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Ab Initio Structures of Metalloenzyme Active Sites: Applications to Metalloglutathione Transferase



Morris Krauss


A possible structure of the active site of a new metalloenzyme family, metalloglutathione transferase (MGT), is deduced from ab initio calculations suggested by the structures of related enzymes, extradiol dioxygenase and glyoxalase I. The active site of the fosfomycin resistance protein (FosA), an MGT enzyme, was reported from EPR studies to have three waters bound in the first shell of the active site. Sequence analysis identifies two conserved ligand binding residues, a glutamate and a histidine. A number of previous studies have determined that a metalloenzyme active site is inherently determined by the ligands and metal and only weakly perturbed by the surrounding protein environment. An ab initio model structure of the active site of extradiol dioxygenase is in good agreement with the x-ray structure and adds support to this observation. If two glutamate and one histidine ligands are assumed to model FosA then a hexacoordinated structure with three internally hydrogen bonded waters is calculated with open shell transition metals such as manganese and cobalt but a pentacoordinated structure is predicted for zinc. When one glutamate and two histidine ligands are chosen, however, the ab initio optimization determines that at most there are two waters coordinated in the first shell. Five coordinate active site structures with two waters are then found to be most stable when five ligands only are considered in the optimization. Starting with six ligands both four and five coordinated first shell active site structures are calculated to be energetically competitive with the four coordinate structures lower in energy generally for zinc, manganese, and cobalt divalent ions. The sixth water is ejected from the first shell in the course of the optimization of the active site structure. Compatibility between the EPR and ab initio calculation suggests that there are two glutamate and one histidine ligands in FosA. The binding of glutathione and the exzyme mechanism is discussed based on the theoretically predicted site.
International Journal of Quantum Chemistry
No. 3


dioxygenase, glyoxalase, metalloenzyme active site, prediction of structure, zinc enzyme


Krauss, M. (2000), Ab Initio Structures of Metalloenzyme Active Sites: Applications to Metalloglutathione Transferase, International Journal of Quantum Chemistry (Accessed June 24, 2024)


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Created January 1, 2000, Updated February 17, 2017