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3-Hydroxykynurenine Oxidizes α-Crystallin:  Potential Role in Cataractogenesis†

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Save Sight Institute, Sydney, NSW 2001, Australia, Australian Cataract Research Foundation, University of Wollongong, Wollongong, NSW 2522, Australia, and School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, Australia
Cite this: Biochemistry 2006, 45, 6, 1852–1860
Publication Date (Web):January 24, 2006
https://doi.org/10.1021/bi051737+
Copyright © 2006 American Chemical Society
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    Abstract

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    The α-, β-, and γ-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine α-crystallin is incubated with 3-hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in αA-crystallin and a similar extent of oxidation of methionines 1 and 68 in αB-crystallin after 48 h. Tryptophans 9 and 60 in αB-crystallin were oxidized to a lesser extent. αA-Crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation of α-crystallin; however, oxidation was detected at methionine 1 in both αA- and αB-crystallin from human cataractous lenses. Age-related nuclear cataract is associated with coloration and insolubilization of lens proteins and extensive oxidation of cysteine and methionine residues. Our findings demonstrate that 3-hydroxykynurenine can readily catalyze the oxidation of methionine residues in both αB- and αA-crystallin, and it has been reported that α-crystallin modified in this way is a poorer chaperone. Thus, 3-hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens.

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    †

     This work is supported by grants from the U.S. National Institutes of Health (RO1EY013570-03) and the Australian National Health and Medical Research Council (NHMRC) (307615). R.J.W.T. is a NHMRC Senior Research Fellow.

    ‡

     Save Sight Institute and Australian Cataract Research Foundation, University of Wollongong.

    *

     To whom correspondence should be addressed. Telephone:  61 (0) 2 4221 3340. Fax:  61 (0) 2 4221 4135. E-mail:  [email protected].

    §

     School of Biological Sciences, University of Wollongong.

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