Xanthurenic acid derivative formation in the lens is responsible for senile cataract in humans.
BACKGROUND
The tryptophan degradation pathway leads to NAD production via 3-hydroxykynurenine. Kynurenine aminotransferase (KAT) transforms 3-hydroxykynurenine into xanthurenic acid. In this study, we measured the activity of KAT in human lenses and studied the consequences of xanthurenic acid formation


METHODS
KAT activity was determined by the method of Tobes. Fluorescence spectroscopy and SDS-PAGE were used for the protein studies. Thin-layer chromatography and infrared and fast atom bombardment spectrometry were used for substance characterization.


RESULTS
The KAT activity was detected in senile cataratous lenses, but was absent in the young lenses. Xanthurenic acid at physiological pH exists in equilibrium with its tautomeric form reported by us as oxo-xanthurenic acid (OXA), which is oxidized to di-oxoxanthurenic acid (DOXA), a naphthoquinone-like substance. The incubation of DOXA with crystallins in a solution of physiological pH led to crystallin crosslinking and formation of conjugates with glutathione.


CONCLUSIONS
Xanthurenic acid is formed in human lenses. Its tautomerization and oxidation leads to a naphthoquinone-like substance, DOXA. DOXA provoked formation of conjugates with glutathione and crosslinking of crystallins. Thus, KAT activity seems to be the initial event in senile cataract formation in humans.
Malina
H Z
HZ
Laboratoire d'Ophtalmologie Expérimentale, Institut d'Ophtalmologie, Lausanne, Switzerland.
Martin
X D
XD
D000328:Adult; D000375:Aging / Q000502:physiology; D002386:Cataract / Q000201:enzymology / Q000209:etiology*; D002855:Chromatography, Thin Layer; D003459:Crystallins / Q000378:metabolism; D003641:Deamination; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism; D007904:Lens Cortex, Crystalline / Q000201:enzymology*; D007907:Lens Nucleus, Crystalline / Q000201:enzymology*; D008190:Lyases; D008875:Middle Aged; D013050:Spectrometry, Fluorescence; D000637:Transaminases / Q000378:metabolism; D014977:Xanthurenates / Q000378:metabolism*
D003459:Crystallins; D014977:Xanthurenates; C005045:3-hydroxykynurenine; D007737:Kynurenine; C028330:xanthurenic acid; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D005978:Glutathione