Accession Number : ADA299339

Title :   Studies on the Molecular Dissection of Human Cholinesterase Variants and their Genomic Origins.

Descriptive Note : Midterm rept. 1 Jun 94-31 May 95,

Corporate Author : HEBREW UNIV JERUSALEM (ISRAEL)

Personal Author(s) : Soreq, Hermona

PDF Url : ADA299339

Report Date : JUN 1995

Pagination or Media Count : 200

Abstract : Research has been focused on the human cholinesterase genes, their variant protein products and the biological roles of these proteins in different tissue - and cell types. To elucidate the biochemical properties and biological functions of this large array of ChE variants, we employed microinjected oocytes and transiently transgenic embryos of Xenopus laevis. This has led to the demonstration that the C-terminal peptide characteristic of the brain and muscle form of acetyicholinesterase (AChE) and butyrylcholinesterase (BuChE) leads to synaptic targeting of these enzymes. Moreover, we were able to show that AChE exerts a morphogenic action on synapse development. The biochemical and biological functions of the BCHE gene and its BuChE protein product were approached by a combination of Xenopus oocyte expression and molecular genetics. Substitution of Asp at position 70 in BuChE by Gly creates an enzyme incapable of hydrolyzing succinylcholine, unlike the native enzyme. This structure-function relationship explained the known clinical syndrome of "succinylcholine apnea". The next step was to replace the BuChE peptide harboring Asp70 with that of AChE. This introduced charge modification in the resultant active chimera and explained many of the differences between AChE and BuChE with respect to drug and poison sensitivities. A population diversity study revealed 11% heterozygotes for Asp/Gly70 among Israelis and shed new light on individual variabilities noted for the newly tested anti-AChE drugs, examined for their potential in Alzheimer's therapy. Our current efforts are to extend these studies to elucidate the protective roles of these proteins against organophosphate intoxication, using transgenic mice overexpressing the human ACHE gene.

Descriptors :   *ACETYLCHOLINESTERASE, *CHOLINESTERASE INHIBITORS, *CHOLINESTERASE, *ORGANOPHOSPHATES, FUNCTIONS, BIOLOGY, BRAIN, HUMANS, MODIFICATION, MOLECULES, PEPTIDES, BIOCHEMISTRY, ENZYMES, PROTEINS, ARRAYS, CLINICAL MEDICINE, SIGNS AND SYMPTOMS, POPULATION, VARIATIONS, TARGETING, MOLECULAR BIOLOGY, GENES, DRUGS, SYNAPSE, GENETICS, PYRIDOSTIGMINE BROMIDE, CARBAMATES, INTOXICATION, DISSECTION, ISRAELIS.

Subject Categories : Biochemistry
      Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE