Signaling and Regulation Through the NAD+ and NADP+ Networks

Significance: NAD(+) and NADP(+) are important cosubstrates in redox reactions and participate in regulatory networks operating in adjustment of metabolic pathways. Moreover, NAD(+) is a cosubstrate in posttranslational modification of proteins and is involved in DNA repair. NADPH is indispensable for reductive syntheses and the redox chemistry involved in attaining and maintaining correct protein conformation. Recent Advances: Within a couple of decades, a wealth of information has been gathered on NAD(H)(+)/NADP(H) redox imaging, regulatory role of redox potential in assembly of spatial protein structures, and the role of ADP-ribosylation of regulatory proteins affecting both gene expression and metabolism. All these have a bearing also on disease, healthy aging, and longevity. Critical Issues: Knowledge of the signal propagation pathways of NAD(+)-dependent posttranslational modifications is still fragmentary for explaining the mechanism of cellular stress effects and nutritional state on these actions. Evaluation of the cosubstrate and regulator roles of NAD(H) and NADP(H) still suffers from some controversies in experimental data. Future Directions: Activating or inhibiting interventions in NAD(+)-dependent protein modifications for medical purposes has shown promise, but restraining tumor growth by inhibiting DNA repair in tumors by means of interference in sirtuins is still in the early stage. The same is true for the use of this technology in improving health and healthy aging. New genetically encoded specific NAD and NADP probes are expected to modernize the research on redox biology.