Binding and Hydrolysis of Soman by Human Serum Albumin

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• 作者：Bin Li ; Patrick Masson ; Florian Nachon ; Marie-Thé ; rè ; se Froment ; Laurent Verdier ; Jean-Claude Debouzy ; Bernardo Brasme ; Emilie Gillon ; Lawrence M. Schopfer ; and Oksana Lockridge
• 刊名：Chemical Research in Toxicology
• 出版年：2008
• 出版时间：February 2008
• 年：2008
• 卷：21
• 期：2
• 页码：421-431
• 全文大小：1,128k
• 年卷期：v.21,no.2(February 2008)
• ISSN：1520-5010

文摘

Human plasma and fatty acid free human albumin were incubated with soman at pH 8.0 and 25 °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 °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 (t_1/2 = 6.5 days). At pH 7.4 and 22 °C, the covalent soman−albumin adduct, measured by MALDI-TOF mass spectrometry, was more stable (t_1/2 = 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.