The cellular 'thiolstat' as an emerging potential target of some plant secondary metabolites

Abstract

Several biological macromolecules can be reversibly oxidized or reduced and this can affect their properties and thus influence their function either positively or negatively. Indeed, this simple fact is the basis of some complex regulatory machinery in the cell. The redox environment in the cell needs to be closely buffered and monitored so that the multiplicity of the cell's biochemistry runs smoothly in an integrated fashion. Over-reduction, leading for example to misfolding of proteins in the endoplasmic reticulum (ER), and over-oxidation are both harmful to the cell's physiology (Delic et al. 2012; Higa and Chevet 2012). The redox state of particular cysteine thiols in the cell depends upon a number of factors such as their accessibility, specific pKa, nature of surrounding amino acids and not just the thermodynamics but also the kinetics of possible oxidation/reduction reactions (Dalle-Donne et al. 2009; Nagy 2013; Winterbourn and Hampton 2008). Two paradigms, which are not mutually exclusive but perhaps also are not equally represented in cells, are relevant to the control of thiol-based micro-switches. In the first of these scenarios a particular thiol is in thermodynamic equilibrium within its subcellular environment and the ratio of oxidized to reduced forms is determined by the local redox potential. In the second scenario thermodynamic equilibrium is not assumed and the kinetics of oxidation of a relatively few target protein thiols 'sense' oxidative changes in the cell and function as signaling intermediates by relaying information, before being enzymatically reduced back to their basal degree of oxidation (Winterbourn and Hampton 2008). Many experimental data tend to support the second scenario but do not rule out the first for specific instances. It is often stated that the glutathione:glutathione disulfide redox couple (GSH:GSSG) buffers changes in cell redox. However, the situation is complex and although oxidative treatments often lead to a shift in the degree of total cellular glutathione oxidation, GSSG may be largely rapidly removed from the cytosol, for example into the vacuole, thus leaving the local electrochemical cell potential unaltered (Morgan et al. 2013). Thus, caution must be exercised in interpreting whole cell GSH:GSSG ratios in terms of electrochemical potentials in specific cellular compartments. Nevertheless, having stated this, it is a fact of physical chemistry that the redox environment, given the above provisos, will influence the oxidation state of accessible thiols. Therefore, it is important to consider how the redox environment in cells is maintained.