Serine organophosphates binding

FIGURE 5.46 Interaction of the serine hydroxyl residue in the catalytically active site of acetylcholinesterase enzyme with esters of organophosphates or carbamates. The interaction leads to binding of the chemical with the enzyme, inhibition of the enzyme, inhibition of acetylcholine hydrolysis, and thus accumulation of acetylcholine in the synapses. 

Substances that block the serine residue in the active center of acetylcholinesterase [2j—e.g., the neurotoxin E605 and other organophosphates—prevent ACh degradation and thus cause prolonged stimulation of the postsynaptic cell. This impairs nerve conduction and muscle contraction. Curare, a paralyzing arrow-poison used by South American Indians, competitively inhibits binding of ACh to its receptor. 

Mechanism of action Isoflurophate [eye soe FLURE oh fate] (diisopropylfluorophosphate, DFP) is an organophosphate that covalently binds to a serine-OH at the active site of acetylcholinesterase (Figure 4.9). Once this occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules. Following covalent modification of acetylcholinesterase, the phosphorylated enzyme slowly releases one of its isopropyl groups (Figure 4.9). The loss of an alkyl group, which is called... 

The discovery that organophosphates such as diisopropyl fluoro-phosphate (DFP) inhibit cholinesterase by irreversible phosphorylation of a basic group at the esteratic site led to the use of P P]DFP to ascertain the chemical nature of the DFP-binding site. Jansz et al. (J2) found that the structure of the P peptide of horse serum cholinesterase was Phe-Glu-Ser-Ala-Gly-Ala-Ala-Ser This indicated the serine hydroxyl as the... 

The active center of A. has two parts, the anionic binding site for the quatemaiy nitrogen (which is responsible for the alcohol specificity) and the esterase center (where a catalytic serine and histidine lyse the ester bond). The enzyme is inactivated by blockage of either the serine hydroxyl (by organic phosphate esters, such as diisopropylfluorophosphate or diethyl p-nitrophenylphosphate), or the anionic center by tri-methylammonium derivatives. If the enzyme has been blocked by organophosphates, it can be reactivated by pralidoxime salti which are therefore used as antidotes to organophosphate poisoning. 

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