Carbon Catabolite Control of the Metabolic Network in Bacillus subtilis

The histidine-containing protein (HPr) is the energy coupling protein of the phosphoenolpyruvate-dependent carbohydrate:phosphotransferase system (PTS), which catalyzes the transport of carbohydrates in bacteria. In Bacillus subtilis and close relatives, global regulation of carbon catabolite control occurs on the binding of the complex of CcpA (catabolite control protein A) and P-Ser-HPr (seryl-phosphorylated form of HPr) to the catabolite responsive elements (cre) of the target operons, the constituent genes of which are roughly estimated to number 300. The complex of CcpA and P-Ser-HPr triggers the expression of several genes involved in the formation of acetate and acetoin, major extracellular products of B. subtilis grown on glucose. It also triggers the expression of an anabolic operon (ilv-leu) involved in the biosynthesis of branched-chain amino acids, which subsequently leads to cell propagation. On the other hand, this complex represses many genes and operons, which include an entrance gene for the TCA cycle (citZ), several transporter genes for TCA cycle-intermediates, some respiration genes, and many catabolic and anabolic genes involved in carbon, nitrogen, and phosphate metabolism, as well as for certain extracellular enzymes and secondary metabolites. Furthermore, these bacteria have CcpA-independent catabolite regulation systems, each of which involves a transcriptional repressor of CggR or CcpN. CggR and CcpN are derepressed under glycolytic and gluconeogenic growth conditions, and enhance glycolysis and gluconeogenesis respectively. Another CcpA-independent catabolite repression system involves P-His-HPr (histidyl-phosphorylated form of HPr). P-His-HPr phosphorylates and activates glycerol kinase, whose product is necessary for antitermination of the glycerol utilization operon through GlpP, the antiterminators (LicT and SacT, Y) of several operons for the utilization of less-preferred PTS-sugars, and some transcriptional activators such as LevR for the levan utilization operon. This phosphorylation is reduced due to the decreased level of P-His-HPr during active transport of a preferred PTS-carbohydrate such as glucose, resulting in catabolite repression of the target operons. Thus CcpA-dependent and independent networks for carbon metabolism play a major role in the coordinate regulation of catabolism and anabolism to ensure optimum cell propagation in the presence and the absence of a preferred PTS-carbohydrate.