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

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.
 ...
PMID:Identification of 3-hydroxykynurenine bound to proteins in the human lens. A possible role in age-related nuclear cataract. 1646 42

The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimer's disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
 ...
PMID:Calpain inhibition: a therapeutic strategy targeting multiple disease states. 1647 52

Hyperglycaemia, triose phosphate decomposition and oxidation reactions generate reactive aldehydes in vivo. These compounds react non-enzymatically with protein side chains and N-terminal amino groups to give adducts and cross-links, and hence modified proteins. Previous studies have shown that free or protein-bound carbonyls inactivate glyceraldehyde-3-phosphate dehydrogenase with concomitant loss of thiol groups [Morgan, Dean and Davies (2002) Arch. Biochem. Biophys. 403, 259-269]. It was therefore hypothesized that modification of lysosomal cysteine proteases (and the structurally related enzyme papain) by free and protein-bound carbonyls may modulate the activity of these components of the cellular proteolytic machinery responsible for the removal of modified proteins and thereby contribute to a decreased removal of modified proteins from cells. It is shown that MGX (methylglyoxal), GO (glyoxal) and glycolaldehyde, but not hydroxyacetone and glucose, inhibit catB (cathepsin B), catL (cathepsin L) and catS (cathepsin S) activity in macrophage cell lysates, in a concentration-dependent manner. Protein-bound carbonyls produced similar inhibition with both cell lysates and intact macrophage cells. Inhibition was also observed with papain, with this paralleled by loss of the active site cysteine residue and formation of the adduct species S-carboxymethylcysteine, from GO, in a concentration-dependent manner. Inhibition of autolysis of papain by MGX, along with cross-link formation, was detected by SDS/PAGE. Treatment of papain and catS with the dialdehyde o-phthalaldehyde resulted in enzyme inactivation and an intra-molecular active site cysteine-lysine cross-link. These results demonstrate that reactive aldehydes inhibit cysteine proteases by modification of the active site cysteine residue. This process may contribute to the accumulation of modified proteins in tissues of people with diabetes and age-related pathologies, including atherosclerosis, cataract and Alzheimer's disease.
 ...
PMID:Evidence for inactivation of cysteine proteases by reactive carbonyls via glycation of active site thiols. 1667 91

1. Reactions of 1,2-naphthaquinone with amino acids, glutathione and proteins of the lens have been studied in connexion with investigations of naphthalene-induced cataract. 2. Cysteine reacts probably through its amino group with 1,2-naphthaquinone to form either purple or brown compounds with characteristic absorption spectra. 3. Glutathione reacts with 1,2-naphthaquinone through its thiol group. 4. Spectroscopic evidence suggests that 1,2-naphthaquinone reacts with the amino group of amino acids. This reaction may take place in the aqueous humour. 5. The proteins of lens react with 1,2-naphthaquinone to form brown compounds. 6. There is loss of protein thiol in this reaction and the products are less easily digestible by pancreatin than normal lens proteins. 7. The compound of alpha-crystallin and 1,2-naphthaquinone is soluble at neutrality, but the compounds of beta-crystallins and of gamma-crystallins are largely insoluble. 8. The brown reaction products of glutathione or cysteine with 1,2-naphthaquinone catalyse the oxidation of ascorbic acid in the same way as 1,2-naphthaquinone itself. 9. These results are discussed in relation to naphthalene-induced cataract.
 ...
PMID:Possible reactions of 1,2-naphthaquinone in the eye. 1674 2

Calpains are intracellular calcium-activated cysteine proteases whose unregulated proteolysis following the loss of calcium homeostasis can lead to acute degeneration during ischemic episodes and trauma, as well as Alzheimer's disease and cataract formation. The determination of the crystal structure of the proteolytic core of mu-calpain (muI-II) in a calcium-bound active conformation has made structure-guided design of active site inhibitors feasible. We present here high-resolution crystal structures of rat muI-II complexed with two reversible calpain-specific inhibitors employing cyclic hemiacetal (SNJ-1715) and alpha-ketoamide (SNJ-1945) chemistries that reveal new details about the interactions of inhibitors with this enzyme. The SNJ-1715 complex confirms that the free aldehyde is the reactive species of the cornea-permeable cyclic hemiacetal. The alpha-ketoamide warhead of SNJ-1945 binds with the hydroxyl group of the tetrahedral adduct pointing toward the catalytic histidine rather than the oxyanion hole. The muI-II-SNJ-1945 complex shows residue Glu261 displaced from the S1' site by the inhibitor, resulting in an extended "open" conformation of the domain II gating loop and an unobstructed S1' site. This conformation offers an additional template for structure-based drug design extending to the primed subsites. An important role for the highly conserved Glu261 is proposed.
 ...
PMID:Calpain inhibition by alpha-ketoamide and cyclic hemiacetal inhibitors revealed by X-ray crystallography. 1676 40

UV filters protect the human lens and retina from UV light-induced damage. Here, we report the identification of a new UV filter, cysteine-l-3-hydroxykynurenine O-beta-d-glucoside, which is present in older normal human lenses. Its structure was confirmed by independent synthesis. It is likely this novel UV filter is formed in the lens by nucleophilic attack of cysteine on the unsaturated ketone derived from deamination of 3-hydroxykynurenine O-beta-d-glucoside. Quantitation studies revealed considerable variation in normal lens levels that may be traced to the marked instability of the cysteine adduct. The novel UV filter was not detected in advanced nuclear cataract lenses.
 ...
PMID:Identification of the new UV filter compound cysteine-L-3-hydroxykynurenine O-beta-d-glucoside in human lenses. 1694 76

We have employed recently developed blind modification search techniques to generate the most comprehensive map of post-translational modifications (PTMs) in human lens constructed to date. Three aged lenses, two of which had moderate cataract, and one young control lens were analyzed using multidimensional liquid chromatography mass spectrometry. In total, 491 modification sites in lens proteins were identified. There were 155 in vivo PTM sites in crystallins: 77 previously reported sites and 78 newly detected PTM sites. Several of these sites had modifications previously undetected by mass spectrometry in lens including carboxymethyl lysine (+58 Da), carboxyethyl lysine (+72 Da), and an arginine modification of +55 Da with yet unknown chemical structure. These new modifications were observed in all three aged lenses but were not found in the young lens. Several new sites of cysteine methylation were identified indicating this modification is more extensive in lens than previously thought. The results were used to estimate the extent of modification at specific sites by spectral counting. We tested the long-standing hypothesis that PTMs contribute to age-related loss of crystallin solubility by comparing spectral counts between the water-soluble and water-insoluble fractions of the aged lenses and found that the extent of deamidation was significantly increased in the water-insoluble fractions. On the basis of spectral counting, the most abundant PTMs in aged lenses were deamidations and methylated cysteines with other PTMs present at lower levels.
 ...
PMID:Age-related changes in human crystallins determined from comparative analysis of post-translational modifications in young and aged lens: does deamidation contribute to crystallin insolubility? 1702 27

In human cataract lenses the UV filters, 3-hydroxykynurenine glucoside (3OHKG) and kynurenine (Kyn) were found to be covalently bound to proteins and the levels in the nucleus were much higher than in the cortex. The levels of the bound UV filters in cataract nuclei were much lower than those in age-matched normal lenses. 3-Hydroxykynurenine could not be detected in cataract lenses. As with normal lenses, protein-bound 3OHKG in cataract lenses was found at the highest levels followed by Kyn. Free UV filter concentrations were also markedly reduced in cataract lenses. This feature may well contribute to the lower protein-bound levels; however, there was no clear relationship between free and bound UV filter contents when individual lenses were examined. We propose that since cysteine is a major site for UV filter binding, the well-documented oxidation of protein sulfhydryl groups during the progression of nuclear cataract may account, in part, for the pronounced decrease in bound UV filters in cataract lenses.
 ...
PMID:Protein-bound and free UV filters in cataract lenses. The concentration of UV filters is much lower than in normal lenses. 1757 41

The eye lens is packed with soluble crystallin proteins, providing a lifetime of transparency and light refraction. gamma-Crystallins are major components of the dense, high refractive index central regions of the lens and generally have high solubility, high stability and high levels of cysteine residues. Human gammaC belongs to a group of gamma-crystallins with a pair of cysteine residues at positions 78 and 79. Unlike other gamma-crystallins it has relatively low solubility, whereas mouse gammaC, which has the exposed C79 replaced with arginine, and a novel mouse splice variant, gammaCins, are both highly soluble. Furthermore, human gammaC is extremely stable, while the mouse orthologs are less stable. Evolutionary pressure may have favoured stability over solubility for human gammaC and the reverse for the orthologs in the mouse. Mutation of C79 to R79, in human gammaC, greatly increased solubility, however, neither form produced crystals. Remarkably, when the human gammaD R36S crystallization cataract mutation was mimicked in human gammaC-crystallin, the solubility of gammaC was dramatically increased, although it still did not crystallize. The highly soluble mouse gammaC-crystallin did crystallize. Its X-ray structure was solved and used in homology modelling of human gammaC, and its mutants C79R and R36S. The human gammaD R36S mutant was also modelled from human gammaD coordinates. Molecular dynamics simulation of the six molecules in the solution state showed that the human gammaCs differed from gammaDs in domain pairing, behaviour that correlates with interface sequence changes. When the fluctuations of the calculated molecular dipoles, for the six structures, over time were analysed, characteristic patterns for soluble gammaC and gammaD proteins were observed. Individual sequence changes that increase or decrease solubility correlated well with changes in the magnitude and direction of these dipoles. It is suggested that changes in surface residues have allowed adaptation for the differing needs of human and mouse lenses.
 ...
PMID:Biophysical properties of gammaC-crystallin in human and mouse eye lens: the role of molecular dipoles. 1765 3

During aging, human lens proteins undergo several post-translational modifications, one of which is glycation. This process leads to the formation of advanced glycation end products (AGEs) which accumulate with time possibly leading to the formation of cataract. alphaB-Crystallin, a predominant protein in the lens, is a member of the small heat shock proteins (sHSPs) which are a ubiquitous class of molecular chaperones that interact with partially denatured proteins to prevent aggregation. This chaperone function is considered to be vital for the maintenance of lens transparency and in the prevention of cataract. In the present study, we introduced an analog of the advanced glycation end product, OP-lysine, at the 90th position of a mutated human alphaB-crystallin (K90C) by covalent modification of the cysteine residue with N-(2-bromoethyl)-3-oxidopyridinium hydrobromide. The AGE-modified K90C-alphaB-crystallin is termed as K90C-OP. We compared the structural and functional properties of K90C-OP with the original K90C mutant, with K90C chemically modified back to a lysine analog (K90C-AE), and with wild-type human alphaB-crystallin. Modified K90C-OP showed decreased intrinsic tryptophan fluorescence and bis-ANS binding without significant alterations in either the secondary, tertiary, or quaternary structure. K90C-OP, however, exhibited a reduced efficiency in the chaperoning ability with alcohol dehydrogenase, insulin, and citrate synthase as substrates compared to the other alpha-crystallin proteins. Therefore, introduction of a single AGE near the chaperone site of human alphaB-crystallin can alter the chaperoning ability of the protein with only minor changes in the local environment of the protein.
 ...
PMID:Effect of a single AGE modification on the structure and chaperone activity of human alphaB-crystallin. 1802 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>