Identification of 3-Hydroxykynurenine Bound to Proteins in the Human Lens. A Possible Role in Age-Related Nuclear Cataract

Abstract

Age-related nuclear (ARN) cataract is a major cause of world blindness. With the onset of ARN cataract, the normally transparent and colorless lens becomes opaque and can take on colors ranging from orange, brown, and even black. The molecular basis for this remarkable transformation is unknown. ARN cataract is also characterized by extensive oxidation, insolubilization, and cross-linking of polypeptides, particularly in the nucleus of the lens. It has been postulated that 3-hydroxykynurenine (3OHKyn) may be involved in these changes. This endogenous tryptophan metabolite is readily oxidized and is involved in the tanning of moth cocoons and the formation of pigments in the eyes of butterflies. 3OHKyn is a component of our primate-specific UV-filter pathway, and the brownish hue of ARN cataract lenses is also unique to humans. Because numerous colored compounds can be produced by autoxidation of 3OHKyn, this process could provide an explanation for the variety of lens colors and other changes seen in ARN cataract. For such a theory to be tenable, it needs to be demonstrated that 3OHKyn is bound to proteins in the human lens. Here, we show that all normal lenses older than 50 have 3OHKyn covalently attached to the nuclear proteins, most likely via cysteine residues. If indeed 3OHKyn is implicated in ARN cataract, a reduction in the levels that are bound in cataract, compared to normal lenses, would be expected. In agreement with this hypothesis, no bound 3OHKyn could be detected in proteins isolated from ARN cataract lenses.

Photochemical Properties of UV Filter Molecules of the Human Eye

“…As we demonstrate here, the quality of the secondary UV filters is inferior compared to primary ones, which makes the old lenses more susceptible to UV light. Beside this, old lenses contain a significant amount of UV filters covalently linked to the lens proteins, 26,[41][42][43] and the quality of kynurenines bound to proteins are much worse than that of the free UV filters (i.e., the singlet lifetimes are longer, and the fluorescence and triplet quantum yields are higher). 24,44,45 Apparently, in a complex biological system that is the human lens many other factors can influence the susceptibility to UV light-in particular, the coloration of the lens proteins due to posttranslational modifications and the abundance of antioxidants which can deactivate photoexcited molecules.…”

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

“…4C). According to Cheng et al (2) and Korlimbinis et al (62,63), the only UVA-responsive sensitizers present in the young lens are mostly free kynurenines. Thus, it is conceivable that most of the UVA-mediated ASC oxidation in young human lenses occurs as a result of direct interaction between the UVA-excited kynurenines.…”

Overview of the Lens

“…Although the human lens is colorless at birth, there is a gradual increase in yellowish pigmentation with age 33 probably due to the production of 3-hydroxykynurenine and other metabolites of tryptophan that filter UV light. 34 The lens transmits light with wavelengths up to 1200 nm efficiently, but transmits very little light below 390 nm. 1200 nm is well above the limit of visual perception, about 720 nm.…”