Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among chaperone-like functioning proteins, the lens alpha-crystallins are of particular interest because they are not renewed, and even minor alterations can hurt their function of maintaining the proper refractive index and avoiding cataract formation in the lens. Several reports have suggested the occurrence of remarkable structural modifications in lens proteins in the presence of endogenous and exogenous sensitizers upon exposure to light. In particular, it has been shown in vitro that hypericin, the active ingredient of Hypericum, can bind to and, in the presence of light, cause the photopolymerization of alpha-crystallin. On the basis of these results it has also been suggested that a subsequent significant impairment of the protein function can occur. Using absorption and emission spectroscopic techniques, as well as circular dichroism, we have studied the structural modifications of alpha-crystallin resulting from its interaction with hypericin after irradiation with visible light. To investigate the chaperone-like function of alpha-crystallin, the heat-induced aggregation kinetics of another lens protein, betaLow-crystallin, was monitored by measuring the apparent absorption due to scattering at 360 nm as a function of time, and no apparent damage to its functional role was observed. Spectroscopic results, on the contrary, show a prominent reduction in both tryptophan and hypericin fluorescence emission intensity after light irradiation, suggesting an alteration in the tryptophan microenvironment and a high degree of packing of the chromophore due to photoinduced modification of the molecular framework. Control experiments on alpha-crystallin structurally modified by light in the presence of hypericin indicated that the protein still retains its ability to chaperone both lens crystallins and insulin.
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PMID:Photosensitized structural modifications of the lens protein alpha-crystallin: do all modifications impair chaperone-like activity? 1281 2

Tryptophan deficiency is known for long time to cause cataract in rats. However, up till now the underlying mechanism is still enigmatic. Histological studies showed an extended lens bow suggesting that the normal breakdown of nuclei in the lens fibres is arrested under these conditions. Using advanced ultrastructural techniques we aimed to clarify this aberrant final differentiation of lens fibres. Albino and pigmented rats were permanently or intermittently raised on a tryptophan deficient diet for 12 and 16 weeks, respectively. Rats of the same age raised on a normal diet served as controls. Lenses were treated for light and electron microscopy. For histology sections were stained for DNA and gamma-crystallins. In addition to routine transmission electron microscopy (TEM), ultrathin sections were subjected to electron tomography and energy dispersive X-ray microanalysis (EDX). Histology verified the extended lens bow for albino and pigmented rats and showed that in the intermittent period of normal diet the fibre nuclei are broken down as in controls. It was further shown that gamma-crystallins are co-localized with DNA in the nuclear domain. TEM revealed that during final differentiation nuclear chromatin becomes highly compacted in a chromosome-like manner and than rapidly evanesces in control rats. This compacted stage persists indefinitely in the tryptophan deficient rats. Electron tomography showed that during differentiation chromatin is first uncoiled to 30 nm solenoids, subsequently to highly compacted 10 nm beads-on-a-string fibrils and than is segregated from the nuclear proteins. EDX revealed that the late stage persisting nuclei consist of domains rich in DNA associated with histones and in domains with mainly proteins. This study corroborates previous findings on the final breakdown of nuclei of lens fibres. It further shows that the chromatin is ultimately uncoiled to beads-on-a-string fibrils and that as the last step chromatin is broken down at this unmasked stage. Except for this last step nuclear breakdown is identical in control and tryptophan deficient rats suggesting that it is not the availability of tryptophan for protein synthesis in general which causes the arrest. Two alternatives for this final arrest are discussed. A low tryptophan content, most pronounced in deeper cortical layers, may inhibit the late synthesis of the DNases and proteases necessary for chromatin breakdown. The radical scavenging by indoleamine 2,3-dioxygenase, which cleaves the pyrrole ring of tryptophan to form formylkynurenine using free oxygen radicals, is impaired by low levels of tryptophan. This decreased scavenging of oxygen radicals will expose the catalytic enzymes for chromatin breakdown, residing in the nucleus in an inactive form for quite a long period, to high levels of oxygen radicals and may affect the activity of these enzymes and therefore the execution of the chromatin breakdown.
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PMID:Tryptophan deficiency arrests chromatin breakdown in secondary lens fibers of rats. 1510 46

Human lens proteins become progressively modified by tryptophan-derived UV filter compounds in an age-dependent manner. One of these compounds, kynurenine, undergoes deamination at physiological pH, and the product binds covalently to nucleophilic residues in proteins via a Michael addition. Here we demonstrate that after covalent attachment of kynurenine, lens proteins become susceptible to photo-oxidation by wavelengths of light that penetrate the cornea. H2O2 and protein-bound peroxides were found to accumulate in a time-dependent manner after exposure to UV light (lambda > 305-385 nm), with shorter-wavelength light giving more peroxides. Peroxide formation was accompanied by increases in the levels of the protein-bound tyrosine oxidation products dityrosine and 3,4-dihydroxyphenylalanine, species known to be elevated in human cataract lens proteins. Experiments using D2O, which enhances the lifetime of singlet oxygen, and azide, a potent scavenger of this species, are consistent with oxidation being mediated by singlet oxygen. These findings provide a mechanistic explanation for UV light-mediated protein oxidation in cataract lenses, and also rationalize the occurrence of age-related cataract in the nuclear region of the lens, as modification of lens proteins by UV filters occurs primarily in this region.
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PMID:Protein-bound kynurenine is a photosensitizer of oxidative damage. 1545 88

Molecular models of human gamma-crystallins and the 'alpha-crystallin domain' of human alphaA-crystallin have been built based on available related X-ray crystal structures. The accessibilities of the component cysteine, methionine and tryptophan side chains in the crystallin models have been calculated. The reactivities of these cysteines, which are oxidised in cataract, are assessed based on their known modifications and within the context of their location within the 3D models.
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PMID:Sulfur in human crystallins. 1564 19

Tryptophan can be oxidized in the eye lens by both enzymatic and non-enzymatic mechanisms. Oxidation products, such as kynurenines, react with proteins to form yellow-brown pigments and cause covalent cross-linking. We generated a monoclonal antibody against 3-hydroxykynurenine (3OHKYN)-modified keyhole limpet hemocyanin and characterized it using 3OHKYN-modified amino acids and proteins. This monoclonal antibody reacted with 3OHKYN-modified N(alpha)-acetyl lysine, N(alpha)-acetyl histidine, N(alpha)-acetyl arginine, and N(alpha)-acetyl cysteine. Among the several tryptophan oxidation products tested, 3OHKYN produced the highest concentration of antigen when reacted with human lens proteins. A major antigen from the reaction of 3OHKYN and N(alpha)-acetyl lysine was purified by reversed phase high pressure liquid chromatography, which was characterized by spectroscopy and identified as 2-amino-3-hydroxyl-alpha-((5S)-5-acetamino-5-carboxypentyl amino)-gamma-oxo-benzene butanoic acid. Enzyme-digested cataractous lens proteins displayed 3OHKYN-derived modifications. Immunohistochemistry revealed 3OHKYN modifications in proteins associated with the lens fiber cell plasma membrane. The low molecular products (<10,000 Da) isolated from normal lenses after reaction with glucosidase followed by incubation with proteins generated 3OHKYN-derived products. Human lens epithelial cells incubated with 3OHKYN showed intense immunoreactivity. We also investigated the effect of glycation on tryptophan oxidation and kynurenine-mediated modification of lens proteins. The results showed that glycation products failed to oxidize tryptophan or generate kynurenine modifications in proteins. Our studies indicate that 3OHKYN modifies lens proteins independent of glycation to form products that may contribute to protein aggregation and browning during cataract formation.
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PMID:3-hydroxykynurenine-mediated modification of human lens proteins: structure determination of a major modification using a monoclonal antibody. 1581 58

Indoleamine 2,3-dioxygenase (EC 1.13.11.42) is a heme-containing dioxygenase which catalyzes the first and rate-limiting step in the major pathway of L-tryptophan catabolism in mammals. Much attention has recently been focused on the dioxygenase because this metabolic pathway is involved not only in a variety of physiological functions but also in many diseases. In this review, the discovery and unique catalytic properties of dioxygenase are described first, and then the recent findings regarding the dioxygenase-initiated tryptophan metabolism are summarized, with special emphasis on the detrimental role of dioxygenase in side effects of interferon-gamma and interleukin-12 (by systemic tryptophan depletion), the escape of malignant tumors from immune surveillance (by immunosuppression caused by tryptophan depletion), several neurodegenerative disorders including Alzheimer's disease (by an aberrant production of neurotoxin, quinolinic acid), and age-related cataract (due to "Kynurenilation," a novel post-translational modification of lens proteins with tryptophan-derived UV filters).
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PMID:Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. 1617 99

The alpha-, beta-, and gamma-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine alpha-crystallin is incubated with 3-hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in alphaA-crystallin and a similar extent of oxidation of methionines 1 and 68 in alphaB-crystallin after 48 h. Tryptophans 9 and 60 in alphaB-crystallin were oxidized to a lesser extent. AlphaA-crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation of alpha-crystallin; however, oxidation was detected at methionine 1 in both alphaA- and alphaB-crystallin from human cataractous lenses. Age-related nuclear cataract is associated with coloration and insolubilization of lens proteins and extensive oxidation of cysteine and methionine residues. Our findings demonstrate that 3-hydroxykynurenine can readily catalyze the oxidation of methionine residues in both alphaB- and alphaA-crystallin, and it has been reported that alpha-crystallin modified in this way is a poorer chaperone. Thus, 3-hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens.
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PMID:3-Hydroxykynurenine oxidizes alpha-crystallin: potential role in cataractogenesis. 1646 31

Age-related nuclear (ARN) cataract is a major cause of world blindness. With the onset of ARN cataract, the normally transparent and colorless lens becomes opaque and can take on colors ranging from orange, brown, and even black. The molecular basis for this remarkable transformation is unknown. ARN cataract is also characterized by extensive oxidation, insolubilization, and cross-linking of polypeptides, particularly in the nucleus of the lens. It has been postulated that 3-hydroxykynurenine (3OHKyn) may be involved in these changes. This endogenous tryptophan metabolite is readily oxidized and is involved in the tanning of moth cocoons and the formation of pigments in the eyes of butterflies. 3OHKyn is a component of our primate-specific UV-filter pathway, and the brownish hue of ARN cataract lenses is also unique to humans. Because numerous colored compounds can be produced by autoxidation of 3OHKyn, this process could provide an explanation for the variety of lens colors and other changes seen in ARN cataract. For such a theory to be tenable, it needs to be demonstrated that 3OHKyn is bound to proteins in the human lens. Here, we show that all normal lenses older than 50 have 3OHKyn covalently attached to the nuclear proteins, most likely via cysteine residues. If indeed 3OHKyn is implicated in ARN cataract, a reduction in the levels that are bound in cataract, compared to normal lenses, would be expected. In agreement with this hypothesis, no bound 3OHKyn could be detected in proteins isolated from ARN cataract lenses.
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PMID:Identification of 3-hydroxykynurenine bound to proteins in the human lens. A possible role in age-related nuclear cataract. 1646 42

We reported previously that chemical modification of human alphaA-crystallin by a metabolic dicarbonyl compound, methylglyoxal (MGO), enhances its chaperone-like function, a phenomenon which we attributed to formation of argpyrimidine at arginine residues (R) 21, 49, and 103. This structural change removes the positive charge on the arginine residues. To explore this mechanism further, we replaced these three R residues with a neutral alanine (A) residue one at a time or in combination and examined the impact on the structure and chaperone function. Measurement of intrinsic tryptophan fluorescence and near-UV CD spectra revealed alteration of the microenvironment of aromatic amino acid residues in mutant proteins. When compared to wild-type (wt) alphaA-crystallin, the chaperone function of R21A and R103A mutants increased 20% and 18% as measured by the insulin aggregation assay and increased it as much as 39% and 28% when measured by the citrate synthase (CS) aggregation assay. While the R49A mutant lost most of its chaperone function, R21A/R103A and R21A/R49A/R103A mutants had slightly better function (6-14% and 10-14%) than the wt protein in these assays. R21A and R103A mutants had higher surface hydrophobicity than wt alphaA-crystallin, but the R49A mutant had lower hydrophobicity. R21A and R103A mutants, but not the R49A mutant, were more efficient than wt protein in refolding guanidine hydrochloride-treated malate dehydrogenase to its native state. Our findings indicate that the positive charges on R21, R49, and R103 are important determinants of the chaperone function of alphaA-crystallin and suggest that chemical modification of arginine residues may play a role in protein aggregation during lens aging and cataract formation.
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PMID:Effect of site-directed mutagenesis of methylglyoxal-modifiable arginine residues on the structure and chaperone function of human alphaA-crystallin. 1658 92

L-Tryptophan (Trp) is an essential amino acid and its deficiency is involved in various pathologies. In this present investigation an attempt was made to study the role of tryptophan and its metabolites in cataract formation in wistar rats. Rats were divided and maintained in 3 groups, Group A--control; Group B--marginal-tryptophan and Group C--Tryptophan-deficient diet for 3 months. Slit lamp microscope observations indicated lenticular opacities in Group-C (tryptophan-deficient) rats. In the rats that were maintained on tryptophan deficient diet, a decrease in protein content, kynurenines, reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-s-tranferase (GSTs) and tryptophan-fluorescence intensities and an increase in lipid peroxidation indicative of oxidative stress have been observed. The above changes were normalized in the rats on supplementation of 0.05% tryptophan (Group-B) in their diets. These results suggest that tryptophan-deficiency in the diet leads to an overall significant decrease in kynurenines and levels of antioxidant enzymes (except SOD) in ocular tissue with a concomitant lenticular opacification. The results suggest that diet with adequate tryptophan has protective influence and is of immense benefit in mitigating the changes that may otherwise contribute to the lenticular opacities.
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PMID:Influence of kynurenines in pathogenesis of cataract formation in tryptophan-deficient regimen in Wistar rats. 1758 90


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