Urease is a Ni-containing enzyme, so to understand the proper mechanism of urease with an amazing 10 14 rate, it is necessary to examine the characteristics of urease-Ni ion . In 2019, Mazzei and co-workers reported that urease has a binuclear active site, and two pseudooctahedral paramagnetic nickel ions (Ni 2+ ), which are separated by the carboxylate group of the carboxylated Lys α217 residue by 3.5 Å. Once the urea arrives into the active site cavity of urease, it opens the conformation in such direction to have the suitable fit of a substrate, and caused the replacing of a substrate with three water hydroxide molecules at active site that change its dimension and molecular shape, and resulting in the formation of hydrogen bonding which provides a tight anchor to stabilize the interactions between the active site of urease and orient the urea in the catalytic activity (Fig. ) . Urea forms a bridge of two metal ions in such a way that one of its amino group binds to Penta-coordinated Ni (I) ion, while hexacoordinated Ni (II) binds to its other amino group with carboxyl oxygen which is stabilized by hydrogen. This bidentate ligation causes the conformation to change back from an open to a closed position, and this arrangement stimulates the inert urea atom by the nucleophilic attack via polarizing the C=O and C-NH2 bonds of the urea molecule. To eliminate the NH2 group from the C-N bond in urea, a proton is required which could support the carboxylate group of Asp α323 and resulting in the reduction of pKa value by the formation of C=O bond (Fig. ).