Redox rebalance against genetic perturbations and modulation of central carbon metabolism by the oxidative stress regulation

Abstract

The micro-aerophilic organisms and aerobes as well as yeast and higher organisms have evolved to gain energy through respiration (via oxidative phosphorylation), thereby enabling them to grow much faster than anaerobes. However, during respiration, reactive oxygen species (ROSs) are inherently (inevitably) generated, and threaten the cell's survival. Therefore, living organisms (or cells) must furnish the potent defense systems to keep such ROSs at harmless level, where the cofactor balance plays crucial roles. Namely, NADH is the source of energy generation (catabolism) in the respiratory chain reactions, through which ROSs are generated, while NADPH plays important roles not only for the cell synthesis (anabolism) but also for detoxifying ROSs. Therefore, the cell must rebalance the redox ratio by modulating the fluxes of the central carbon metabolism (CCM) by regulating the multi-level regulation machinery upon genetic perturbations and the change in the growth conditions. Here, we discuss about how aerobes accomplish such cofactor homeostasis against redox perturbations. In particular, we consider how single-gene mutants (including pgi, pfk, zwf, gnd and pyk mutants) modulate their metabolisms in relation to cofactor rebalance (and also by adaptive laboratory evolution). We also discuss about how the overproduction of NADPH (by the pathway gene mutation) can be utilized for the efficient production of useful value-added chemicals such as medicinal compounds, polyhydroxyalkanoates, and amino acids, all of which require NADPH in their synthetic pathways. We then discuss about the metabolic responses against oxidative stress, where αketoacids play important roles not only for the coordination between catabolism and anabolism, but also for detoxifying ROSs by non-enzymatic reactions, as well as for reducing the production of ROSs by repressing the activities of the TCA cycle and respiration (via carbon catabolite repression). Thus, we discuss about the mechanisms (basic strategies) that modulate the metabolism from respiration to respiro-fermentative metabolism causing overflow, based on the role of Pyk activity, affecting the NADPH production at the oxidative pentose phosphate (PP) pathway, and the roles of αketoacids for the change in the source of energy generation from the oxidative phosphorylation to the substrate level phosphorylation.

Keywords: Escherichia coli; Genetic perturbation; Glucose 6-phosphate dehydrogenase (G6PDH); Overflow metabolism; Oxidative stress regulation; Pyruvate kinase (Pyk); Reactive oxygen species (ROSs); Redox balance; Transhydrogenase; αketoacid.