Fig. 9

Intertwining model of PykA catalytic activity regulation and PykA-driven metabolic control of DNA replication. A Regulation of PykA catalytic activity. Several metabolites (PEP, ATP, ADP, AMP, R5P…) are used as signaling molecules for PykA regulation. They gear Cat-metabolite interactions, Cat-PEPut interaction, and TSH motif phosphorylation in PEPut. In response to these signals, PykA adopts different conformations with different types and levels of TSH motif phosphorylation. These multiple forms of PykA typify the cellular metabolic state and drive allosteric regulation of PykA catalytic activity. This regulation impacts the metabolome and the concentration of signaling metabolites. This mechanism can be implemented by posttranslational modifications (PTMs) of PykA. B Metabolic control of DNA replication by PykA. The ability of PykA to sense signaling metabolites (effectors and phosphoryl donors) and adopt multiple forms typifying the nutritional environment is used by cells to convey a metabolic signal to the replication machinery and regulate DNA synthesis in a large range of nutritional conditions. Top panel: metabolic control of initiation. (i) In response to the concentration of a phosphoryl donor and the activity of a kinase/phosphatase system, the phosphorylation level of the T residue in the TSH motif of PEPut varies. Initiation is inhibited at low- and activated at high phosphorylation levels. High phosphorylation level may be powered by a metabolic cycle causing periodic accumulation of the phosphoryl donor at the age of initiation. Bottom panel: metabolic control of elongation. The balance between the multiple forms of PykA is sensed by replication enzymes for modulating elongation. Previous data suggest that receptors of metabolic signals conveyed by PykA are the helicase DnaC, the primase DnaG, and the lagging strand polymerase DnaE which are essential for both replication initiation and elongation (see the “Background” section). The metabolic control of initiation and elongation help cells to properly time replication in the cell cycle in a large range of nutritional conditions