Homocysteine Thiolactone and Human Cholinesterases
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1. The cholinergic system is important in cognition and behavior as well as in the function of the cerebral vasculature.
2. Hyperhomocysteinemia is a risk factor for development of both dementia and cerebrovascular disease.
3. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine, a key process in the regulation of the cholinergic system.
4. It has been hypothesized that the deleterious effects of elevated homocysteine may, in part, be due to its actions on cholinesterases.
5. To further test this hypothesis, homocysteine and a number of its metabolites and analogues were examined for effects on the activity of human cholinesterases.
6. Homocysteine itself did not have any measurable effect on the activity of these enzymes.
7. Homocysteine thiolactone, the cyclic metabolite of homocysteine, slowly and irreversibly inhibited the activity of human AChE.
8. Conversely, this metabolite and some of its analogues significantly enhanced the activity of human BuChE.
9. Structure–activity studies indicated that the unprotonated amino group of homocysteine thiolactone and related compounds represents the essential feature for activation of BuChE, whereas the thioester linkage appears to be responsible for the slow AChE inactivation.
10. It is concluded that hyperhomocysteinemia may exert its adverse effects, in part, through the metabolite of homocysteine, homocysteine thiolactone, which is capable of altering the activity of human cholinesterases, the most pronounced effect being BuChE activation.
KEY WORDSacetylcholinesterase butyrylcholinesterase acetylcholine homocysteine Alzheimer’s disease vascular dementia
This study was supported by the Canadian Institutes of Health Research, Nova Scotia Health Research Foundation, Capital District Health Authority Research Fund, Brain Tumour Foundation of Canada, the Natural Sciences Engineering Research Council of Canada, the Committee on Research and Publications of Mount Saint Vincent University, and Alzheimer Society of Nova Scotia for Phyllis Horton Bursary (RW).
- Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., and Bourne P. E. (2000). The protein data bank. Nucleic Acids Res. 28:235–242. Retrieved from (http://www.pdb.org/).Google Scholar
- Clayden, J., Greeves, N., Warren, S., and Wothers, P. (2001). Organic Chemistry. Oxford University Press, New York.Google Scholar
- Cornish-Bowden, A. (1995). Fundamentals of Enzyme Kinetics, 2nd edn. Portland Press, London.Google Scholar
- Darvesh, S., Walsh, R., and Martin, E. (2003b). Interaction of homocysteine metabolites with butyrylcholinesterase: A risk for Alzheimer’s disease. Can. J. Neurol. Sci. 30:S48.Google Scholar
- DeLano, W. L. (2002). The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA Retrieved from http://www.pymol.org.Google Scholar
- Dixon, M., and Webb, E. C. (1979). Enzymes, 3rd edn. Academic Press, New York.Google Scholar
- Elias, M. F., Sullivan, L. M., D’Agostino, R. B., Elias, P. K., Jacques, P. F., Selhub, J., Seshadri, S., Au, R., Beiser, A., and Wolf, P. A. (2005). Homocysteine and cognitive performance in the Framingham offspring study: Age is important. Am. J. Epidemiol. 162:644–653.PubMedCrossRefGoogle Scholar
- Giacobini, E.(2000). Cholinesterases and Cholinesterase Inhibitors. Martin Dunitz, London.Google Scholar
- Giacobini, E. (2003). Butyrylcholinesterase: Its Function and Inhibitors. Martin Dunitz, London.Google Scholar
- Gibson, J. B., Carson A. J., and Neill, D. W. (1964). Pathological findings in homocystinuria. J. Clin. Pathol. 17: 427–437.Google Scholar
- Greig, N. H., Utsuki, T., Ingram, D. K., Wang, Y., Pepeu, G., Scali, C., Yu, Q. S., Mamczarz, J., Holloway, H. W., Giordano, T., Chen, D., Furukawa, K., Sambamurti, K., Brossi, A., and Lahiri, D. K. (2005). Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc. Natl. Acad. Sci. U.S.A. 102:17213– 17218.PubMedCrossRefGoogle Scholar
- Kryger, G., Harel, M., Giles, K., Toker, L., Velan, B., Lazar, A., Kronman, C., Barak, D., Ariel, N., Shafferman, A., Silman, I., and Sussman, J. L. (2000). Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr. D Biol. Crystallogr. 56:1385–1394 (PDB ID: 1B41).PubMedCrossRefGoogle Scholar
- Reiner, E., and Radić, Z. (2000). Mechanism of action of cholinesterase inhibitors. In Giacobini, E. (ed.), Cholinesterases and Cholinesterase Inhibitors. Martin Dunitz, London, pp. 103–119.Google Scholar
- Román, G. C., and Kalaria, R. N. (in press). Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol. Aging.Google Scholar
- Sauls, D. L., Lockhart, E., Warren, M. E., Lenkowski, A., Wilhelm, S. E., and Hoffman, M. (2006). Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: A potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry 45:2480–2487.PubMedCrossRefGoogle Scholar
- Shi, J., Zhang, S., Tang, M., Liu, X., Li, T., Han, H., Wang, Y., Guo, Y., Zhao, J., Li, H., and Ma, C. (2004). Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer’s disease in Chinese. Brain Res. Mol. Brain Res. 120:201–204.PubMedCrossRefGoogle Scholar
- Webb, J. L. (1963). Enzyme and Metabolic Inhibitors, Vol. I. Academic Press, New York, pp. 535–603.Google Scholar