Enough is enough: feedback control of specialized metabolism.

Recent advances in our understanding of plant metabolism have highlighted the significance of specialized metabolites in the regulation of gene expression associated with biosynthetic networks. This opinion article focuses on the molecular mechanisms of small-molecule-mediated feedback regulation at the transcriptional level and its potential modes of action, including metabolite signal perception, the nature of the sensor, and the signaling transduction mechanisms leading to transcriptional and post-transcriptional regulation, based on evidence available from plants and other kingdoms of life. We also discuss the challenges associated with identifying the occurrences, effects, and localization of small molecule-protein interactions. Further understanding of small-molecule-controlled metabolic fluxes will enable rational design of transcriptional regulation systems in metabolic engineering to produce high-value specialized metabolites.