Binding and Hydrolysis of Soman by Human Serum Albumin
| Autor: | Oksana Lockridge, Emilie Gillon, Jean Claude Debouzy, Lawrence M. Schopfer, Laurent Verdier, Bin Li, Bernardo Brasme, Marie Thérèse Froment, Florian Nachon, Patrick Masson |
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| Rok vydání: | 2007 |
| Předmět: |
Magnetic Resonance Spectroscopy
Soman Organophosphonates Serum albumin Toxicology Tandem mass spectrometry Amidohydrolases Adduct Fluorides chemistry.chemical_compound Tandem Mass Spectrometry medicine Humans Chemical Warfare Agents Serum Albumin Nerve agent Binding Sites Chromatography biology Hydrolysis Albumin Phosphorus Isotopes Stereoisomerism General Medicine Human serum albumin chemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Aryl-acylamidase activity biology.protein medicine.drug |
| Zdroj: | Chemical Research in Toxicology. 21:421-431 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx700339m |
| Popis: | Human plasma and fatty acid free human albumin were incubated with soman at pH 8.0 and 25 degrees C. Four methods were used to monitor the reaction of albumin with soman: progressive inhibition of the aryl acylamidase activity of albumin, the release of fluoride ion from soman, 31P NMR, and mass spectrometry. Inhibition (phosphonylation) was slow with a bimolecular rate constant of 15 +/- 3 M(-1) min (-1). MALDI-TOF and tandem mass spectrometry of the soman-albumin adduct showed that albumin was phosphonylated on tyrosine 411. No secondary dealkylation of the adduct (aging) occurred. Covalent docking simulations and 31P NMR experiments showed that albumin has no enantiomeric preference for the four stereoisomers of soman. Spontaneous reactivation at pH 8.0 and 25 degrees C, measured as regaining of aryl acylamidase activity and decrease of covalent adduct (pinacolyl methylphosphonylated albumin) by NMR, occurred at a rate of 0.0044 h (-1), indicating that the adduct is quite stable ( t1/2 = 6.5 days). At pH 7.4 and 22 degrees C, the covalent soman-albumin adduct, measured by MALDI-TOF mass spectrometry, was more stable ( t1/2 = 20 days). Though the concentration of albumin in plasma is very high (about 0.6 mM), its reactivity with soman (phosphonylation and phosphotriesterase activity) is too slow to play a major role in detoxification of the highly toxic organophosphorus compound soman. Increasing the bimolecular rate constant of albumin for organophosphates is a protein engineering challenge that could lead to a new class of bioscavengers to be used against poisoning by nerve agents. Soman-albumin adducts detected by mass spectrometry could be useful for the diagnosis of soman exposure. |
| Databáze: | OpenAIRE |
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