A Quantum Mechanics/Molecular Mechanics (QM/MM) computational investigation of the catalytic mechanism of the human glutathione transferase A3-3 (hGSTA3-3) has been carried out. The results demonstrate that the isomerization reaction is concerted, but highly asynchronous: in the first reaction phase the glutathione (GSH) negative sulfur (thiolate) acts as a base and deprotonates carbon C4 of the substrate Delta(5)-androstene-3,17-dione (Delta(5)-AD); in the second reaction phase the hydroxyl proton of the tyrosine fragment Y9 is AD). The initial state of the enzyme is subsequently restored by transferred to C6 affording the Delta(4)-androstene-3,17-dione product (Delta(4)-transferring a proton from the GSH sulfur to the tyrosine negative oxygen. There is no evidence for a "genuine" stepwise mechanism involving the formation of a real dienolate intermediate as suggested in previous papers. Furthermore, our computations have evidenced that, when we consider the whole process (including the restoring of the enzyme), GSH behaves as a base/acid catalyst (as hypothesized by some authors), but it requires the participation of the tyrosine Y9 acting as a proton shuttle. A "fingerprint analysis" has been used to rank the electrostatic effects on the catalysis of the various residues surrounding the active site. This analysis highlights the role played by the arginine residue R15 in stabilizing the initial complex in agreement with previous suggestions based on-crystal structures.