Cellular and Molecular Neurobiology

, Volume 27, Issue 1, pp 33–48

Homocysteine Thiolactone and Human Cholinesterases

Authors

    • Department of Medicine (Neurology and Geriatric Medicine)Dalhousie University
    • Department of Anatomy and NeurobiologyDalhousie University
    • Department of ChemistryMount Saint Vincent University
    • QEII Health Sciences CentreCamp Hill Veterans’ Memorial
  • Ryan Walsh
    • Department of Anatomy and NeurobiologyDalhousie University
    • Department of ChemistryMount Saint Vincent University
  • Earl Martin
    • Department of ChemistryMount Saint Vincent University
Article

DOI: 10.1007/s10571-006-9114-0

Cite this article as:
Darvesh, S., Walsh, R. & Martin, E. Cell Mol Neurobiol (2007) 27: 33. doi:10.1007/s10571-006-9114-0

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 WORDS

acetylcholinesterasebutyrylcholinesteraseacetylcholinehomocysteineAlzheimer’s diseasevascular dementia

Copyright information

© Springer Science+Business Media, Inc. 2006