An agent cleaving glucose-derived protein crosslinks in vitro and in vivo

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Njoroge, F. G. & Monnier, V. M. Progr. clin. Biol. Res. 304, 85–107 (1989).

  2. 2

    Bucala, R. & Cerami, A. Adv. Pharmac. 23, 1–34 (1992).

  3. 3

    Monnier, V. M., Kohn, R. R. & Cerami, A. Proc. natn. Acad. Sci. U.S.A. 81, 583–587 (1984).

  4. 4

    Monnier, V. M. et al. New Engl. J. Med. 314, 403–408 (1986).

  5. 5

    Vlassara, H., Brownlee, M., Manogue, K. R., Dinarello, C. & Pasagian, A. Science 240, 1546–1548 (1988).

  6. 6

    Esposito, C., Gerlach, H., Brett, J., Stern, D. & Vlassara, H. J. exp. Med. 174, 1387–1407 (1989).

  7. 7

    Vlassara, H. et al. Proc. natn. Acad. Sci. U.S.A. 89, 12043–12047 (1992).

  8. 8

    Doi, T. et al. Proc. natn. Acad. Sci. U.S.A. 89, 2873–2877 (1992).

  9. 9

    Vlassara, V., Fuh, H., Donnelly, T. & Cybulsky, M. Molec. Med. 1, 447–456 (1995).

  10. 10

    Bucala, R., Makita, Z., Koschinsky, T., Cerami, A. & Vlassara, H. Proc. natn. Acad. Sci. U.S.A. 90, 6434–6438 (1993).

  11. 11

    Bucala, R. et al. Proc. natn. Acad. Sci. U.S.A. 91, 9441–9445 (1994).

  12. 12

    Vitek, M. P. et al. Proc. natn. Acad. Sci. U.S.A. 91, 4766–4670 (1994).

  13. 13

    Smith, M. A. et al. Proc. natn. Acad. Sci. U.S.A. 91, 5710–5714 (1994).

  14. 14

    Chen, H.-J. & Cerami, A. J. Carbohydr. Chem. 12, 731–742 (1993).

  15. 15

    Estendorfer, S., Ledl, F. & Severin, T. Angew. Chem. intl Ed. Engl. 29, 536–537 (1990).

  16. 16

    Vovk, A. I., Murav'eva, I. V. & Yasnikov, A. A. Ukr. Khim. Zh. 51, 521 (1985).

  17. 17

    Ledl, F. & Schleicher, E. Angew. Chem. 29, 565–593 (1990).

  18. 18

    Eble, A. S., Thorpe, S. R. & Baynes, J. W. J. biol. Chem. 258, 9406–9412 (1983).

  19. 19

    Makita, Z. et al. Science 258, 651–653 (1992).

  20. 20

    Miyata, T. et al. J. clin. Invest. 92, 1243–1252 (1993).

  21. 21

    Danze, P. M., Tarjoman, A., Rousseaux, J., Fossati, P. & Dautrevaux, M. Clin. chim. Acta. 166, 143–153 (1987).

  22. 22

    Cotra, R. S., Kumar, V. & Robbins, S. L. Robbins Pathologic Basis of Disease 5th edn, 231–238 (Saunders, Philadelphia, 1994).

  23. 23

    Ukai, O. K. et al. Yakugaku Zasshi 63, 296 (1943).

  24. 24

    Makita, Z., Vlassara, H., Cerami, A. & Bucala, R. J. biol. Chem. 267, 5133–5138 (1992).

  25. 25

    Bochantin, J. & Mays, L. L. Expl Gerontol. 16, 101–106 (1981).

  26. 26

    Itakura, M. et al. Life Sci. 49, 889–897 (1991).

  27. 27

    Stegeman, H. & Stadler, K. Clin. chim. Acta 18, 267–273 (1967).

Download references

Author information

Correspondence to Richard Bucala.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.