Kiruba G S M, Xu Jiahui, Zelikson Victoria, Lee Jeehiun K
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA.
Chemistry. 2016 Mar 7;22(11):3881-90. doi: 10.1002/chem.201505003. Epub 2016 Feb 19.
Gas-phase thermochemical properties (tautomerism, acidity, and proton affinity) have been measured and calculated for a series of nucleobase derivatives that have not heretofore been examined under vacuum. The studied species are substrates for the enzyme formamidopyrimidine glycosylase (Fpg), which cleaves damaged nucleobases from DNA. The gas-phase results are compared and contrasted to solution-phase data, to afford insight into the Fpg mechanism. Calculations are also used to probe the energetics of various possible mechanisms and to predict isotope effects that could potentially allow for discrimination between different mechanisms. Specifically, (18) O substitution at the ribose O4' is predicted to result in a normal kinetic isotope effect (KIE) for a ring-opening "endocyclic" mechanism and an inverse KIE for a direct base excision "exocyclic" pathway.
已对一系列此前未在真空条件下研究过的核碱基衍生物的气相热化学性质（互变异构、酸度和质子亲和力）进行了测量和计算。所研究的物质是甲酰胺嘧啶糖基化酶（Fpg）的底物，该酶可从DNA中切割受损的核碱基。将气相结果与溶液相数据进行比较和对比，以深入了解Fpg机制。计算还用于探究各种可能机制的能量学，并预测可能有助于区分不同机制的同位素效应。具体而言，预计核糖O4'处的(18)O取代对于开环“内环”机制会产生正常动力学同位素效应（KIE），而对于直接碱基切除“外环”途径会产生反向KIE。
