期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 9, 期 8, 页码 2083-2091出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0968-0896(01)00113-4
关键词
-
资金
- NIGMS NIH HHS [GM-33894] Funding Source: Medline
The catalytic activity of the bacterial phosphotriesterase (PTE) toward a series of chiral analogues of the chemical warfare agents sarin and soman was measured. Chemical procedures were developed for the chiral syntheses of the S-P- and R-P-enantiomers of O-isopropyl p-nitrophenyl methylphosphonate (sarin analogue) in high enantiomeric excess. The R-P-enantiomer of the sarin analogue (k(cat) = 2600 s(-1)) was the preferred substrate for the wild-type PTE relative to the corresponding S-P-enantiomer (k(cat) = 290 s(-1)). The observed stereoselectivity was reversed using the PTE mutant, 1106A/F132A/H254Y where the k(cat) values for the R-P- and S-P-enantiomers were 410 and 4200 s(-1), respectively. A chemo-enzymatic procedure was developed for the chiral synthesis of the four stereoisomers of O-pinacolyl p-nitrophenyl methylphosphonate (soman analogue) with high diastereomeric excess. The RPRC-stereoisomer of the soman analogue was the preferred substrate for PTE. The ka, values for the soman analogues were measured as follows: RPRC, 48 s(-1); RPSC, 4.8 s(-1); SPRC, 0.3 s(-1), and SPSC, 0.04 s(-1). With the 1106A/F132A/H254Y mutant of PTE the stereoselectivity toward the chiral phosphorus center was reversed. With the triple mutant the k(cat) values for the soman analogues were found to be as follows: RPRC, 0.3 s(-1); RPSC, 0.3 s(-1); SPRC, 11 s(-1), and SPSC, 2.1 s(-1). Prior investigations have demonstrated that the S-P-enantiomers of sarin and soman are significantly more toxic than the R-P-enantiomers. This investigation has demonstrated that mutants of the wild-type PTE can be readily constructed with enhanced catalytic activities toward the most toxic stereoisomers of sarin and soman. (C) 2001 Elsevier Science Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据