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J. Biol. Chem., Vol. 279, Issue 44, 45441-45449, October 29, 2004

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Structure Elucidation of a Novel Yellow Chromophore from Human Lens Protein^*

Rongzhu Cheng, Qi Feng, Ognyan K. Argirov, and Beryl J. Ortwerth

From the Mason Eye Institute, The University of Missouri, Columbia, Missouri 65201

We report here the isolation of a novel acid-labile yellow chromophore from the enzymatic digest of human lens proteins and the identification of its chemical structure by liquid chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, and ¹H, ¹³C, and two-dimensional NMR. This new chromophore exhibited a UV absorbance maximum at 343 nm and fluorescence at 410 nm when excited at 343 nm. Analysis of the purified compound by reversed-phase HPLC with in-line electrospray ionization mass spectrometry revealed a molecular mass of 370 Da. One- and two-dimensional NMR analyses elucidated the structure to be 1-(5-amino-5-carboxypentyl)-4-(5-amino-5-carboxypentylamino)-3-hydroxy-2,3-dihydropyridinium, a cross-link between the -amino groups of two lysine residues, and a five-carbon ring. Because this cross-link contains two lysine residues and a dihydropyridinium ring, we assigned it the trivial name of K2P. Quantitative determinations of K2P in individual normal human lens or cataract lens water-soluble and water-insoluble protein digests were made using a high-performance liquid chromatograph equipped with a diode array detector. These measurements revealed a significant enhancement of K2P in cataract lens proteins (613 ± 362 pmol/mg of water-insoluble sonicate supernatant (WISS) protein or 85 ± 51 pmol/mg of WS protein) when compared with aged normal human lens proteins (261 ± 93 pmol/mg of WISS protein or 23 ± 15 pmol/mg of water-soluble (WS) protein). These data provide chemical evidence for increased protein cross-linking during aging and cataract development in vivo. This new cross-link may serve as a quantitatively more significant biomarker for assessing the role of lens protein modifications during aging and in the pathogenesis of cataract.

Received for publication, May 20, 2004 , and in revised form, August 16, 2004.

^* This work was supported in part by National Institutes of Health Grant EY07070 and in part by a department grant from Research to Prevent Blindness, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Mason Eye Institute-East, The University of Missouri-Columbia, 404 Portland St., Columbia, MO 65201. Tel.: 573-882-6093; Fax: 573-884-4868; E-mail: chengr{at}health.missouri.edu.

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