectively directed toward a limited subset of tyrosine residues. Precise identification and quantitation of 3-nitrotyrosine in proteins has represented a "tour de force" for researchers. Recent Advances: A small number of proteins are preferential targets of nitration (usually less than 100 proteins per proteome), contrasting with the large number of proteins modified by other post-translational modifications such as phosphorylation, acetylation, and, notably, S-nitrosation. Proteomic approaches have revealed key features of tyrosine nitration both in vivo and in vitro, including selectivity, site specificity, and effects in protein structure and function.
CRITICAL ISSUES
Identification of 3-nitrotyrosine-containing proteins and mapping nitrated residues is challenging, due to low abundance of this oxidative modification in biological samples and its unfriendly behavior in mass spectrometry (MS)-based technologies, that is, MALDI, electrospray ionization, and collision-induced dissociation.
FUTURE DIRECTIONS
The use of (i) classical two-dimensional electrophoresis with immunochemical detection of nitrated proteins followed by protein ID by regular MS/MS in combination with (ii) immuno-enrichment of tyrosine-nitrated peptides and (iii) identification of nitrated peptides by a MIDAS™ experiment is arising as a potent methodology to unambiguously map and quantitate tyrosine-nitrated proteins in vivo. Antioxid. Redox Signal. 26, 313-328.
Topics: Animals; Humans; Mass Spectrometry; Nitrates; Nitrosation; Protein Processing, Post-Translational; Proteins; Proteome; Proteomics; Sensitivity and Specificity; Tyrosine
PubMed: 27324931
DOI: 10.1089/ars.2016.6787 -
Current Opinion in Structural Biology Jun 2020Post-translational modifications (PTMs) drive the diversity of the proteome and broadly regulate protein function. Interplay between different types of PTMs further... (Review)
Review
Post-translational modifications (PTMs) drive the diversity of the proteome and broadly regulate protein function. Interplay between different types of PTMs further enables tight and dynamic fine-tuning of molecular functions. O-glycosylation on serine, threonine, and tyrosine residues is a major PTM with diverse roles in development, differentiation, pathogenesis, and proteolytic processing. Other examples of cross-talk between PTMs also exists, such as PSGL-1, where the combined presence of N-terminal sulfotyrosines and O-glycans is pivotal for selectin binding. A handful of other related examples of O-glycans and sulfotyrosine co-localization has been described but it is not yet recognized as a general regulatory phenomenon. In this review, we highlight the emerging global pattern of co-localization of cell-surface and extracellular sulfotyrosines with O-glycans, which we term ‘multi-motif’ interactions, from a wide range of protein classes. We also discuss the barriers, and existing and future tools needed to dissect the biological impact and biomedical potential.
Topics: Animals; Glycomics; Glycoproteins; Glycosylation; Humans; Protein Processing, Post-Translational; Tyrosine
PubMed: 31927217
DOI: 10.1016/j.sbi.2019.12.002 -
Accounts of Chemical Research Aug 2018Work on the electronic structures of metal-oxo complexes began in Copenhagen over 50 years ago. This work led to the prediction that tetragonal multiply bonded...
Work on the electronic structures of metal-oxo complexes began in Copenhagen over 50 years ago. This work led to the prediction that tetragonal multiply bonded transition metal-oxos would not be stable beyond the iron-ruthenium-osmium oxo wall in the periodic table and that triply bonded metal-oxos could not be protonated, even in the strongest Brønsted acids. In this theory, only double bonded metal-oxos could attract protons, with basicities being a function of the electron donating ability of ancillary ligands. Such correlations of electronic structure with reactivity have gained importance in recent years, most notably owing to the widespread recognition that high-valent iron-oxos are intermediates in biological reactions critical to life on Earth. In this Account, we focus attention on the oxygenations of inert organic substrates by cytochromes P450, as these reactions involve multiply bonded iron-oxos. We emphasize that P450 iron-oxos are strong oxidants, so strong that they would destroy nearby amino acids if substrates are not oxygenated rapidly; it is our view that these high-valent iron-oxos are such dangerous reactive oxygen species that Nature surely found ways to disable them. Looking more deeply into this matter, mainly by examining many thousands of structures in the Protein Data Bank, we have found that P450s and other enzymes that require oxygen for function have chains of tyrosines and tryptophans that extend from active-site regions to protein surfaces. Tyrosines are near the heme active sites in bacterial P450s, whereas tryptophan is closest in most human enzymes. High-valent iron-oxo survival times taken from hole hopping maps range from a few nanoseconds to milliseconds, depending on the distance of the closest Trp or Tyr residue to the heme. In our proposed mechanism, multistep hole tunneling (hopping) through Tyr/Trp chains guides the damaging oxidizing hole to the protein surface, where it can be quenched by soluble protein or small molecule reductants. As the Earth's oxygenic atmosphere is believed to have developed about 2.5 billion years ago, the increase in occurrence frequency of tyrosine and tryptophan since the last universal evolutionary ancestor may be in part a consequence of enzyme protective functions that developed to cope with the environmental toxin, O.
Topics: Catalytic Domain; Coordination Complexes; Cysteine; Cytochrome P-450 Enzyme System; Heme; Metals, Heavy; Methionine; Oxidation-Reduction; Oxygen; Protein Structural Elements; Tryptophan; Tyrosine
PubMed: 30016077
DOI: 10.1021/acs.accounts.8b00245 -
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