title: 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.
authors.affiliation: a Department of Chemistry and Biomolecular Sciences , Macquarie University , Sydney , NSW , Australia.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Tweeddale
authors.affiliation: b The Heart Research Institute , Sydney , NSW , Australia.|c Sydney Medical School, University of Sydney , Sydney , NSW , Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Hawkins
authors.affiliation: a Department of Chemistry and Biomolecular Sciences , Macquarie University , Sydney , NSW , Australia.
authors.forename: Joane F
authors.initials: JF
authors.lastname: Janmie
authors.affiliation: d Illawarra Health and Medical Research Institute, University of Wollongong , Wollongong , NSW , Australia.
authors.forename: Roger J W
authors.initials: RJ
authors.lastname: Truscott
authors.affiliation: b The Heart Research Institute , Sydney , NSW , Australia.|c Sydney Medical School, University of Sydney , Sydney , NSW , Australia.|e Department of Biomedical Sciences , Panum Institute, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D002386:Cataract / Q000209:etiology*; D003459:Crystallins / Q000378:metabolism*; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism*; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D003459:Crystallins; D014364:Tryptophan
keywords: 3-hydroxykynurenine; Cataract; cross-linking; lens; metal ions; protein oxidation