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Cells have evolved a metabolic control of DNA replication to respond to awide range of nutritional conditions. Accumulating data suggest that thispoorly understood control depends, at least in part, on Central CarbonMetabolism (CCM). In Bacillus subtilis , the glycolytic pyruvate kinase (PykA)is intricately linked to replication. This 585 amino-acid-long enzyme comprisesa catalytic (Cat) domain that binds to phosphoenolpyruvate (PEP) and ADP toproduce pyruvate and ATP, and a C-terminal domain of unknown function.Interestingly, the C-terminal domain termed PEPut interacts with Cat and ishomologous a domain that, in other metabolic enzymes, are phosphorylated at aconserved TSH motif at the expense of PEP and ATP to drive sugar import andcatalytic or regulatory activities. To gain insights into the role of PykA inreplication, DNA synthesis was analyzed in various Cat and PEPut mutants grownin a medium where the metabolic activity of PykA is dispensable for growth.Measurements of replication parameters ( ori/ter ratio, C period and forkspeed) and of the pyruvate kinase activity showed that PykA mutants exhibitreplication defects resulting from side chain modifications in the PykA proteinrather than from a reduction of its metabolic activity. Interestingly, Cat andPEPut have distinct commitments in replication: while Cat impacts positivelyand negatively replication fork speed, PEPut stimulates initiation through aprocess depending on Cat-PEPut interaction and growth conditions. Residuesbinding to PEP and ADP in Cat, stabilizing the Cat-PEPut interaction andbelonging to the TSH motif of PEPut were found important for the commitment ofPykA in replication. In vitro , PykA affects the activities of replicationenzymes (the polymerase DnaE, helicase DnaC and primase DnaG) essential forinitiation and elongation and genetically linked to pykA . Our results thusconnect replication initiation and elongation to CCM metabolites (PEP, ATP andADP), critical Cat and PEPut residues and to multiple links between PykA andthe replication enzymes DnaE, DnaC and DnaG. We propose that PykA is endowedwith a moonlighting activity that senses the concentration of signalingmetabolites and interacts with replication enzymes to convey information on thecellular metabolic state to the replication machinery and adjust replicationinitiation and elongation to metabolism. This defines a new type of replicationregulator proposed to be part of the metabolic control that gates replicationin the cell cycle.

Glycolytic pyruvate kinase moonlighting activities in DNA replication initiation and elongation