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Homocysteine thiolactone and human cholinesterases
Sultan Darvesh1, Ryan Walsh, Earl Martin
1Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, Canada. sultan.darvesh@dal.ca
Cellular and Molecular Neurobiology
|September 7, 2006
Summary
Homocysteine thiolactone, a metabolite of homocysteine, alters cholinesterase activity. It inhibits acetylcholinesterase (AChE) and activates butyrylcholinesterase (BuChE), potentially explaining hyperhomocysteinemia
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- The cholinergic system is crucial for cognition, behavior, and cerebral vasculature function.
- Hyperhomocysteinemia is a known risk factor for dementia and cerebrovascular disease.
- Cholinesterases, including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), regulate the cholinergic system by hydrolyzing acetylcholine.
Purpose of the Study:
- To investigate the hypothesis that elevated homocysteine affects cholinesterases.
- To examine the impact of homocysteine and its metabolites/analogues on human cholinesterase activity.
Main Methods:
- In vitro assays were used to measure the effects of homocysteine, homocysteine thiolactone, and related compounds on human AChE and BuChE activity.
- Structure-activity relationship studies were conducted to identify key molecular features responsible for observed effects.
Main Results:
- Homocysteine itself did not significantly alter cholinesterase activity.
- Homocysteine thiolactone demonstrated slow, irreversible inhibition of human AChE.
- Homocysteine thiolactone and some analogues significantly enhanced human BuChE activity.
- Specific structural features of homocysteine thiolactone were identified as responsible for BuChE activation and AChE inhibition.
Conclusions:
- Hyperhomocysteinemia may contribute to adverse neurological and vascular effects through its metabolite, homocysteine thiolactone.
- Homocysteine thiolactone's modulation of human cholinesterase activity, particularly BuChE activation, is a key mechanism.
- These findings highlight a potential therapeutic target for conditions associated with hyperhomocysteinemia.
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