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)

In Part I1 of this study, the thermolability of lens hexokinase was implicated in the development of an experimental "hypoglycemic" cataract. After eight hours of glucose deprivation, there is a precipitous loss of lens hexokinase. This occurs approximately nine hours prior to the disorganization of the other enzymatic steps in glycolysis. Epithelial hexokinase, as an immediate response to glucose deficiency, shifts from the soluble to the insoluble phase. There is no such shift in the cortex-nucleus where only soluble hexokinase is found. After eight hours of glucose deprivation, both soluble and insoluble hexokinases throughout the lens undergo rapid deactivations. During the first eight hours of glucose deprivation the loss of lenticular ATP and K+ and the gain in wet weight can be reversed by restoring normal glucose levels; beyond eight hours the changes are irreversible. During the period of reversibility, hexokinase activity levels are normal; during the period of irreversibility hexokinase activity is 10 to 20 per cent of normal. Of the substances tested (mannose, galactose, fructose, glutamine, adenosine) only mannose could sustain the lens in the absnece of glucose. Neither endogenous free glucose nor glycogen could sustain the lens in the face of glucose deprivation. There appear to be no alternative exogenous or endogenous energy yielding substrates. The younger the animal, the more susceptible is its lens to glucose deprivation. This most certainly is a reflection of the increased susceptibility of younger lenses to osmotic stress, since lenses in each age group manifested similar changes in hexokinase activity, ATP, Na+, and K+ level.
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PMID:Mechanism of "hypoglycemic" cataract formation in the rat lens. II. Further studies on the role of hexokinase instability. 93 98

Eight patients with Fuchs' corneal dystrophy and 11 matched senile cataract patients were examined at the time of surgery for aqueous humor amino acid levels. The cataract patients had amino acid levels that did not differ significantly from control values. The anterior chamber concentrations of threonine, glutamine, and arginine were found to be significantly increased in the patients with Fuchs' corneal dystrophy. Asparagine, phosphoserine, and phosphoethanolamine were found to be significantly decreased in patients with Fuchs' dystrophy.
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PMID:Aqueous amino acid levels in Fuchs' corneal dystrophy. 349 Jul 89

Fasting plasma amino-acid profiles were determined in 32 subjects with either cataractous lenses (24 subjects) or normal lenses (eight subjects). The findings were compared with established laboratory normal values. The amino-acid levels of all subjects with normal lenses were within the normal range for the subjects' age groups. In contrast, subjects with presenile or senile cataracts had markedly elevated levels of glutamine, with similar elevations of alanine in presenile cataract and of histidine in senile cataract. To the best of our knowledge, this is the first report of such a plasma amino-acid pattern in subjects with presenile and senile cataracts.
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PMID:Plasma amino acid levels in cataract. 395 97

21 amino acids have been determined in aqueous humor obtained during microsurgical intraocular procedures in 30 patients with senile cataract and 27 patients with primary open-angle glaucoma. All individual amino acids showed higher levels in the glaucomas than in the cataracts: this is valid at 2p less than 0.05 for threonine, serine, asparagine, glutamine, methionine, tyrosine, phenylalanine, histidine, tryptophan, and arginine.
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PMID:Amino acid pattern in human aqueous humor of patients with senile cataract and primary open-angle glaucoma. 406 71

The distribution of free amino acids and their related compounds has been determined in the aqueous humors of Wistar strain and Ihara cataract f-strain (ICR) aging rats. Taurine was the most abundant amino acid in aqueous humors except in ICR rats of 16 and 70 weeks. It was supposed that the increase of serine and glutamine, and the decrease of aspartate, proline and glycine in aqueous humors were related to aging. There were interesting changes in amino acids related to opacity of lens, concentration of taurine was lower than that of Wistar rats in ICR rats of 4, 16, and 70 weeks, alanine and citrulline increased in Wistar rats and decreased in ICR rats, and histidine increased in ICR rats with aging. The changes in free amino acids in aqueous humors were the greatest in ICR rats, and these data will provide useful clues for the formation of cataract and the transportation of amino acids.
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PMID:[Distribution of free amino acids and related compounds in ocular fluids of rat--I. Aging and inherited cataracts]. 778 8

The levels of alanine, aspartate and glutamine transaminase increase considerably in some diseases. We measured the activity of these enzymes and of the transaminase of 3-hydroxykynurenine, an aminoacid, which acts as a UV lens filter. Alanine and glutamine transaminases (carboxypeptidase) were not detected in normal and cataractous human lenses, and aspartate transaminase was found only in the cortex of normal lenses. 3-hydroxykynurenine transaminase was not found in lenses from persons below thirty years of age, but was found in lenses at about fifty years of age, and in cataractous lenses. Transamination of 3-hydroxykynurenine leads to the formation of xanthurenic acid and its derivatives. These substances appear to be responsible for the increase of lens fluorescence during cataract development.
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PMID:3-hydroxykynurenine transamination leads to the formation of the fluorescent substances in human lenses. 890 29

Post-translational modifications by transglutaminase may contribute to the remodeling of cellular architecture in the development of lens fiber cells, and there is evidence that the enzyme may also play a role in cataract formation. It catalyses hydrolytic deamidations as well as amide exchanges on select glutamine side chains at endo positions in a small subset of proteins of the lens. N epsilon(gamma-glutamyl)lysine crosslinks, the characteristic hallmarks of transglutaminase activity, were identified in polymers isolated from human cataract. Following up on our earlier studies relating to the inhibition of protein crosslinking by the Ca(2+)-activated transglutaminase in the lens, we have now examined the effects of 2-[(2-oxopropyl)thio]-imidazolium derivatives, recently described as active site-directed inhibitors for this family of enzymes. First, we have shown that the compounds at concentrations of 1-2 microM were effective in blocking the transamidating activities of partially purified lens transglutaminase. Then we focused on their efficacy in preventing the formation of the ca. 55 kDa beta crystallin dimers in the whole lens tissue. The production of these dimers, crosslinked by N epsilon(gamma-glutamyl)lysine isopeptide bridges, is an early sign of transglutaminase action in rabbit lens, and it can be readily documented by the SDS-PAGE analysis of proteins remaining in the soluble phase after brief exposure of the homogenate to Ca2+. The new compounds proved to be potent inhibitors of transglutaminase also in this preparation, preventing the crosslinking event at ca. 1 microM concentration. Moreover, even when applied at a 1,000-fold greater concentration (2 mM), they did not interfere with the action of calpain which, similarly to the activation of the transglutaminase system, is triggered by the addition of Ca2+. The high selectivity of the new compounds for differentially blocking only the transglutaminase and not the calpain of the lens, is all the more remarkable because these two enzymes share several mechanistic and structural similarities.
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PMID:Novel inhibitors against the transglutaminase-catalysed crosslinking of lens proteins. 962

Galactokinase (GALK1) deficiency is an autosomal recessive disorder, which causes cataract formation in children not maintained on a lactose-free diet. Galactokinase deficiency results from mutation in the GALK1 gene mapped on 17q24. Since GK1 cDNA was cloned about 20 mutations (prevalently deletions and missense) have been reported to date. Most of these reported mutations are confined to single families, and only one of them, P28T, has been referred as the founder Romani mutation. In this paper we report two novel missense mutations in GALK1 gene, identified in two unrelated patients with galactokinase deficiency. One mutation, g.575G>A, substitutes a valine for a methionine at amino acid 32 (p.V32M), while the other mutation, g.2839G>A, results in the arginine to glutamine substitution p.R239Q (GenBank sequence L76927). Biochemical studies demonstrate that these mutations led to a drastic modification in GALK activity when individual mutant cDNAs were expressed in an E. coli system. These findings indicate the pathogeneticity of these mutations causing GALK deficiency.
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PMID:Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. 1502 38

Human gammaD crystallin (HgammaD-Crys) is a two domain, beta-sheet eye lens protein that must remain soluble throughout life for lens transparency. Single amino acid substitutions of HgammaD-Crys are associated with juvenile-onset cataracts. Features of the interface between the two domains conserved among gamma-crystallins are a central six-residue hydrophobic cluster, and two pairs of interacting residues flanking the cluster. In HgammaD-Crys these pairs are Gln54/Gln143 and Arg79/Met147. We previously reported contributions of the hydrophobic cluster residues to protein stability. In this study alanine substitutions of the flanking residue pairs were constructed and analyzed. Equilibrium unfolding/refolding experiments at 37 degrees C revealed a plateau in the unfolding/refolding transitions, suggesting population of a partially folded intermediate with a folded C-terminal domain (C-td) and unfolded N-terminal domain (N-td). The N-td was destabilized by substituting residues from both domains. In contrast, the C-td was not significantly affected by substitutions of either domain. Refolding rates of the N-td were significantly decreased for mutants of either domain. In contrast, refolding rates of the C-td were similar to wild type for mutants of either domain. Therefore, domain interface residues of the folded C-td probably nucleate refolding of the N-td. We suggest that these residues stabilize the native state by shielding the central hydrophobic cluster from solvent. Glutamine and methionine side chains are among the residues covalently damaged in aged and cataractous lenses. Such damage may generate partially unfolded, aggregation- prone conformations of HgammaD-Crys that could be significant in cataract.
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PMID:Interdomain side-chain interactions in human gammaD crystallin influencing folding and stability. 1604 26

Human eye lens transparency requires life long stability and solubility of the crystallin proteins. Aged crystallins have high levels of covalent damage, including glutamine deamidation. Human gammaD-crystallin (HgammaD-Crys) is a two-domain beta-sheet protein of the lens nucleus. The two domains interact through interdomain side chain contacts, including Gln-54 and Gln-143, which are critical for stability and folding of the N-terminal domain of HgammaD-Crys. To test the effects of interface deamidation on stability and folding, single and double glutamine to glutamate substitutions were constructed. Equilibrium unfolding/refolding experiments of the proteins were performed in guanidine hydrochloride at pH 7.0, 37 degrees C, or urea at pH 3.0, 20 degrees C. Compared with wild type, the deamidation mutants were destabilized at pH 7.0. The proteins populated a partially unfolded intermediate that likely had a structured C-terminal domain and unstructured N-terminal domain. However, at pH 3.0, equilibrium unfolding transitions of wild type and the deamidation mutants were indistinguishable. In contrast, the double alanine mutant Q54A/Q143A was destabilized at both pH 7.0 and 3.0. Thermal stabilities of the deamidation mutants were also reduced at pH 7.0. Similarly, the deamidation mutants lowered the kinetic barrier to unfolding of the N-terminal domain. These data indicate that interface deamidation decreases the thermodynamic stability of HgammaD-Crys and lowers the kinetic barrier to unfolding due to introduction of a negative charge into the domain interface. Such effects may be significant for cataract formation by inducing protein aggregation or insolubility.
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PMID:Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. 1689 14


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