Significance: The importance of oxidoreductases in energy metabolism together with the occurrence of enzymes of central metabolism in the nucleus gave rise to the active research field aiming to understand moonlighting enzymes that undergo post-translational modifications (PTMs) before carrying out new tasks. Recent Advances: Cytosolic enzymes were shown to induce gene transcription after PTM and concomitant translocation to the nucleus. Changed properties of the oxidized forms of cytosolic glyceraldehyde 3-phosphate dehydrogenase, and also malate dehydrogenases and others, are the basis for a hypothesis suggesting moonlighting functions that directly link energy metabolism to adaptive responses required for maintenance of redox-homeostasis in all eukaryotes. Critical Issues: Small molecules, such as metabolic intermediates, coenzymes, or reduced glutathione, were shown to fine-tune the redox switches, interlinking redox state, metabolism, and induction of new functions via nuclear gene expression. The cytosol with its metabolic enzymes connecting energy fluxes between the various cell compartments can be seen as a hub for redox signaling, integrating the different signals for graded and directed responses in stressful situations. Future Directions: Enzymes of central metabolism were shown to interact with p53 or the assumed plant homologue suppressor of gamma response 1 (SOG1), an NAM, ATAF, and CUC transcription factor involved in the stress response upon ultraviolet exposure. Metabolic enzymes serve as sensors for imbalances, their inhibition leading to changed energy metabolism, and the adoption of transcriptional coactivator activities. Depending on the intensity of the impact, rerouting of energy metabolism, proliferation, DNA repair, cell cycle arrest, immune responses, or cell death will be induced. Antioxid. Redox Signal. 34, 1025-1047.
Keywords: GAPDH; energy metabolism; moonlighting; redox sensing; redox signaling; thiol switches.