Glucose 6-phosphate is transported into the cell via the Uhp system (Uptake hexose phosphate) which is inducible by extracellular glucose 6-phophate. The Uhp system consists of a permease UhpT (encoded by uhpT) whose transcription is regulated by the UhpABC system [UhpT at UniProtKB]. UhpA and UhpB belong to the family of 'two-component regulatory systems' [Nat Struct Biol]. In the presence of external glucose 6-phosphate, membrane-bound UhpC interacts with membrane-bound UhpB, the sensor kinase. Phosphorylation of UhpA (the response regulator) by UhpB promotes transcription of the uhpT gene. Interestingly, it was shown that the kinase domain of inactive UhpB can bind and sequester UhpA [J Bacteriol]. Finally, efficient transcription of uhpT requires both UhpA and the CAP-cAMP complex [J Mol Biol].
UhpT has a broad range of substrates. Cyclic AMP levels in strains growing in minimal medium supplemented with any one of the UhpT substrates are low (in fact among the lowest as compared to other carbon sources including glucose) provided that the Uhp system is fully induced. Unfortunately, it is still not understood how glucose 6-phosphate transport and/or utilization affect adenylate cyclase activity. Phosphorylated Enzyme IIAGlc, the major regulator of adenylate cyclase, is not a priori involved in glucose 6-phosphate transport and utilization. However, one can question the phosphorylation state of Enzyme IIAGlc during glucose 6-phosphate transport and utilization.
In 1996, it was shown by Dumay, Danchin and Crasnier that glucose 6-phosphate does not cause inducer exclusion [Microbiology]1. It is therefore unlikely that glucose 6-phosphate transport and/or utilization indirectly regulate adenylate cyclase by a mechanism involving dephosphorylation of Enzyme IIAGlc. Furthermore it was concluded by Dumay, Danchin and Crasnier that regulation of adenylate cyclase is not related to glucose 6-phosphate metabolism but occurs during glucose 6-phosphate transport by a still unknown mechanism.
In 1998, the finding that glucose 6-phosphate does not cause inducer exclusion was challenged by Hogema et al. [Mol Microbiol]2. It was proposed that Enzyme IIAGlc is dephosphorylated upon addition of glucose 6-phosphate in the culture medium. The proposal however should be re-analyzed as E. coli Genetic Stock Center strain MG1655 (the only wild type strain used in the study) has been shown to present special features [J Bacteriol]3. It was further proposed that glucose 6-phosphate metabolism is essential for controlling the phosphorylation state of Enzyme IIAGlc [Mol Microbiol].
In 2002, Eppler et al. reported, in agreement with the findings by Dumay, Danchin and Crasnier, that metabolism of glucose 6-phosphate does not account for adenylate cyclase regulation [J Bacteriol]. Also in agreement with Dumay, Danchin and Crasnier, they concluded that Enzyme IIAGlc is not dephosphorylated during glucose 6-phosphate transport. They proposed that glucose 6-phosphate per se prevents the activation of adenylate cyclase by phosphorylated Enzyme IIAGlc.
Previously, in 1973, it was shown by Kornberg that transport, the primary function of the PTS, is inhibited by glucose 6-phosphate [PubMed]. The molecular mechanism leading to this inhibition has yet to be established. However one can question if it is the same mechanism that prevents activation of adenylate cyclase by phosphorylated Enzyme IIAGlc during glucose 6-phosphate transport.
Because PTS transport is inhibited by glucose 6-phosphate transport, glucose 6-phosphate is taken up preferentially when glucose (or any PTS-sugar) and glucose 6-phosphate are present in the culture medium. This indicates that there is selectivity in transport leading to preferential uptake of substrates whose metabolism is most beneficial to Escherichia coli.
1 Dumay, Danchin and Crasnier stated that the mechanism of ‘catabolite repression’ by hexose phosphate [as referred to the mechanism of adenylate cyclase regulation] may be different from the one occurring with glucose unlike the misquoted statement found in the 2007 J Bacteriol article "Correlation between growth rates, EIIA phosphorylation, and intracellular cAMP levels in Escherichia coli K-12" wherein Bettenbrock et al. improperly stated that Dumay, Danchin and Crasnier reported that glucose 6-phosphate did not elicit catabolite repression although cAMP levels were very low during growth with glucose 6-phosphate.
2 The authors mistakenly considered the possibility that in wild type strains glucose 6-phosphate was converted to glucose by a periplasmic phosphatase by referring to data by Dumay and Crasnier (1993). Dumay and Crasnier [FEMS Microbiol Lett] demonstrated that glucose 6-phosphate is converted to glucose by a periplasmic phosphatase but only in uhp mutant strains.
3 Gene deletion in the same strain causes spontaneous secondary deletions in the flagellar regulon [J Bacteriol].