The imbroglio of the physiological Cra effector clarified at last

Abstract

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.

What are the signals that control catabolite repression in Pseudomonas?

“…For example, the E. coli transcriptional regulator Cra can regulate the direction of carbon flux by inhibiting glycolytic enzyme expression and activating enzymes involved in gluconeogenesis depending on the level of fructose‐1‐phosphate (F1P) and fructose‐1,6‐biphosphate (FBP) (Figure 1A ; Ramseier, 1996 ; Kochanowski et al., 2013 ). Although the real effector of Cra is F1P, rather than FBP (Bley Folly et al., 2018 ; Chavarria & de Lorenzo, 2018 ), FBP can apparently be converted to F1P in vivo by the FruK enzyme (Singh et al., 2017 ). Since FBP is an intermediate of the upper glycolytic pathway, Cra acts as a glycolytic flux sensor.…”

Escherichia coli segments its controls on carbon‐dependent gene expression into global and specific regulations

“…It has been discovered that the metabolite of fructose-1-phosphate (F1P) in the glycolysis pathway functioned as a Cra inhibitor (Chavarria, et al, 2014;Bley Folly, et al, 2018;Chavarria and de Lorenzo, 2018). The intracellular level of F1P was found to be the lowest in succinate and acetate when it was compared to that in the glycolytic substrates (Kochanowski, et al, 2017).…”