Interactions of no with hemoglobin: From microbes to man

Hemoglobins are found in organisms from every major phylum and subserve life-sustaining respiratory functions across a broad continuum. Sustainable aerobic respiration in mammals and birds relies on the regulated delivery of oxygen (O-2) and nitric oxide (NO) bioactivity by hemoglobin, through reversible binding of NO and O-2 to hernes as well as S-nitrosylation of cysteine thiols (SNO synthase activity). In contrast, bacterial and yeast flavohemoglobins function in vivo as denitrosylases (O-2 nitroxylases), and some multimeric, invertebrate hemoglobins function as deoxygenases (Cys-dependent NO dioxygenases), which efficiently consume rather than deliver NO and O-2, respectively. Analogous mechanisms may operate in plants. Bacteria and fungi deficient in flavohemoglobin show compromised virulence in animals that results from impaired resistance to NO, whereas animals and humans deficient in S-nitrosylated Hb exhibit altered vasoactivity. NO-related functions of hemoglobins center on reactions with ferric (FeIII) heme iron, which is exploited in enzymatic reactions that address organismal requirements for delivery or detoxification of NO and O-2. Delivery versus detoxification of NO/O-2 is largely achieved through structural changes and amino acid rearrangements within the heme pockets, thereby influencing the propensity for heme/cysteine thiol redox coupling. Additionally, the behavior exhibited by hemoglobin in vivo may be profoundly dependent both on the abundance of NO and O-2 and on the allosteric effects of heterotropic ligands. Here we review well-documented examples of redox interactions between NO and hemoglobin, with an emphasis on biochemical mechanisms and physiological significance.