A rationally designed mutant of plasma platelet-activating factor acetylhydrolase hydrolyzes the organophosphorus nerve agent soman

Biochim Biophys Acta. 2015 Dec;1854(12):1809-1815. doi: 10.1016/j.bbapap.2015.09.001. Epub 2015 Sep 3.


Organophosphorus compounds (OPs) such as sarin and soman are some of the most toxic chemicals synthesized by man. They exert toxic effects by inactivating acetylcholinesterase (AChE) and bind secondary target protein. Organophosphorus compounds are hemi-substrates for enzymes of the serine hydrolase superfamily. Enzymes can be engineered by amino acid substitution into OP-hydrolyzing variants (bioscavengers) and used as therapeutics. Some enzymes associated with lipoproteins, such as human plasma platelet-activating factor acetylhydrolase (pPAF-AH), are also inhibited by OPs; these proteins have largely been ignored for engineering purposes because of complex interfacial kinetics and a lack of structural data. We have expressed active human pPAF-AH in bacteria and previously solved the crystal structure of this enzyme with OP adducts. Using these structures as a guide, we created histidine mutations near the active site of pPAF-AH (F322H, W298H, L153H) in an attempt to generate novel OP-hydrolase activity. Wild-type pPAF-AH, L153H, and F322H have essentially no hydrolytic activity against the nerve agents tested. In contrast, the W298H mutant displayed novel somanase activity with a kcat of 5min(-1) and a KM of 590μM at pH7.5. There was no selective preference for hydrolysis of any of the four soman stereoisomers.

Keywords: Bioscavenger; Nerve agents; Organophosphorus compounds; Plasma platelet-activating factor acetylhydrolase; Soman.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Chemical Warfare Agents / toxicity*
  • Hydrolysis
  • Mutation
  • Soman / toxicity*


  • Chemical Warfare Agents
  • Soman
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase