| Kinetics of Torpedo californica Acetylcholinesterase Inhibition by Bisnorcymserine and Crystal Structure of the Complex with its Leaving Group. | |
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MedLine Citation:
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PMID: 22390827 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Natural and synthetic carbamates act as pseudo irreversible inhibitors of acetylcholinesterase (AChE) as well as butyrylcholinesterase (BChE), two enzymes involved in neuronal function as well as in the development and progression of Alzheimer's disease (AD). The AChE mode of action is characterized by a rapid carbamoylation of the active site Ser200 with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic, bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Torpedo californica AChE and, based on the results, crystallized the complex between Torpedo californica AChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically bisnoreseroline interacts in a non-covalent way with Ser200 and His440, disrupting the existing interactions within the catalytic triad, and it stacks with Trp84 at the bottom of the gorge giving rise to an unprecedented hydrogen bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis. |
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Authors:
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Cecilia Bartolucci; Jure Stojan; Qian-Sheng Yu; Nigel H Greig; Doriano Lamba |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-3-6 |
Journal Detail:
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Title: The Biochemical journal Volume: - ISSN: 1470-8728 ISO Abbreviation: - Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-3-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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