The role of peroxide in haem degradation. A study of the oxidation of ferrihaems by hydrogen peroxide

Abstract

The oxidation of ferrihaems by H2O2 was studied as a model for haem catabolism. Rates of ferrihaem oxidation were evaluated by using a new computer-based method that measures the loss in catalytic activity of the ferrihaem during oxidation. For protoferrihaem, deuteroferrihaem, coproferrihaem and mesoferrihaem, oxidation proceeded via the monomeric species and no dimer contribution was detectable. The pH-dependence of oxidation was studied in the range 6.5--11. Within experimental error, the data were compatible with an inverse linear dependence on [H+]. This was interpreted in terms of attack by HO2- on monomeric ferrihaem. The specific second-order rate constants for oxidation of monomeric species by HO2- were of the same order of magnitude for all the ferrihaems, and were in the sequence coproferrihaem greater than protoferrihaem greater than mesoferrihaem congruent to deuteroferrihaem. A model is suggested involving formation of a ferrihaem monomerperoxide complex, which may either dissociate with the formation of a peroxidatic intermediate or be involved in an intramolecular oxidation of the ferrihaem. Haem catabolism may occur via the same or a similar intermediate.

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

“…The rate of destruction of haem was slightly lower at pH 5.2 than at pH 7.4 (results not shown), however, the decomposition rate was still quite rapid under the presumed conditions of the food vacuole (50 % decomposition in 20 min). In agreement with a previous report [25], we found that the rate of peroxidative destruction of haem decreased in an almost linear fashion with decreasing concentrations of H # O # and increased with increasing haem concentrations. For example, at an equimolar ratio of H # O # and haem (100 µM each), 20 % of the haem was decomposed in a 30 min time period (results not shown).…”

“…Transfer of electrons within the Fe(IV) intermediate of haem results in the opening of the porphyrin ring (Scheme 1B, reaction c). This pathway is similar to that catalysed by haem oxygenase except that the billirubin intermediate is rapidly converted to colourless dipyrrolic fragments [25]. Chelation of the haem moiety has been shown to prevent the formation of the ferryl intermediate [12,14] and would be expected to decrease the rate of haem destruction.…”

“…We therefore explored the possibility that the haem molecules might be degraded by a nonenzymic route. An interesting observation from the early work of Brown et al [25] was that haem can react with H # O # to bring about its own peroxidative decomposition (Scheme 1B, reaction c). It is possible that peroxidative destruction of haem occurs under the conditions of the food vacuole as H # O # is produced during haemoglobin degradation (Scheme 1A).…”

“…The peroxidative degradation of haem is thought to involve a reaction with H # O # to form a ferryl intermediate [14,25] (Scheme 1B, reaction c). Transfer of electrons within the Fe(IV) intermediate of haem results in the opening of the porphyrin ring (Scheme 1B, reaction c).…”

Hydrogen peroxide-mediated alteration of the heme prosthetic group of metmyoglobin to an iron chlorin product: Evidence for a novel oxidative pathway

“…This paper describes the complete structural elucidation of this product as an iron hydroxychlorin compound with saturation of ring D and reports the kinetics of the compound's formation and subsequent hydrolysis to form a corresponding diol. Although oxidation of the heme at the meso position has been proposed to occur during peroxidemediated alteration of metmyoglobin (11), cytochrome P450 (29), ferric heme (29,30), and model ferric hemes (31), we found in the current study that iron hydroxychlorins are formed.…”