Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:EXPT03141 (L-tyrosine)
 2,375 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study dealt with the formation of dityrosine - a cross-link in some proteins including collagen - by human salivary lactoperoxidase. Dityrosine formation was found at pH range 6.6 to 9.3 with maximum reaction velocity at pH 8.5. However, thiocyanate ions at physiological salivary concentrations inhibited dityrosine formation by 70 to 80 per cent compared with the optimum rate. The inhibition seemed to result from the competition of SCN ions and L-tyrosine for the same binding site on enzyme surface. The possibility of dityrosine cross-linking in vivo in human oral fluid seems to be limited compared with e.g. human milk or macaque saliva where the concentration of SCN ions is low but the activity of lactoperoxidase is considerably high.
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PMID:Formation of dityrosine by human salivary lactoperoxidase in vitro. 3 19

Dityrosine is a sporulation-specific component of the yeast ascospore wall that is essential for the resistance of the spores to adverse environmental conditions. Dityrosine in vivo exists in both the LL and DL configurations and is part of an insoluble macromolecule of unknown structure. Here we present data indicating that dityrosine of the yeast spore wall is biosynthesized by a different mechanism than dityrosine in other biological systems--e.g., the hard fertilization membrane of the sea urchin egg. We identified two soluble, low molecular weight LL-dityrosine-containing spore wall precursors in extracts of sporulating cells and one precursor containing L-tyrosine. By expression of the previously described sporulation-specific genes DIT1 and DIT2 in vegetative cells, it was shown that DIT1 catalyzes the reaction leading from L-tyrosine to the tyrosine-containing precursor. DIT2, which is a member of the cytochrome P450 superfamily, is responsible for the dimerization reaction leading to the dityrosine-containing precursors. Epimerization of LL- to DL-dityrosine is one of the latest steps in spore wall formation and takes place after the dityrosine-containing precursors are incorporated into the spore wall. On the basis of these findings we suggest a biosynthetic pathway for the top layer of the yeast spore wall.
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PMID:The sporulation-specific enzymes encoded by the DIT1 and DIT2 genes catalyze a two-step reaction leading to a soluble LL-dityrosine-containing precursor of the yeast spore wall. 818 42

Lipoprotein oxidation is thought to play a pivotal role in atherogenesis, yet the underlying reaction mechanisms remain poorly understood. We have explored the possibility that high density lipoprotein (HDL) might be oxidized by peroxidase-generated tyrosyl radical. Exposure of HDL to L-tyrosine, H2O2, and horseradish peroxidase crosslinked its apolipoproteins and strikingly increased protein-associated fluorescence. The reaction required L-tyrosine but was independent of free metal ions; it was blocked by either catalase or the heme poison aminotriazole. Dityrosine and other tyrosine oxidation products were detected in the apolipoproteins of HDL modified by the peroxidase/L-tyrosine/H2O2 system, implicating tyrosyl radical in the reaction pathway. Further evidence suggests that tyrosylated HDL removes cholesterol from cultured cells more effectively than does HDL. Tyrosylated HDL was more potent than HDL at inhibiting cholesterol esterification by the acyl-CoA:cholesterol acyltransferase reaction, stimulating the incorporation of [14C]acetate into [14C]cholesterol, and depleting cholesteryl ester stores in human skin fibroblasts. Moreover, exposure of mouse macrophage foam cells to tyrosylated HDL markedly diminished cholesteryl ester and free cholesterol mass. We have recently found that myeloperoxidase, a heme protein secreted by activated phagocytes, can also convert L-tyrosine to o,o'-dityrosine. This raises the possibility that myeloperoxidase-generated tyrosyl radical may modify HDL, enabling the lipoprotein to protect the artery wall against pathological cholesterol accumulation.
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PMID:Oxidative tyrosylation of high density lipoprotein by peroxidase enhances cholesterol removal from cultured fibroblasts and macrophage foam cells. 834 80

Myeloperoxidase, secreted by activated phagocytes, produces the powerful cytotoxin hypochlorous acid from H2O2 and Cl-. We show that the enzyme can also employ H2O2 to oxidize L-tyrosine to tyrosyl radical, yielding the stable cross-linked product dityrosine. Dityrosine synthesis by the myeloperoxidase-H2O2 system did not require halide and was partially inhibited by Cl-. At physiological concentrations of Cl-, L-tyrosine, and other plasma amino acids, purified myeloperoxidase utilized 26% of the H2O2 in the reaction mixture to form dityrosine. Aminotriazole, cyanide, and azide inhibited the reaction. Phorbol ester-stimulated human neutrophils and monocyte-derived macrophages similarly generated dityrosine from L-tyrosine by a pathway inhibited by catalase, aminotriazole, and azide. The requirement for H2O2 and the inhibition by heme poisons suggest that activated phagocytes synthesize dityrosine by a peroxidative mechanism. These results indicate that L-tyrosine can compete effectively with Cl- as a substrate for myeloperoxidase and raise the possibility that formation of tyrosyl radical may play a role in the phagocyte inflammatory response. Because dityrosine is protease-resistant, stable to acid hydrolysis, and intensely fluorescent, its identification in tissues may pinpoint targets where phagocytes inflict oxidative damage in vivo.
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PMID:Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages. 838 89

Phagocytes generate H2O2 for use by a secreted heme enzyme, myeloperoxidase, to kill invading bacteria, viruses, and fungi. We have explored the possibility that myeloperoxidase might also convert L-tyrosine to a radical catalyst that cross-links proteins. Protein-bound tyrosyl residues exposed to myeloperoxidase, H2O2, and L-tyrosine were oxidized to o,o'-dityrosine, a stable product of the tyrosyl radical. The cross-linking reaction required L-tyrosine but was independent of halide and free transition metal ions; the heme poisons azide and aminotriazole were inhibitory. Activated neutrophils likewise converted polypeptide tyrosines to dityrosine. The pathway for oxidation of peptide tyrosyl residues was dependent upon L-tyrosine and was inhibited by heme poisons and catalase. Dityrosine synthesis was little affected by plasma concentrations of Cl- and amino acids, suggesting that the reaction pathway might be physiologically relevant. The requirement for free L-tyrosine and H2O2 for dityrosine formation and the inhibition by heme poisons support the hypothesis that myeloperoxidase catalyzes the cross-linking of proteins by a peroxidative mechanism involving tyrosyl radical. In striking contrast to the pathways generally used to study protein oxidation in vitro, the reaction does not require free metal ions. We speculate that protein dityrosine cross-linking by myeloperoxidase may play a role in bacterial killing or injuring normal tissue. The intense fluorescence and stability of biphenolic compounds may allow dityrosine to act as a marker for proteins oxidatively damaged by myeloperoxidase in phagocyte-rich inflammatory lesions.
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PMID:Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins. 839 Apr 91

Generation of reactive oxygen species in vivo results in oxidative-damage to cellular components, including proteins. Due to the relatively long half-lives of several blood proteins the cumulative formation of oxidatively damaged proteins might serve as a biomarker for reactive oxygen species formation. The most prominent sources of reactive oxygen species in vivo are site-specific metal ion-catalyzed reactions of the Fenton and Haber-Weiss types and the H2O2/peroxidase system. In vitro oxidation of L-tyrosine using a peroxidase or Cu++/H2O2 system gives rise to the formation of a highly fluorescent substance, bityrosine. High-performance liquid chromatography (HPLC) analysis of acid hydrolyzed serum albumin after oxidation with peroxidase/H2O2 or with Cu++/H2O2 showed that bityrosine had been formed whereas oxidation of this protein with Fe(III)/ascorbate did not result in the formation of bityrosine. Bityrosine could not be detected in human plasma proteins or haemoglobin with the detection limit of one pmol per mg protein.
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PMID:Analysis of native human plasma proteins and haemoglobin for the presence of bityrosine by high-performance liquid chromatography. 939 84

To kill invading bacteria, viruses, and fungi, phagocytes secrete hydrogen peroxide (H(2)O(2)) and the heme enzyme myeloperoxidase. We have explored the possibility that myeloperoxidase might use H(2)O(2) to convert L-tyrosine to tyrosyl radical. Activated human neutrophils and monocytes used the system to oxidize free L-tyrosine to o,o'-dityrosine, a stable product of tyrosyl radical. Protein-bound tyrosyl residues exposed to myeloperoxidase, H(2)O(2), and L-tyrosine were also oxidized to o,o'-dityrosine. The cross-linking reaction required free L-tyrosine, suggesting that myeloperoxidase converts the amino acid to a diffusible radical catalyst that promotes protein oxidation. We used electron paramagnetic resonance to provide direct evidence that the oxidizing intermediate is free tyrosyl radical. Myeloperoxidase-generated tyrosyl radical also initiates lipid peroxidation, suggesting that activated phagocytes might also be able to oxidize lipids in host tissues. Moreover, myeloperoxidase is present and active in human atherosclerotic tissue, and levels of protein-bound dityrosine are elevated in such lesions. Our recent studies indicate that activated neutrophils use oxidants generated by the phagocyte NADPH oxidase to produce protein-bound dityrosine during acute inflammation. Collectively, these findings suggest that generation of tyrosyl radical by myeloperoxidase allows activated phagocytes to damage both proteins and lipids. Elevated levels of o,o'-dityrosine have been detected in inflammatory lung disease, neurodegenerative disorders, and aging. Thus, oxidation of tyrosine to tyrosyl radical might play a role in the pathogenesis of many diseases.
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PMID:Tyrosyl radical production by myeloperoxidase: a phagocyte pathway for lipid peroxidation and dityrosine cross-linking of proteins. 1212 92

We report the first characterization and classification of Orf13 (S. refuineus) as a heme-dependent peroxidase catalyzing the ortho-hydroxylation of L-tyrosine to L-DOPA. The putative tyrosine hydroxylase coded by orf13 of the anthramycin biosynthesis gene cluster has been expressed and purified. Heme b has been identified as the required cofactor for catalysis, and maximal L-tyrosine conversion to L-DOPA is observed in the presence of hydrogen peroxide. Preincubation of L-tyrosine with Orf13 prior to the addition of hydrogen peroxide is required for L-DOPA production. However, the enzyme becomes inactivated by hydrogen peroxide during catalysis. Steady-state kinetic analysis of L-tyrosine hydroxylation revealed similar catalytic efficiency for both L-tyrosine and hydrogen peroxide. Spectroscopic data from a reduced-CO(g) UV-vis spectrum of Orf13 and electron paramagnetic resonance of ferric heme Orf13 are consistent with heme peroxidases that have a histidyl-ligated heme iron. Contrary to the classical heme peroxidase oxidation reaction with hydrogen peroxide that produces coupled aromatic products such as o,o'-dityrosine, Orf13 is novel in its ability to catalyze aromatic amino acid hydroxylation with hydrogen peroxide, in the substrate addition order and for its substrate specificity for L-tyrosine. Peroxygenase activity of Orf13 for the ortho-hydroxylation of L-tyrosine to L-DOPA by a molecular oxygen dependent pathway in the presence of dihydroxyfumaric acid is also observed. This reaction behavior is consistent with peroxygenase activity reported with horseradish peroxidase for the hydroxylation of phenol. Overall, the putative function of Orf13 as a tyrosine hydroxylase has been confirmed and establishes the first bacterial class of tyrosine hydroxylases.
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PMID:A heme peroxidase with a functional role as an L-tyrosine hydroxylase in the biosynthesis of anthramycin. 2191 39