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)

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.
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PMID:Evidence for inactivation of cysteine proteases by reactive carbonyls via glycation of active site thiols. 1667 91

The overexpression of the cysteine protease calpain is associated with many diseases, including brain trauma, spinal cord injury, Alzheimer's disease, Parkinson's disease, muscular dystrophy, arthritis, and cataract. Calpastatin is the naturally occurring specific regulator of calpain activity. It has previously been reported that a 20-mer peptide truncated from region B of calpastatin inhibitory domain 1 (named CP1B) retains both the affinity and selectivity of calpastatin toward calpain, exhibiting a K(i) of 26 nM against mu-calpain, and is 1000-fold more selective for mu-calpain than cathepsin L. Both the wild-type and beta-Ala mutant CP1B peptides exhibit a propensity to adopt a looplike conformation between Glu10 and Lys13. A computational study of human wild-type CP1B and the beta-Ala mutants of this peptide was conducted. The resulting structural predictions were compared with the crystal structure of the calpain-calpastatin complex and were correlated with experimental IC(50) values. These findings suggest that the conformational preference of the loop region between Glu10 and Lys13 of CP1B in the absence of calpain may contribute to the inhibitory activity of this series of peptides against calpain.
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PMID:Molecular modeling studies of peptide inhibitors highlight the importance of conformational prearrangement for inhibition of calpain. 2049 28