Kronman Chanoch, Cohen Ofer, Velan Baruch, Shafferman Avigdor
Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
Chem Biol Interact. 2005 Dec 15;157-158:51-5. doi: 10.1016/j.cbi.2005.10.005. Epub 2005 Nov 9.
Primates are characterized by a paucity of soluble acetylcholinesterase (AChE) in the circulation at the adult stage, where the predominant circulating cholinesterase is butyrylcholinesterase. In recent years, we subjected recombinant human and bovine acetylcholinesterase to extensive pharmacokinetic studies in mice, an animal system which also displays very low levels of circulating AChE. In this system, a post-translation-related hierarchical pattern governing circulatory residence through AChE sialylation, subunit tetramerization and glycan loading was elucidated. Based on these studies, coordinated modulation of the sialic acid contents, state of subunit assembly and number of glycans allowed us to generate human or bovine AChE forms which reside in the circulation of mice for long periods of time, mimicking the pharmacokinetic behavior of native serum-derived cholinesterases. However, extension of the pharmacokinetic studies to primates, revealed an additional element, which affects circulatory residence of AChEs in this animal system. Unlike in the case of bovine AChE, optimization of subunit assembly and glycan loading of the primate versions of AChE (human or rhesus) did not increase their circulatory lifetime in rhesus macaques. This differential pharmacokinetic behavior of bovine and primate AChEs in macaques appears to be related to the 35 diverging bovine/primate AChE amino acids which are clustered within three defined domains at the enzyme surface, and thereby may facilitate the specific removal of "self" or "self-like" cholinesterases from the circulation of monkeys and thus provide an explanation for the absence of soluble AChE in the circulation of primates.
灵长类动物的特征是在成年阶段循环系统中可溶性乙酰胆碱酯酶（AChE）含量稀少，其中主要的循环胆碱酯酶是丁酰胆碱酯酶。近年来，我们对重组人源和牛源乙酰胆碱酯酶在小鼠体内进行了广泛的药代动力学研究，小鼠这个动物系统中循环AChE水平也非常低。在这个系统中，阐明了一种与翻译后相关的分级模式，该模式通过AChE的唾液酸化、亚基四聚化和聚糖负载来控制循环停留时间。基于这些研究，对唾液酸含量、亚基组装状态和聚糖数量的协同调节使我们能够生成在小鼠循环系统中长时间停留的人源或牛源AChE形式，模仿天然血清来源胆碱酯酶的药代动力学行为。然而，将药代动力学研究扩展到灵长类动物后，发现了一个额外的因素，它影响AChE在这个动物系统中的循环停留。与牛源AChE不同，优化灵长类动物版本的AChE（人源或恒河猴源）的亚基组装和聚糖负载并没有增加它们在恒河猴体内的循环寿命。牛源和灵长类动物源AChE在猕猴体内这种不同的药代动力学行为似乎与35个不同的牛/灵长类动物AChE氨基酸有关，这些氨基酸聚集在酶表面的三个特定结构域内，从而可能有助于从猴子的循环系统中特异性清除“自身”或“类自身”胆碱酯酶，进而为灵长类动物循环系统中不存在可溶性AChE提供了解释。
