Precise coupling of spatially separated intracellular ATP-producing and ATP-consuming processes is fundamental to the bioenergetics of living organisms, ensuring a fail-safe operation of the energetic system over a broad range of cellular functional activities. Here, we provide an overview of the role of spatially arranged enzymatic networks, catalyzed by creatine kinase, adenylate kinase, carbonic anhydrase and glycolytic enzymes, in efficient high-energy phosphoryl transfer and signal communication in the cell. Studies of transgenic creatine kinase and adenylate kinase deficient mice, along with pharmacological targeting of individual enzymes, have revealed the importance of near-equilibrium reactions in the dissipation of metabolite gradients and communication of energetic signals to distinct intracellular compartments, including the cell nucleus and membrane metabolic sensors. Enzymatic capacities, isoform distribution and the dynamics of net phosphoryl flux through the integrated phosphotransfer systems tightly correlate with cellular functions, indicating a critical role of such networks in efficient energy transfer and distribution, thereby securing the cellular economy and energetic homeostasis under stress.