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R. H. Nagaraj, S. Padmanabha, L. Mun, M. Linetsky; Modulation of AGE synthesis in human lens proteins by Kynurenines. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2129.
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Human lens proteins (HLP) can be modified by kynurenines and reactive carbonyl-mediated glycation during aging and cataractogenesis. Glycation initiators, such as, ascorbate and methylglyoxal produce advanced glycation end products (AGEs) and kynurenines produce Michael adducts and other protein crosslinking structures in HLP. In this study, we have investigated how kynurenines affect AGE formation in HLP.
HLP (1mg/ml) was incubated with ascorbate, ribose or methylglyoxal at 5 mM concentration in the presence or absence of 20-100 µM of a kynurenine for 7 days at 370C and pH 7.4. Kynurenines used were N-formylkynurenine (NFKyn), kynurenine (Kyn) and 3OH-kynurenine (3OHKyn). We measured AGEs, pentosidine, CML and argpyrimidine by HPLC or ELISA. Protein crosslinking was assessed by SDS-PAGE.
NFKyn promoted pentosidine synthesis from ribose at concentrations ≥ 40 µM. Both NFKyn and Kyn promoted pentosidine synthesis from ascorbate at concentrations > 60 µM. 3OHKyn had disparate effects; at low concentrations (≤ 20 µM) it promoted pentosidine synthesis, but at higher concentrations (> 60 µM) inhibited it. In contrast to their effects on pentosidine, NFKyn and Kyn had no effect on CML synthesis from ribose or ascorbate. However, substantial inhibition in CML formation occurred with 3OHKyn at concentrations ≥ 20 µM. Argpyrimidine formation from MGO was unaffected by kynurenines. Protein crosslinking studies using lysozyme as a model protein revealed that 3OHKyn is an inhibitor of ascorbate and ribose-mediated inter-molecular protein crosslinking.
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