An agent cleaving glucose-derived protein crosslinks in vitro and in vivo (original) (raw)

Nature volume 382, pages 275–278 (1996) Cite this article

Abstract

GLUCOSE and other reducing sugars react with proteins by a non-enzymatic, post-translational modification process called non-enzymatic glycosylation or glycation. The sugar-derived carbonyl group adds to a free amine, forming a reversible adduct which over time rearranges to produce a class of products termed advanced-glycation end-products (AGEs). These remain irreversibly bound to macromolecules and can covalently crosslink proximate amino groups1,2. The formation of AGEs on long-lived connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal ageing and which occurs at an accelerated rate in diabetes3,4. AGEs can activate cellular receptors and initiate a variety of pathophysiological responses5–9. They modify an appreciable fraction of circulating low-density lipoproteins preventing uptake of these particles by their high-affinity tissue receptors10,11. Advanced glycation has also been implicated in the pathology of Alzheimer's disease12,13. Because AGEs may form by a pathway involving reactive α-dicarbonyl intermediates1,2,14, we investigated a potential pharmacological strategy for selectively cleaving the resultant glucose-derived protein crosslinks. We now describe a prototypic AGE crosslink 'breaker', _N_-phenacylthiazolium bromide (PTB), which reacts with and cleaves covalent, AGE-derived protein crosslinks. The ability of PTB to break AGE crosslinks in vivo points to the importance of an α-dicarbonyl intermediate in the advanced glycation pathway and offers a potential therapeutic approach for the removal of established AGE crosslinks.

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Authors and Affiliations

  1. The Picower Institute for Medical Research, 350 Community Drive, Manhasset, New York, 11030, USA
    Xini Zhang, Aphrodite Kapurniotu, Jürgen Bernhagen, Richard Bucala, Anthony Cerami & Peter Ulrich
  2. Alteon Inc. Ramsey, New Jersey, 07446, USA
    Sara Vasan, Xin Zhang, Dilip Wagle, David Shih, Ihor Terlecky & John Egan
  3. North Shore University Hospital, Manhassett, New York, 11030, USA
    Saul Teichberg
  4. University of Minnesota School of Medicine, Minneapolis, Minnesota, 55455, USA
    John Basgen

Authors

  1. Sara Vasan
  2. Xin Zhang
  3. Xini Zhang
  4. Aphrodite Kapurniotu
  5. Jürgen Bernhagen
  6. Saul Teichberg
  7. John Basgen
  8. Dilip Wagle
  9. David Shih
  10. Ihor Terlecky
  11. Richard Bucala
  12. Anthony Cerami
  13. John Egan
  14. Peter Ulrich

Corresponding author

Correspondence toRichard Bucala.

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Vasan, S., Zhang, X., Zhang, X. et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo.Nature 382, 275–278 (1996). https://doi.org/10.1038/382275a0

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