Acetylcholinesterase Inhibition created by Sofía Sola Sancho and Maria Hemme Acetylcholinesterase Binding Site Nerve Agent Molecular Shape and Size Step 1 Acetylcholine The AChE active site is bur- The primary toxicity of organophosphorus Acetylcholine nerve agents results from the inhibition of ied deep within the enzyme. Sarin It contains three amino acid the enzyme Acetylcholinesterase (AChE). LD50 = 0.015 mg/kg residues crucial for catalytic Step 2 (i.v. rabbit)* O O AChE, H2O + N activity: serine 200, histidine N (very fast) O O HO 440 and glutamate 327. The Acetylcholine (ACh) Acetate Choline Cyclo-Sarin Hexyl-Sarin nerve agent binds to serine Butyl-Sarin LD = 0.018 mg/kg t LD = 0.145 mg/kg 200. 50 LD = 0.012 mg/kg 50 AChE is responsible for breaking down the Step 3 (i.v. rabbit)* 50 (i.v. rabbit)* neurotransmitter acetylcholine (ACh). This (i.v. rabbit)* switches a nerve signal from on to off. If the enzyme is inhibited, ACh accumulates Toxicity of an organophosphorus nerve agent depends in the synapse and the signal continues to on the ability to access the AChE binding site. Size, Step 4 transmit. shape and hydrophobicity of the nerve agent exerts Figure 2: Breakdown of ACh by AChE (the an effect. As alkyl substituents increase in size and de- Figure 1: Life Cycle of ACh. normal function of the enzyme). grees of freedom, toxicity decreases. Figure 3: Mechanism of in- mirror plane O O hibition of AChE by Sarin. H3C H H CH3 P P F Enantiomers F O O Effects and Symptoms Treatment CH3 H3C N OH Inhibition of AChE in muscarinic Atropine blocks the action C(R)P(R)-Soman C(S)P(S)-Soman O LD = > 5 mg/kg synapses (neuromuscular system) of ACh at muscarinic recep- 50 (s.c.) LD50 (s.c.)= 0.038 mg/kg tors and treats SLUDGE. induces cholinergic crisis. Nicotinic O Racemic mixture of Soman Atropine synapses (central nervous system, LD50 = 0.71 mg/kg (skin exposure) Oximes such as 2-PAM (pralidoxime) can reac- e.g. brain) are also effected. O mirror plane O {SLUDGE tivate inhibited AChE, but only before the ag- H CH3 H3C H ing process. N Cl P Enantiomers P Symptoms include sweating, saliva- F F N O O (Fig. 3, Step 3) OH tion, miosis (pinpoint pupils), pa- 2-PAM CH3 H3C O O P H ralysis, respiratory failure, seizures O O Cl CH2 Reversible Effect CH2 N and eventually death. + O O N P O inhibited regenerated AChE C(S)P(R)-Soman C(R)P(S)-Soman AChE LD = >2 mg/kg 50 (s.c.) LD50 (s.c.)= 0.099 mg/kg Aging (irreversible deactivation) Figure 5: printed 3D O O P Model of AChE O The spatial orientation (shape) of the molecule also Figure 4: Inhibition of AChE by Sarin and CH2 Treatment with Atropine and 2-PAM. matters, as illustrated by toxicity differences across the four stereoisomers of Soman. @opcw Figure 6: printed 3D Model /opcwonline /opcwonline /company/opcw /opcw of the AChE surface * = Black, R. M., & Harrison, J. M. (2009). The Chemistry of Organophosphorus Chemical Warfare Agents. PATAI’S Chemistry @opcw_st of Functional Groups. doi:10.1002/9780470682531.pat0070.