The imbroglio of the physiological Cra effector clarified at last

Owing to its role in controlling carbon and energy metabolism, the catabolite repressor/activator protein Cra has been one of the most studied prokaryotic regulators of the last 30 years. Yet, a key mechanistic detail of its biological function – i.e. the nature of the metabolic effector that rules its DNA‐binding ability – has remained controversial. Despite the high affinity of Cra for fructose‐1‐phosphate (F1P), the prevailing view claimed that fructose‐1,6‐biphosphate (FBP) was the key physiological effector. Building on such responsiveness to FBP, Cra was proposed to act as a glycolytic flux sensor and central regulator of critical metabolic transactions. At the same time, data raised on the Cra protein of Pseudomonas putida ruled out that FBP could be an effector – but instead suggested that it was the unintentional carrier of a small contamination by F1P, the actual signal molecule. While these data on the P. putida Cra were received with skepticism – if not dismissal – by the community of the time, the paper by (Bley‐Folly et al, 2018) now demonstrates beyond any reasonable doubt that the one and only effector of E. coli Cra is F1P and that every action of FBP on this regulator can be traced to its systematic mix with the authentic binder.