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Structure Elucidation of a Senescence Cross-Link from Human Extracellular Matrix

Implication of Pentoses in the Aging Process*
  • D R Sell
    Affiliations
    Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
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  • V M Monnier
    Affiliations
    Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
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  • Author Footnotes
    * This work was supported by Grants AG 05601 and AG 06927 from the National Institute on Aging, Grant EY 07099 from the National Eye Institute, and a grant from the American Federation for Aging Research. The Michigan State University Mass Spectrometry Facility was supported by Grant DRR-00480 from the Biotechnology Resources Branch, Division of Research Resources, National Institutes of Health. 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” accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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      Isolation and structure elucidation of an acid-resistant fluorescent molecule from human extracellular matrix revealed the presence of an imidazo[4,5-b]pyridinium molecule comprising a lysine and an arginine residue cross-linked by a pentose. Structure confirmation was achieved in vitro by the nonenzymatic reaction of ribose with lysine and arginine residues. The cross-link, named pentosidine, could also be synthesized with isomers of ribose, arabinose, xylose, and lyxose as well as by incubating young human collagen with these sugars at 37 ° C. Pentosidine was found in a variety of human tissues including plasma proteins and red blood cells. Its presence in cells grown in culture strongly suggests ribose or ribonucleotide metabolites as precursors. The unexpected discovery of pentose-mediated protein cross-linking raises new questions concerning the aging process.

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