Cross-linking of lens crystallin proteins induced by tryptophan metabolites and metal ions: implications for cataract development

Abstract

Long-wavelength solar UV radiation is implicated in photodamage to the human eye. The human lens contains multiple tryptophan-derived compounds that have significant absorbance bands in the UVA region (λ 315–400 nm) that act as efficient physical filters for these wavelengths. The concentrations of many of these UV filter compounds decrease with increase in age, resulting in diminished protection, increased oxidative damage and the accumulation of modified proteins implicated in nuclear cataract formation. This damage may arise via the formation of α,β-unsaturated carbonyls from the UV filter compounds, adduction to lens proteins and subsequent action as photosensitizers, and/or via the reactions of redox-active transition metal ions that accumulate in aged human lenses. The latter may promote the oxidation of free, or protein-bound, o-aminophenols, such as the UV filter compounds 3-hydroxykynurenine (3OHKyn) and 3-hydroxyanthranilic acid (3OHAA). It is shown here that Cu(II), and to a lesser extent Fe(III), enhance oxidation of free 3OHKyn, 3OHAA and 3OHKyn bound to specific amino acids and lens proteins, with this resulting in increased cross-linking of lens proteins. These data indicate that elevated levels of transition metal ions in aging lenses can enhance the loss of protective UV filter compounds, and contribute to the formation of high-molecular-mass dysfunctional crystallin proteins in a light-independent manner. These reactions may contribute to the formation of lens cataracts in humans.

Keywords:

• Cataract
• lens
• metal ions
• 3-hydroxykynurenine
• cross-linking
• protein oxidation

Acknowledgements

The authors thank Dr Nicholas Gad and Dr Isla Hains (both Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, Australia) for kindly supplying the BLP with adducted 3OHKyn, and the adducts arising from reaction of 3OHKyn with Cys, Lys and His, respectively.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

The authors gratefully acknowledge financial support from the Australian Research Council (through the Centres of Excellence Scheme, CE0561607, and Discovery Program grants DP0988311 and DP140103116) and the Novo Nordisk Foundation (Laureate Research Grant NNF13OC0004294 to MJD).