Fig. 3. Integrated communication between cellular sites of ATP-utilization and ATP-generation. Cells utilize enzymatic shuttles to promote ATP delivery and removal of ATPase byproducts, ADP, P_i and H⁺, to sustain efficient energy utilization. Shuttles comprise near-equilibrium enzymes capable of facilitating ligand transfer between cellular compartments by rapidly relaying the displacement of equilibrium. ATP delivery is facilitated through creatine kinase (CK), adenylate kinase (AK), and the glycolytic system, which includes hexokinase (Hex), pyruvate kinase (PK) and 3-phosphoglycerate kinase (PGK). ADP is removed by CK, AK and PGK shuttles. P_i transfer is catalyzed by the near-equilibrium glyceraldehyde 3-phosphate dehydrogenase (GAPDH) shuttle. H⁺ removal is facilitated by CK and carbonic anhydrase (CA) shuttles. As these shuttle systems operate in parallel, a diminished activity of a single enzyme is rather well tolerated. However, a decrease in the activity of several enzymes could lead to a cumulative impairment in the communication between ATP-generating and ATP-consuming sites (Dzeja et al., 2000). Gl, glucose; PEP, phospho-enol pyruvate; Pyr, pyruvate; Cr, creatine.

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