Expression of multiple cytochrome oxidase isoforms by combinations of multiple isosubunits in .

The ubiquitous opportunistic human pathogen has five terminal oxidases for aerobic respiration and uses them under different growth conditions. Two of them are -type cytochrome oxidases encoded by the gene clusters and , which are the main terminal oxidases under high- and low-oxygen conditions, respectively. also has two orphan gene clusters, and , encoding the core catalytic CcoN isosubunits, but the roles of these genes have not been clarified. We found that 16 active isoforms could be produced by combinations of four CcoN, two CcoO, and two CcoP isosubunits. The CcoN3- or CcoN4-containing isoforms were produced in the WT cell membrane in response to nitrite and cyanide, respectively. The strains carrying these isoforms were more resistant to nitrite or cyanide under low-oxygen conditions. These results indicate that gains resistance to respiratory inhibitors using multiple isoforms with different features, which are produced through exchanges of multiple core catalytic isosubunits.