Functional coupling of oxygen binding and vasoactivity in S-nitrosohemoglobin.
S-Nitrosohemoglobin (SNO-Hb) is a vasodilator whose activity is allosterically modulated by oxygen ("thermodyamic linkage"). Blood vessel contractions are favored in the oxygenated structure, and vasorelaxant activity is "linked" to deoxygenation, as illustrated herein. We further show that transnitrosation reactions between SNO-Hb and ambient thiols transduce the NO-related bioactivity, whereas NO itself is inactive. One remaining problem is that the amounts of SNO-Hb present in vivo are so large as to be incompatible with life were all the S-nitrosothiols transformed into bioactive equivalents during each arterial-venous cycle. Experiments were therefore undertaken to address how SNO-Hb conserves its NO-related activity. Our studies show that 1) increased O(2) affinity of SNO-Hb (which otherwise retains allosteric responsivity) restricts the hypoxia-induced allosteric transition that exchanges NO groups with ambient thiols for vasorelaxation; 2) some NO groups released from Cys(beta93) upon transition to T structure are autocaptured by the hemes, even in the presence of glutathione; and 3) an O(2)-dependent equilibrium between SNO-Hb and iron nitrosylhemoglobin acts to conserve NO. Thus, by sequestering a significant fraction of NO liberated upon transition to T structure, Hb can conserve NO groups that would otherwise be released in an untimely or deleterious manner.
McMahon
T J
TJ
Howard Hughes Medical Institute, Department of Medicine, and the Nicholas School for the Environment, Duke University Medical Center, Durham, North Carolina 27710, USA.
Stone
A E
AE
Bonaventura
J
J
Singel
D J
DJ
Stamler
J S
JS
D000494:Allosteric Regulation; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D010100:Oxygen / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits
D006454:Hemoglobins; D010710:Phosphates; C103574:S-nitrosohemoglobin; D005978:Glutathione; D010100:Oxygen