Lefentse Mashamaite

Thioredoxin, glutaredoxin, and peroxiredoxin systems play critical roles in a large number of redox-sensitive cellular processes. These systems are linked to each other by coupled redox cycles and common reaction intermediates into a larger network. Given the scale and connectivity of this network, computational approaches are required to analyze its dynamics and organization. Theoretical advances, as well as new redox proteomic methods, have led to the development of both top-down and bottom-up systems biology approaches to analyze the these systems and the network as a whole. Top-down approaches have been based on modifications to the Nernst equation or on graph theoretical approaches, while bottom-up approaches have been based on kinetic or stoichiometric modeling techniques. This review will consider the rationale behind these approaches and focus on their advantages and limitations. Further, the review will discuss modeling standards to ensure model accuracy and availability. Top-down and bottom-up approaches have distinct strengths and limitations in describing cellular redoxin networks. The availability of methods to overcome these limitations, together with the adoption of common modeling standards, is expected to increase the pace of model-led discovery within the redox biology field.

Glutathionylation plays a central role in cellular redox regulation and anti-oxidative defense. Glutaredoxins are primarily responsible reversing glutathionylation and their activity therefore affects a range of cellular processes, making them prime candidates for computational systems biology studies. However, two distinct kinetic mechanisms involving either one (monothiol) or both (dithiol) active-site cysteines have been proposed for their deglutathionylation activity and initial studies predicted that computational models based on either of these mechanisms will have different structural and kinetic properties. Further, a number of other discrepancies including the relative activity of active-site mutants and contrasting reciprocal plot kinetics have also been reported for these redoxins. Using kinetic modeling, we show that the dithiol and monothiol mechanisms are identical and, we were also able to explain much of the discrepant data found within the literature on glutaredoxin...