The heme oxygenase HugZ from Helicobacter pylori plays essential roles in the colonization of the bacteria in human hosts and is required for the utilization of heme as the sole iron source. Residue His245, which is highly conserved, coordinates the heme iron through its sidechain imidazole group. Surprisingly, this residue was not required for the enzymatic activities of HugZ. To investigate the roles played by His245 in heme binding and enzymatic mechanisms of HugZ, we have solved the crystal structure of HugZ mutant H245A at 2.55Å resolution and found that a nearby histidine residue, His249, coordinates the heme iron. This substitution is made possible by the fact that both residues 245 and 249 are located in a flexible loop region ranged from Gly239 to the C-terminus. Similar structural features have not been observed in other heme oxygenases so far. We have also performed spectroscopic studies on the heme-binding properties of HugZ and relevant mutants and our results suggest that the flexible C-terminal loop region of HugZ and the presence of multiple histidine residues in this region may play important roles in heme recruiting and in the catalytic mechanisms of HugZ.