Sanan Toby T, Muthukrishnan Sivaramakrishnan, Beck Jeremy M, Tao Peng, Hayes Carrigan J, Otto Tamara C, Cerasoli Douglas M, Lenz David E, Hadad Christopher M
Department of Chemistry, 100 West 18 Avenue, Ohio State University, Columbus, Ohio 43210.
J Phys Org Chem. 2010 Apr 1;23(4):357-369. doi: 10.1002/poc.1678.
The enzyme human paraoxonase 1 (huPON1) has demonstrated significant potential for use as a bioscavenger for treatment of exposure to organophosphorus (OP) nerve agents. Herein we report the development of protein models for the human isoform derived from a crystal structure of a chimeric version of the protein (pdb ID: 1V04) and a homology model derived from the related enzyme diisopropylfluorophosphatase (pdb ID: 1XHR). From these structural models, binding modes for OP substrates are predicted, and these poses are found to orient substrates in proximity to residues known to modulate specificity of the enzyme. Predictions are made with regard to the role that residues play in altering substrate binding and turnover, in particular with regard to the stereoselectivity of the enzyme, and the known differences in activity related to a natural polymorphism in the enzyme. Potential mechanisms of action of the protein for catalytic hydrolysis of OP substrates are also evaluated in light of the proposed binding modes.
人对氧磷酶1（huPON1）作为一种生物清除剂，在治疗有机磷（OP）神经毒剂暴露方面已显示出巨大潜力。在此，我们报告了基于该蛋白嵌合版本的晶体结构（pdb ID：1V04）和源自相关酶二异丙基氟磷酸酶的同源模型（pdb ID：1XHR）开发的人异构体蛋白模型。从这些结构模型中，预测了OP底物的结合模式，发现这些构象可使底物靠近已知调节酶特异性的残基。针对残基在改变底物结合和周转中所起的作用进行了预测，特别是关于酶的立体选择性以及与酶中天然多态性相关的已知活性差异。还根据提出的结合模式评估了该蛋白催化水解OP底物的潜在作用机制。
