Modulation of advanced glycation endproduct synthesis by kynurenines in human lens proteins

Abstract

Human lens proteins (HLP) become chemically modified by kynurenines and advanced glycation end products (AGEs) during aging and cataractogenesis. We investigated the effects of kynurenines on AGE synthesis in HLP. We found that incubation with 5 mM ribose or 5 mM ascorbate produced significant quantities of pentosidine, and this was further enhanced in the presence of two different kynurenines (200-500 µM): N-formylkynurenine (Nfk) and kynurenine (Kyn). Another related compound, 3-hydroxykynurenine (3OH-Kyn), had disparate effects; low concentrations (10-200 µM) promoted pentosidine synthesis, but high concentrations (200-500 µM) inhibited it. 3OH-Kyn showed similar effects on pentosidine synthesis from Amadori-enriched HLP or ribated lysine. Chelex-100 treatment of phosphate buffer reduced pentosidine synthesis from Amadori-enriched HLP by ~90%, but it did not inhibit the stimulating effect of 3OH-Kyn and EDTA. 3OH-Kyn (100-500 µM) spontaneously produced copious amounts of H 2 O 2 (10-25 µM), but externally added H 2 O 2 had only a mild stimulating effect on pentosidine but had no effect on N ε -carboxymethyl lysine (CML) synthesis in HLP from ribose and ascorbate. Further, human lens epithelial cells incubated with ribose and 3OH-Kyn showed higher intracellular pentosidine than cells incubated with ribose alone. CML synthesis from glycating agents was inhibited 30 to 50% by 3OH-Kyn at concentrations of 100-500 µM. Argpyrimidine synthesis from 5 mM methylglyoxal was slightly inhibited by all kynurenines at concentrations of 100-500 µM. These results suggest that AGE synthesis in HLP is modulated by kynurenines, and such effects indicate a mode of interplay between kynurenines and carbohydrates important for AGE formation during lens aging and cataract formation.

Lutein as a Modulator of Oxidative Stress-Mediated Inflammatory Diseases

“…The risk factors attributed to the onset of cataracts include aging, diabetes, exposure to UV light, hypertension, and oxidative stress [ 55 ]. ROS cause cross-linking and degradation of lens proteins, thereby initiating cataractogenesis [ 56 ]. Padmanabha and Vallikannan [ 57 ] showed that eicosapentaenoic acid and docosahexaenoic acid increased the anti-cataract activity of lutein.…”

“…Thus, it prevents age-related macular degeneration. In addition, lutein prevents oxidative stress-mediated G2/M arrest and apoptosis in retinal pigmental epithelial cells [ 48 ] and cross-linking and degradation of lens proteins which prevents cataractogenesis [ 56 ]. IL, interleukin; MCP-1; monocyte chemoattratant protein-1; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor-α.…”

UVA Light-excited Kynurenines Oxidize Ascorbate and Modify Lens Proteins through the Formation of Advanced Glycation End Products

“…Thus, a vicious cycle could form in which AGEs promote AGE synthesis and consequently propagate lens protein modification. We have previously shown that 3OHKyn can promote pentosidine synthesis from ASC under aerobic conditions (74). Thus, there may be additional UVA-independent mechanisms for the formation of AGEs in lens proteins.…”

Identification of Kynoxazine, a Novel Fluorescent Product of the Reaction between 3-Hydroxykynurenine and Erythrulose in the Human Lens, and Its Role in Protein Modification

“…The kynurenine pathway and ascorbate-mediated AGE synthesis in the lens appear to be interlinked because kynurenines modulate AGEs synthesized from ascorbate (26). In addition, kynurenines become photosensitizers upon UVA light exposure and stimulate ascorbate oxidation, thereby promoting AGE synthesis in lens proteins (27).…”