A first step necessary for a search of targets of OPs which could be responsible for their unexplained effects is to review the proteins interacting with these compounds. This last category includes Gulf war syndrome 2. Last, chronic neurological effects which are poorly understood and may also be due to the effects of long term or low dose exposure to OP which did not give rise to acute or intermediate symptoms. Third, the organophosphate-induced delayed neuropathy (OPIDN) caused by the inhibition and subsequent aging (dealkylation) of neuropathy target esterase (NTE). Second, the intermediate syndrome which is a relapse after apparent resolution of cholinergic symptoms involving the onset of muscle paralysis one to three days after OP exposure and is often associated with the development of respiratory failure. First, the acute cholinergic clinical crisis which is due to the covalent inactivation of AChE. In man exposure to OPs can cause several toxic effects. 76 of the 120 have been experimentally shown to bind an OP.Īcetylcholinesterase (AChE) is the main critical target of synthetic OPs (insecticides, nerve agents, anti-Alzheimer drugs…), although it may not be the only or even the most inhibited enzyme (in human BChE can be fully inhibited before AChE is affected). Among the 120 human α/β hydrolase fold proteins, 102 have a serine in the consensus GXSXG pentapeptide compatible with an active site, 6 have an aspartate or a cysteine as the active site nucleophile residue, and 12 evidently lack an active site. Second, we compile the human α/β hydrolases and review those that have been experimentally shown to interact with OPs.
In this review, we first situate the α/β hydrolase fold proteins among the distinctively folded proteins known to interact with OPs, in particular the different lipases, peptidases, and enzymes hydrolyzing OPs.
However, hundreds of serine hydrolases are expressed in the human proteome, and many of them are potential targets for OP adduction. Because of the central role of acetylcholinesterase cholinergic neurotransmission in humans, one of the main purposes for using OPs is inactivation of the enzyme by phosphorylation of the nucleophilic serine residue in the active center. Organophosphates (OPs) are either found in nature or synthetized for use as pesticides, flame retardants, neurotoxic warfare agents or drugs (cholinergic enhancers in Alzheimer's disease and myasthenia gravis, or inhibitors of lipases in metabolic diseases).