Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Hemoglobin Bohr Effects: Analysis of the Histidine Residue Contributions

The Bohr effect in hemoglobin, which refers to the dependence of the oxygen affinity on the pH, plays an important role in its cooperativity and physiological function. The dominant contribution to the Bohr effect arises from the difference in the pKa values of this residue of the unliganded (deoxy) and liganded (carbonmonoxy) structures. Using recent high resolution structures for the two states, the residue pKa values corresponding to the two structures are calculated with a method based on determining the electrostatic interaction with the linearized finite difference Poisson-Boltzmann equation and Monte Carlo sampling of protonation states. Good agreement with the available experimental values is observed, so that a meaningful analysis of the origin of the pKa shift between the two structures can be made. By decomposing the contributions to the pKa shift, it is shown that the salt bridge involving His146 plays an important role in the alkaline Bohr effect, as suggested by Perutz, but many other interactions are significant as well. The method used is summarized and the implemented program is described in the Appendix