Homocysteine Thiolactone and Human Cholinesterases
- Sultan DarveshAffiliated withDepartment of Medicine (Neurology and Geriatric Medicine), Dalhousie UniversityDepartment of Anatomy and Neurobiology, Dalhousie UniversityDepartment of Chemistry, Mount Saint Vincent UniversityQEII Health Sciences Centre, Camp Hill Veterans’ Memorial Email author
- , Ryan WalshAffiliated withDepartment of Anatomy and Neurobiology, Dalhousie UniversityDepartment of Chemistry, Mount Saint Vincent University
- , Earl MartinAffiliated withDepartment of Chemistry, Mount Saint Vincent University
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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
- Homocysteine Thiolactone and Human Cholinesterases
Cellular and Molecular Neurobiology
Volume 27, Issue 1 , pp 33-48
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- Springer US
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- Alzheimer’s disease
- vascular dementia
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- Author Affiliations
- 1. Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, Canada
- 2. Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada
- 3. Department of Chemistry, Mount Saint Vincent University, Halifax, Nova Scotia, Canada
- 4. QEII Health Sciences Centre, Camp Hill Veterans’ Memorial, 5955 Veterans’ Memorial Lane, Halifax, Nova Scotia, Canada, B3H 2E1