Host-regulated disposition of mammalian AChEs.
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.
Kronman
Chanoch
C
Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
Cohen
Ofer
O
Velan
Baruch
B
Shafferman
Avigdor
A
D000110:Acetylcholinesterase / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002417:Cattle; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D013045:Species Specificity
D011994:Recombinant Proteins; D000110:Acetylcholinesterase