Characterization of the lysine decarboxylase activity of human ornithine decarboxylase and identification of lysine-like inhibitors.

Ornithine decarboxylase (ODC) catalyzes the first step in the polyamines (PAs) biosynthesis pathway. These biomolecules are polycations that participate in many cellular processes. However, the non-physiological increase of human ODC (HsODC) expression can lead to the accumulation of PAs, and consequently, to the development of various types of cancer. Despite several inhibitors of HsODC have been proposed for cancer treatment, only the administration of difluoromethylornithine (DFMO) has been accepted as a drug for preventing the relapse of neuroblastoma. Thus, the search for other HsODC inhibitors continues. Previously, an alternative l-lysine decarboxylase activity was described in yeast and rat ODC. In this work, we expressed and purified the recombinant HsODC. Then, we kinetically characterized the ornithine and lysine decarboxylase (LDC) activities of the enzyme with Vmax/KM of 25.4 and 0.353 mL min-1 mg protein-1, respectively. Then, we selected 30 lysine-analogues from 300 candidate ligands for HsODC by molecular docking. The binding of these thirty molecules to HsODC was evaluated through thermal shift assays (TSA), obtaining nine binding molecules. Finally, the HsODC kinetic inhibition assays demonstrated that 7 compounds can inhibit this enzyme in vitro (with Ki ranging from 3.8 nM to 523.5 μM). With our results, we suggest these compounds as candidates to be explored as HsODC inhibitors in cell lines and in vivo models.