Silman Israel, Sussman Joel L
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Curr Opin Pharmacol. 2005 Jun;5(3):293-302. doi: 10.1016/j.coph.2005.01.014.
The synaptic enzyme acetylcholinesterase (AChE) terminates transmission at cholinergic synapses by rapidly hydrolysing acetylcholine. It is anchored within the synaptic cleft by a highly specialized anchoring device in which catalytic subunit tetramers assemble around a polyproline II helix. AChE is the target of nerve agents, insecticides and therapeutic drugs, in particular the first generation of anti-Alzheimer drugs. Both target-guided synthesis and structure-based drug design have been used effectively to obtain potent anticholinesterase agents. In addition, AChE is believed to play 'non-classical' roles in addition to its 'classical' role in terminating synaptic transmission (e.g. as an adhesion protein). It also accelerates assembly of Abeta into amyloid fibrils. Both of these actions involve the so-called 'peripheral' anionic site at the entrance to the active-site gorge. Novel anticholinesterases are targeted against this site, rather than against the active site at the bottom of the gorge.
突触酶乙酰胆碱酯酶（AChE）通过快速水解乙酰胆碱来终止胆碱能突触处的传递。它通过一种高度专业化的锚定装置固定在突触间隙内，在该装置中，催化亚基四聚体围绕多聚脯氨酸II螺旋组装。AChE是神经毒剂、杀虫剂和治疗药物的作用靶点，尤其是第一代抗阿尔茨海默病药物的靶点。靶向导向合成和基于结构的药物设计都已被有效地用于获得强效抗胆碱酯酶剂。此外，人们认为AChE除了在终止突触传递中的“经典”作用外，还发挥“非经典”作用（例如作为一种粘附蛋白）。它还加速β淀粉样蛋白组装成淀粉样纤维。这两种作用都涉及活性位点峡谷入口处所谓的“外周”阴离子位点。新型抗胆碱酯酶药物针对的是这个位点，而不是峡谷底部的活性位点。
