It is known that human dipeptidyl peptidase III (hDPP III) cleaves several neuropeptides in vitro, and participates in the cellular oxidative stress response through the involvement in Keap1-Nrf2 signalling pathway. The aim of the proposed research is to advance the knowledge on biological relevance of this zinc dependent exopeptidase and its influence on human health. In order to achieve this, we plan to: (1) develop new parameters for Zn2+ ion in proteins and optimize the computational approaches in the study of metalloenzyme structure, (2) come closer in understanding the role hDPP III has in the oxidative stress by studying its involvement in the Nrf2-Keap1 signalling pathway, (3) study the binding of several metal dications (Zn2+, Cu2+, Mn2+, and Co2+ ) to hDPP III and mechanism of their exchange, as well as to find the potential inhibitory metal binding site, (4) improve the knowledge on DPP III natural substrates in human, and (5) search for new, potent inhibitors of the hDPP III catalytic function.The newly developed parameters will be beneficial not only for hDPP III but also for the other zinc dependent proteins with similar metal binding site. The combined computational and experimental (kinetic, spectrometric, structural and thermodynamic) approach should advance the knowledge of the molecular basis of protein-protein (hDPP III – Keap1) and protein-ligand (hDPP III – peptides/inhibitors) interactions and their implications on cell signalling. The study should suggest directions for the development of pharmacological molecules with potential to control processes in which human DPP III participates.