Modulation of advanced glycation endproduct synthesis by kynurenines in human lens proteins.
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 microM): N-formylkynurenine (Nfk) and kynurenine (Kyn). Another related compound, 3-hydroxykynurenine (3OH-Kyn), had disparate effects; low concentrations (10-200 microM) promoted pentosidine synthesis, but high concentrations (200-500 microM) 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 approximately 90%, but it did not inhibit the stimulating effect of 3OH-Kyn and EDTA. 3OH-Kyn (100-500 microM) spontaneously produced copious amounts of H(2)O(2) (10-25 microM), but externally added H(2)O(2) had only a mild stimulating effect on pentosidine but had no effect on N(epsilon)-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 microM. Argpyrimidine synthesis from 5mM methylglyoxal was slightly inhibited by all kynurenines at concentrations of 100-500 microM. 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.
Nagaraj
Ram H
RH
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Institute of Pathology, Cleveland, OH 44106, USA. ram.nagaraj@case.edu
Padmanabha
Smitha
S
Mailankot
Maneesh
M
Staniszewska
Magdalena
M
Mun
Liew Jun
LJ
Glomb
Marcus A
MA
Linetsky
Mikhail D
MD
D001120:Arginine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry; D002021:Buffers; D002460:Cell Line; D003459:Crystallins / Q000737:chemistry / Q000378:metabolism*; D004492:Edetic Acid; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry; D015416:Maillard Reaction; D008954:Models, Biological; D012117:Resins, Synthetic
D002021:Buffers; D003459:Crystallins; D017127:Glycation End Products, Advanced; D012117:Resins, Synthetic; C007772:N'-formylkynurenine; C024997:Chelex 100; C005045:3-hydroxykynurenine; D007737:Kynurenine; D001120:Arginine; D004492:Edetic Acid; D006861:Hydrogen Peroxide; C062187:pentosidine; D008239:Lysine