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)

Pyrraline is an advanced Maillard reaction product formed by the non-enzymatic reaction initiated by glucose with lysine residues on proteins. This reaction involves an intermediate, 3-deoxyglucosone, concentration of which is shown to be elevated in plasma and lenses during diabetes. Bovine lens alpha crystallins incubated with 3-deoxyglucosone showed that pyrraline formation was a major modification and its quantification by two different methods revealed time-dependent accumulation. Pyrraline was quantified in normal, senile cataractous and diabetic lenses. Although a wide variation was observed, the mean value in cataractous lenses (mean +/- S.E.: 48.4 +/- 12.67 pmol/mg protein) was higher than in age-matched normal lenses (30.9 +/- 10.26 pmol). Surprisingly, in diabetic lenses, the mean value was lower than normal lenses (28.4 +/- 15.3 pmol). These results suggest that glucose-specific advanced Maillard products occur in the human lens and such modifications may play a role in lens aging and cataract formation.
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PMID:The presence of a glucose-derived Maillard reaction product in the human lens. 860 76

Bendazac has been used as an anti-cataractogenic drug. It has been reported that this acts by preventing protein denaturation. In this study the ability of bendazac to inhibit in vitro glycation of human lens crystallins was evaluated. Possible effects of bendazac were detected by incubation of WS crystallins with the reducing sugars glucose and fructose. The efficiency of bendazac was evaluated by means of selected parameters including: browning, glycation (measured as tyrosine content) and specific NTP-fluorescence. The results showed clearly that bendazac (bendazac L-lysine and sodium) inhibits the early stages of protein glycation, as well as the formation of fluorescent advanced glycation products. Bendazac lysine (20 mM) proved to be more effective in inhibiting fluorescence development (67% inhibition) that the corresponding sodium salt (35% inhibition). No significant differences were found with respect to furosine levels; about 40% inhibition was produced with either bendazac lysine or sodium salt bendazac clearly inhibits glycation of human lens crystallins, as can be efficiently monitored by following specific changes in lens protein fluorescence. These results may constitute a new and relevant therapeutic approach to monitoring cataract development.
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PMID:Bendazac decreases in vitro glycation of human lens crystallins. Decrease of in vitro protein glycation by bendazac. 862 Aug 22

The amino acids lysine and glycine are reported to react with glucose at physiological pH and temperature and undergo non-enzymic glycation. Three other amino acids present in relatively larger amounts in the lens i.e. alanine, aspartic acid and glutamic acid were also found to undergo non-enzymic glycation as found by incorporation of uniformly labelled (U-[14C]) glucose into the amino acids. The glucose incorporation was 1.6 to 2.5% for alanine, 35 to 50% for aspartic acid and 2.3 to 3.3% for glutamic acid. Each amino acid of varying concentrations lowered the extent of in vitro glycation of lens proteins significantly in glucose-treated homogenates of normal lens from humans. The decrease in glycation for alanine was between 32 and 69%, that for aspartate was between 18 and 74%, and for glutamate was between 52 to 74%. Decreased glycation was greater for higher concentrations of glucose. Scavenging of intracellular glucose and decreasing the extent of glycation of lens proteins could be the mechanism of action by which the amino acids alanine, aspartic acid and glutamic acid could exercise a beneficial effect on cataract and diabetic retinopathy.
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PMID:Free alanine, aspartic acid, or glutamic acid reduce the glycation of human lens proteins. 887 7

Both the structural and chaperone-like properties of lens alpha-crystallins have been implicated in maintaining lens transparency. Modifications of lens alpha-crystallins may lead to formation of cataract by affecting the close-packing of the crystallins or by reducing the chaperone-like activity of the alpha-crystallins. A previously unreported modified alphaB-crystallin, whose molecular weight is 72 u greater than unmodified alphaB-crystallin, has been isolated from human lenses by size exclusion chromatography, reversed phase HPLC and ion exchange HPLC. Approximately one nanomole of this modified alphaB-crystallin was obtained from each of five human eye lenses. Molecular weight determinations of peptides produced by digestion with trypsin or endoproteinase Asp-N showed that the modification is in the C-terminal region of alphaB-crystallin. The fragmentation pattern of peptides from the C-terminal region, analysed by tandem mass spectrometry, located the modification of the epsilon-amino group of the C-terminal lysine. The elemental composition of this modification, determined from its exact mass, is C3H4O2. Because this modification decreases the net charge of alphaB-crystallin by one unit, and because the C-terminus has been implicated in the chaperone activity attributed to alphaB-crystallin, this modification at Lys 175 may have a significant role in cataractogenesis.
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PMID:In vivo modification of the C-terminal lysine of human lens alphaB-crystallin. 936 47

Mere addition of Ca2+ to a lens cortical homogenate (bovine) generates a series of products composed of a variety of high molecular weight vimentin species. The Ca2+-induced cross-linking of this cytoskeletal element seems to be mediated by the intrinsic transglutaminase of lens, because the reaction could be blocked at the monomeric state of vimentin by the inclusion of small synthetic substrates of the enzyme dansylcadaverine or dansyl-epsilon-aminocaproyl-Gln-Gln-Ile-Val. These compounds are known to compete against the Gln or Lys functionalities of proteins that would participate in forming the Nepsilon(gamma-glutamyl)lysine protein-to-protein cross-links. The cytosolic transglutaminase-catalyzed reactions could be reproduced with purified bovine lens vimentin and also with recombinant human vimentin preparations. Employing the latter system, we have titrated the transglutaminase-reactive sites of vimentin and, by sequencing the dansyl-tracer-labeled segments of the protein, we have shown that residues Gln453 and Gln460 served as acceptor functionalities and Lys97, Lys104, Lys294, and Lys439 as electron donor functionalities in vimentin. The transglutaminase-dependent reaction of this intermediate filament protein might influence the shape and plasticity of the fiber cells, and the enzyme-catalyzed cross-linking of vimentin, in conjunction with other lens constituents, may contribute to the process of cataract formation.
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PMID:The intermediate filament protein, vimentin, in the lens is a target for cross-linking by transglutaminase. 951 64

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

Posttranslational modification of protein lysyl residues that change the net charge of the molecule may alter the protein conformation. Such modifications are of particular significance among lens proteins, because conformational changes are associated with the development of cataract. A previously unidentified acetylated form of alphaA-crystallin has been isolated from the water-soluble portion of human lenses. The alphaA-crystallins were fractionated by anion exchange HPLC into seven peaks, each containing more than one form of alphaA-crystallin. The previously reported deamidated and phosphorylated forms were identified by their molecular masses, determined by electrospray ionization mass spectrometry. In addition to these modifications, approximately 5% of alphaA-crystallin had a modification that decreased the charge by one and increased the molecular mass by 42 u. This modification, identified as acetylation, was located uniquely at Lys 70. Like any modification that alters the surface charge, acetylation may affect protein conformation and intermolecular interactions, thereby altering the solubility or chaperone properties of alphaA-crystallin. Acetylation of lysine 70 is potentially significant since it is located in a region that has been implicated in the chaperone activity of alphaA-crystallin.
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PMID:In vivo acetylation identified at lysine 70 of human lens alphaA-crystallin. 965 50

Nonenzymatic glycation by glucose and/or ascorbate leads to the formation of advanced glycation end products (AGEs), which are thought to be a critical element in lens protein aging and cataract formation. The relative participation of these two glycating agents was evaluated in vitro. The incubation of 100 mM [U-14C]-D-glucose and 10 mM [U-14C]-L-ascorbate with lens proteins resulted in an increasing incorporation over 3 weeks, reaching a maximum of 100 nMol mg-1 protein and 160 nMol mg-1 protein with ascorbate. Glycation was proportional to carbohydrate concentration with both reagents, however ascorbate was 18-fold more reactive with lens proteins than glucose. Protein crosslinking was not obvious with 250 mM glucose as measured by SDS-PAGE, however, ascorbate caused extensive crosslinking even at 3.0 mM. The sugar-dependent incorporation of N alpha-formyl-[U-14C]-L-lysine ([U-14C]Nfl) into proteins, gave values of 1.5 nMol mg-1 protein after 3 weeks with 100 mM glucose compared to 11 nMol mg-1 protein with 10 mM ascorbate. On a molar basis, ascorbate was 70-fold more active than glucose and 100-fold more active than fructose in the crosslinking assay. N alpha-formyl-N epsilon-fructosyllysine (1.0 mM) dissociated to cause the incorporation of 1.2 nMol of [U-14C]NfL, but 1.0 mM 3-deoxyglucosone, the putative active dissociation product of fructosyl-lysine, produced only 1.5 nMol mg-1 protein of crosslinks. The chelator, DTPA, had little or no effect on crosslinking in our assay except at the highest carbohydrate level. These data argue that glucose crosslinking can be shown in vitro with lens proteins, however, it does not proceed significantly via 3-deoxyglucosone, and does not require transition metal ion-mediated oxidation to occur. Quantitatively, however, it is almost two orders of magnitude less than the crosslinking by ascorbate oxidation products in vitro.
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PMID:The relative ability of glucose and ascorbate to glycate and crosslink lens proteins in vitro. off. 970 82

The glycation reaction by fructose, as well as that by glucose, in control and diabetic rat lens was analyzed by using antibodies which specifically recognize adducts of lysine with fructose and with glucose. Levels of fructose adducts in diabetic rat lens were 2.5 times that of the control, and correlated with sorbitol levels. This was mainly due to enhanced glycation of beta- and gamma-crystallins by fructose under diabetic conditions. These data suggest that glycation by fructose may also play a role in cataract formation under conditions of diabetes and aging.
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PMID:Specific detections of the early process of the glycation reaction by fructose and glucose in diabetic rat lens. 987 77

Rats were given a single injection of streptozotocin. They became diabetic with a blood sugar of around 300 mg dL-1. They were divided into three groups of six rats each. Group II was the diabetic control. Each one of group III diabetic rats received daily 2 ml of 2% solution of lysine supplement orally. Group IV received daily 2 ml of a 2% solution of a mixture of amino acids supplement for 120 days. In addition there were 6 rats as normal control (Group I). Periodically ophthalmic examination was done by slit lamp. Blood glucose, proteins, hemoglobin, free amino acids, glycosylated hemoglobin and glycated lens proteins were also analysed. Body weight was recorded. The diabetic controls decreased in body weight. The blood sugar levels were lowered from about 295 mg dL-1 to 99 mg dL-1 in the lysine-fed group and from 268 mg dL-1 to 126 mg dL-1 in the amino acids mixture-fed group. The levels of glycosylated hemoglobin and glycated lens proteins increased in diabetic controls while they were normal in other groups. The free amino acid levels in blood were lower in groups receiving lysine or amino acids than in diabetic controls indicating their better utilization. In diabetic control, all the animals developed cataract in 70-90 days; five out of six did not develop cataract in the lysine supplemented group. Four of six did not develop cataract in the amino acid mixture-supplemented group. None developed cataract in normal controls. Lysine and amino acids have anticataractous and antidiabetic effects.
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PMID:Beneficial effect of lysine and amino acids on cataractogenesis in experimental diabetes through possible antiglycation of lens proteins. 987 22


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