Walsh Ryan, Martin Earl, Darvesh Sultan
Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Biochim Biophys Acta. 2007 May;1770(5):733-46. doi: 10.1016/j.bbagen.2007.01.001. Epub 2007 Jan 10.
Current treatments for Alzheimer's disease involve inhibiting cholinesterases. Conversely, cholinesterase stimulation may be deleterious. Homocysteine is a known risk factor for Alzheimer's and vascular diseases and its active metabolite, homocysteine thiolactone, stimulates butyrylcholinesterase. Considering the opposing effects on butyrylcholinesterase of homocysteine thiolactone and cholinesterase inhibitors, understanding how these molecules alter this enzyme may provide new insights in the management of dementia. Butyrylcholinesterase does not strictly adhere to Michaelis-Menten parameters since, at higher substrate concentrations, enzyme activation occurs. The substrate activation equation for butyrylcholinesterase does not describe the effects of inhibitors or non-substrate activators. To address this, global data fitting was used to generate a flexible equation based on Michaelis-Menten principles. This methodology was first tested to model complexities encountered in inhibition by imidazole of beta-galactosidase, an enzyme that obeys Michaelis-Menten kinetics. The resulting equation was sufficiently flexible to permit expansion for modeling activation or inhibition of butyrylcholinesterase, while accounting for substrate activation of this enzyme. This versatile equation suggests that both the inhibitor and non-substrate activator examined here have little effect on the substrate-activated form of butyrylcholinesterase. Given that butyrylcholinesterase inhibition can antagonize stimulation of this enzyme by homocysteine thiolactone, cholinesterase inhibition may have a role in treating Alzheimer and vascular diseases related to hyperhomocysteinemia.
目前针对阿尔茨海默病的治疗方法包括抑制胆碱酯酶。相反，胆碱酯酶的刺激可能是有害的。同型半胱氨酸是阿尔茨海默病和血管疾病的已知风险因素，其活性代谢物同型半胱氨酸硫内酯可刺激丁酰胆碱酯酶。考虑到同型半胱氨酸硫内酯和胆碱酯酶抑制剂对丁酰胆碱酯酶的相反作用，了解这些分子如何改变这种酶可能为痴呆症的管理提供新的见解。丁酰胆碱酯酶并不严格遵循米氏参数，因为在较高底物浓度下会发生酶激活。丁酰胆碱酯酶的底物激活方程无法描述抑制剂或非底物激活剂的作用。为了解决这个问题，采用全局数据拟合基于米氏原理生成一个灵活的方程。该方法首先用于模拟咪唑对β-半乳糖苷酶抑制过程中遇到的复杂性，β-半乳糖苷酶是一种遵循米氏动力学的酶。所得方程足够灵活，可扩展用于模拟丁酰胆碱酯酶的激活或抑制，同时考虑到该酶的底物激活。这个通用方程表明，此处研究的抑制剂和非底物激活剂对丁酰胆碱酯酶的底物激活形式几乎没有影响。鉴于丁酰胆碱酯酶抑制可拮抗同型半胱氨酸硫内酯对该酶的刺激，胆碱酯酶抑制可能在治疗与高同型半胱氨酸血症相关的阿尔茨海默病和血管疾病中发挥作用。
