Cellular redox potential and the biomolecular electrochemical series: a systems hypothesis

The role of cellular redox potential in the regulation of protein activity is becoming increasingly appreciated and characterized. In this paper we put forward a new hypothesis relating to redox regulation of cellular physiology. We have exemplified our hypothesis using apoptosis since its redox phenomenology is well established, but believe that it is equally applicable to several other pathways. Our hypothesis is that since multiple proteins in the apoptosis pathway are thought to be regulated via oxidation/reduction reactions and since cellular redox potentials have been shown to become progressively more oxidative during apoptosis, that the proteins could be arranged in an electrochemical series where the protein's standard potential correlates with its position in the pathway. Since the most stable oxidation state of the protein is determined by its standard potential and the redox potential of its environment (in a way predictable by the Nernst equation), a quantitative model of the redox regulation of the pathway could be developed. We have outlined our hypothesis, illustrating it using a pathway map which assembles a selection of the literature on apoptosis into a readable graphical format. We have also outlined experimental approaches suitable for testing our hypothesis.