5 A cetykholinesterase

Acetylcholinesterase is found in nervous tissue of all species of animals and besides its hydrolytic activity there has been some suggestion that it may function as a physiological receptor, and inhibitors of the enzyme are toxic, and some anticholinesters are used as war gases and as insecticides.

Abstract

Acetylcholinesterase is found in nervous tissue of all species of animals and besides its hydrolytic activity there has been some suggestion that it may function as a physiological receptor. Inhibitors of the enzyme are toxic, and some anticholinesterases are used as war gases and as insecticides. Others find use in the treatment of glaucoma and myasthenia gravis. The enzyme from the electric organ of electric eel, Electrophorus electricus, has been highly purified and crystallized. The active site of acetylcholinesterase consists of two subsites: an anionic site and an esteratic site. The anionic site determines specificity with respect to the alcohol moiety, and the esteratic site is involved in the actual catalytic process. Because an acetyl enzyme derivative of the esteratic site is involved in the catalytic process, it is apparent that the structure about this subsite determines specificity with respect to the acid function of the substrate. As its name implies, the anionic site is the locus of an electrically negative potential, which attracts the quaternary ammonium head of acetylcholine. This interaction makes a binding contribution of about 2 kcal/mole of free energy corresponding to the measured difference of a factor of 30 in the binding of a charged molecule as compared to its uncharged isosteric analog. A sizable area comprising the anionic site seems to be hydrophobic as the introduction of larger hydrocarbon chains or rings almost always increases binding. Thus phenyltrimethylammonium, N-methylquinolinium, and isoquinolinium, and N-methylacridinium ions are increasingly potent inhibitors.