Data Sheet 1_Systems biology can provide guidance to synthetic biology in the pursuit of new drug targets.pdf

Many diseases are caused by an elevated or decreased level of some metabolite but it is not always a priory clear which process or processes associated with the metabolite could or should be altered pharmaceutically to effect a return to normalcy. With a case study, this perspective article demonstrates the power of systems biological analysis for guiding drug targeting. The case study analyzes a seemingly simple linear metabolic pathway whose end product triggers the activation of a transcription factor that controls the gene coding for an enzyme catalyzing an upstream step within the pathway. This physiological feedback mechanism might seem artificial but constitutes a type of circuit observed in physiology and pathology. For example, the illustration pathway is a simplified version of a cancer-related redox circuit involving the enzyme NQO1 (NAD(P)H:quinone oxidoreductase 1), which is protective against oxidative stress. The circuit can be pharmaceutically manipulated with the anti-cancer agent β-lapachone, which induces apoptosis through the generation of reactive oxygen species and thereby inhibits tumor growth. The catalysis of β-lapachone by NQO1 results in the generation of hydrogen peroxide, which activates a transcription factor controlling the synthesis of NQO1, thereby closing a positive feedback loop. The analysis of a simplified version of this scenario demonstrates how a physiological circuit can lead our intuition astray. Dynamic modeling easily overcomes this challenge and thereby offers a powerful exploratory tool for the targeted design of pharmaceutical interventions. It permits reliable explanations and prescriptions for feasible solutions that might be implemented with methods of synthetic biology.