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Phosphotransfer networks and cellular energetics

Petras P. Dzeja^* and Andre Terzic

Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA

View larger version (12K): [in a new window]   Fig. 1. Adenylate energetic cycle. Diffusional exchange of nucleotides between ATPases and ATPsynthases requires establishment of concentration gradients, which would compromise the kinetic and thermodynamic efficiency of energy transfer. –H, change in enthalpy of ATP hydrolysis; G1(ATP) and G2(ATP), free energy of ATP hydrolysis at ATP synthesis and ATP consumption sites, respectively.

View larger version (54K): [in a new window]   Fig. 2. Energy export from mitochondria matrix and intracristal space. Restricted diffusion of nucleotides from the narrow intracristal space to the external compartment could be overcome by an enzymatic system and/or by high-throughput contact sites traversing the inner (im) and outer (om) membranes. In some circumstances, contact sites could provide direct access to ATP in the matrix compartment, while intracristal space could be used for proton confinement leading to efficient ATP synthesis. E, E1, E2, near-equilibrium phosphotransfer enzymes; ANT, adenine nucleotide translocator.

View larger version (47K): [in a new window]   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, Pi 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. Pi 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.

View larger version (70K): [in a new window]   Fig. 4. Energy support relays for nucleocytoplasmic communication. Mitochondria clustered around the nucleus generate the majority of ATP required for nuclear processes. Export of ATP from the mitochondrial intracristal space is facilitated by near-equilibrium reactions catalyzed by mitochondrial isoforms of adenylate kinase (AK2), creatine kinase (Mi-CK) and nucleoside diphosphate kinase (NDPK). Subsequently, high-energy phosphoryls are navigated through the diffusionally restricted perinuclear space to ATP consumption sites at the nuclear envelope and inside the nucleus by cytosolic and nuclear isoforms of AK, CK and NDPK. Interaction and complementation between these systems secure proper nucleotide ratios at and across the nuclear envelope, sustaining the high energy of ATP and GTP hydrolysis. For other abbreviations, see Fig. 3.