Ab initio calculations on hidden modulators of theta class glutathione transferase activity

The glutathione transferases decrease the pKa of glutathione, allowing its deprotonation and the formation of the more reactive thiolate anion. The th iolate is maintained in the active site through a weak conventional hydroge n bond first sphere interaction donated by a Tyr hydroxyl in the Alpha, Mu, Pi, and Sigma glutathione transferase classes that can be modified by othe r second sphere or indirect thiolate contacts, However, the Theta and Delta class isoforms use a Ser hydroxyl for stabilizing the GSH thiolate, and as such, have a different chemical system compared with that of the Tyr posse ssed by other classes. We have used high level ab initio methods to investi gate this interaction by using a simple methanol methanethiol system as a m odel. The hydrogen bond strength of this initial first sphere interaction w as calculated to be less than that of the Tyr interaction, A putative secon d sphere interaction exists in the Theta and Delta class structures between Cys or Ser-14 and Ser-11 in the mammalian Theta subclass 1 and 2, respecti vely, The effect of this interaction on the first sphere interaction has al so been investigated and found to significantly increase the energy of the bond. (C) 2000 Wiley-Liss, Inc.