Oxygen-carrying proteins: three solutions to a common problem.

Nature has used transition-metal ions with unpaired d-electrons to overcome the kinetic inertness of O2 and to control its thermodynamic tendency towards reduction. High-resolution X-ray crystal structures of O2-carrying proteins show that Nature has devised three distinct solutions to the problem of reversible O2 binding. The three types can be classified according to their active sites: Hb (haem iron); Hr (non-haem di-iron); and Hcy (dicopper). The reversible O2 binding to the three types of active site are formally oxidative additions: Fe(II) to Fe(III)-O2- for Hb; [Fe(II),Fe(II)] to [Fe(III),Fe(III)O(2)2-] for Hr; and [Cu(I),Cu(I)] to [Cu(II)(mu-O(2)2-) Cu(II)] for Hcy. In all cases the O-O bond is weakened, but not cleaved, upon binding. The 'textbook' explanation for discrimination against CO and O2 binding to Hb has been revised: steric constraints to the preferred linear Fe-C-O geometry imposed by the 'distal' histidine are no longer thought to play a major role. Instead, recent experimental evidence indicates that the polarity of the binding pocket favours the polar Fe-O-O unit over the relatively non-polar Fe-C-O unit, and that a C-O-binding pocket near the haem also inhibits the preferred linear Fe-C-O geometry. Reversible O2 binding to the di-iron site of Hr involves an internal proton transfer as well as electron transfer to O2, but the elementary steps governing the rates of O2 binding and release, especially the effects of the surrounding protein, remain to be delineated. An unusual side-on-bonded O2 that bridges the two copper ions explains both the unusually low O-O stretching frequency and the diamagnetism of oxyHcy. O2-activating-enzyme counterparts exist for each of the three known types of O2-carrying protein. Detailed comparisons of these protein/enzyme pairs are likely to clarify the factors that tune the delicate balance between reversible O2 binding and controlled O-O bond cleavage.