Adenylate kinase: Kinetic behavior in intact cells indicates it is integral to multiple cellular processes

Dzeja, Petras P.; Zeleznikar, Robert J.; Goldberg, Nelson D.

doi:10.1007/978-1-4615-5653-4_13

Cited by 87 publications

(167 citation statements)

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“…Metabolic consequences of this structural and functional organisation of cardiac muscle cells are that mitochondrial function, and thus cell respiration and free energy transductions, is regulated in vivo by channeling of substrates, such as ADP and ATP, in the energy-transfer and signalling creatine kinase and adenylate kinase networks within these functional complexes. This is due to tight functional coupling of enzymes and protein-protein interactions (Dzeja et al, 1998(Dzeja et al, , 1999Saks et al, 1998b;Walsh et al, 2001;Weiss and Korge, 2001), which may also include the rather tight control of the outer mitochondrial membrane . Thus, the metabolic regulation in cardiac cells is an organised process, leaving little space for random events that usually determine the kinetics of enzyme reactions in diluted homogenous solutions and, as a consequence, excluding the equilibrium kinetics of respiration regulation usually accepted in the literature.…”

Section: Discussionmentioning

confidence: 99%

Metabolic consequences of functional complexes of mitochondria,myofibrils and sarcoplasmic reticulum in muscle cells

Andrienko

Kuznetsov

Käämbre

et al. 2003

Journal of Experimental Biology

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In spite of intensive studies, the intracellular mechanisms of regulation of mitochondrial function in heart and skeletal muscle are still obscure. One of the interesting observations in this area, made in numerous laboratories, is that in permeabilized oxidative muscle cells the apparent Km for exogenous ADP in the control of mitochondrial respiration is very high, in the range of 200-300·µmol·l -1 , in contrast to permeabilized fibers from fast-twitch skeletal muscles and isolated mitochondria in vitro: in both cases, the apparent Km for ADP is 15-20·µmol·l -1 (Anflous et al., 2001;Braun et al., 2001;Burelle and Hochachka, 2002;Dos Santos et al., 2002;Fontaine et al., 1995;Kay et al., 1997;Kummel, 1988;Kuznetsov et al., 1996;Liobikas et al., 2001;Milner et al., 2000;Saks et al., 1991Saks et al., , 1993Saks et al., , 1994Saks et al., , 1995Saks et al., , 1998aSaks et al., , 2001Seppet et al., 2001;Toleikis et al., 2001;Veksler et al., 1995). A trivial explanation of this phenomenon by formation of ADP concentration gradients between the medium and the core of the cells is excluded (Kay et al., 1997), since the Brownian movement of adenine nucleotides in water solution across the diffusion distance of <10·µm (permeabilized cardiomyocytes) is more rapid than the metabolic turnover of ADP and ATP . Besides, this trivial explanation is in conflict with the tissue specificity of the phenomenon mentioned above (Kuznetsov et al., 1996;Veksler et al., 1995). Another important recent observation is that the kinetics of regulation of mitochondrial respiration in ADP is approximately 20·µmol·l -1 ). An increase in the free Ca 2+ concentration (up to 3·µmol·l -1 , which is within physiological range), resulted in a very significant decrease of the apparent Km value to 20-30·µmol·l -1 , a decrease of Vmax of respiration in permeabilized intact fibers and a strong contraction of sarcomeres. In ghost cardiac fibers, from which myosin was extracted but mitochondria were intact, neither the high apparent Km for ADP (300-350·µmol·l -1 ) nor Vmax of respiration changed in the range of free Ca 2+ concentration studied, and no sarcomere contraction was observed. The exogenous-ADP-trapping system (pyruvate kinase + phosphoenolpyruvate) inhibited endogenous-ADP-supported respiration in permeabilized cells by no more than 40%, and this inhibition was reversed by creatine due to activation of mitochondrial creatine kinase. These results are taken to show strong structural associations (functional complexes) among mitochondria, sarcomeres and sarcoplasmic reticulum. Inside these complexes, mitochondrial functional state is controlled by channeling of ADP, mostly via energy-and phosphoryltransfer networks, and apparently depends on the state of sarcomere structures.

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Section: Discussionmentioning

confidence: 99%

Metabolic consequences of functional complexes of mitochondria,myofibrils and sarcoplasmic reticulum in muscle cells

Andrienko

Kuznetsov

Käämbre

et al. 2003

Journal of Experimental Biology

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“…energy metabolism; adenine nucleotides; glycolysis; phosphotransfer; oxygen-18 phosphoryl labeling; phosphorus-31 nuclear magnetic resonance MAINTENANCE OF OPTIMAL CARDIAC function requires precise control of cellular nucleotide ratios and high-energy phosphoryl fluxes (11,22,30,32,33,36,40). Within the cellular energetic infrastructure, adenylate kinase has been recognized as an important phosphotransfer enzyme that catalyzes adenine nucleotide exchange (ATP ϩ AMP ª 2ADP) and facilitates transfer of both ␤-and ␥-phosphoryls in ATP (9,15,24,25,43). In this way, adenylate kinase doubles the energetic potential of ATP as a high-energy-phosphoryl carrying molecule and provides an additional energy source under conditions of increased demand and/or compromised metabolic state (13-15, 31, 35, 42).…”

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confidence: 99%

Adenylate kinase AK1 knockout heart: energetics and functional performance under ischemia-reperfusion

Pucar

Bast

Gumina

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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letion of the major adenylate kinase AK1 isoform, which catalyzes adenine nucleotide exchange, disrupts cellular energetic economy and compromises metabolic signal transduction. However, the consequences of deleting the AK1 gene on cardiac energetic dynamics and performance in the setting of ischemia-reperfusion have not been determined. Here, at the onset of ischemia, AK1 knockout mice hearts displayed accelerated loss of contractile force compared with wild-type controls, indicating reduced tolerance to ischemic stress. On reperfusion, AK1 knockout hearts demonstrated reduced nucleotide salvage, resulting in lower ATP, GTP, ADP, and GDP levels and an altered metabolic steady state associated with diminished ATP-to-P i and creatine phosphate-to-Pi ratios. Postischemic AK1 knockout hearts maintained ϳ40% of ␤-phosphoryl turnover, suggesting increased phosphotransfer flux through remaining adenylate kinase isoforms. This was associated with sustained creatine kinase flux and elevated cellular glucose-6-phosphate levels as the cellular energetic system adapted to deletion of AK1. Such metabolic rearrangements, along with sustained ATP-to-ADP ratio and total ATP turnover rate, maintained postischemic contractile recovery of AK1 knockout hearts at wild-type levels. Thus deletion of the AK1 gene reveals that adenylate kinase phosphotransfer supports myocardial function on initiation of ischemic stress and safeguards intracellular nucleotide pools in postischemic recovery. energy metabolism; adenine nucleotides; glycolysis; phosphotransfer; oxygen-18 phosphoryl labeling; phosphorus-31 nuclear magnetic resonance MAINTENANCE OF OPTIMAL CARDIAC function requires precise control of cellular nucleotide ratios and high-energy phosphoryl fluxes (11,22,30,32,33,36,40). Within the cellular energetic infrastructure, adenylate kinase has been recognized as an important phosphotransfer enzyme that catalyzes adenine nucleotide exchange (ATP ϩ AMP ª 2ADP) and facilitates transfer of both ␤-and ␥-phosphoryls in ATP (9,15,24,25,43). In this way, adenylate kinase doubles the energetic potential of ATP as a high-energy-phosphoryl carrying molecule and provides an additional energy source under conditions of increased demand and/or compromised metabolic state (13-15, 31, 35, 42). By regulating adenine nucleotide processing, adenylate kinase has been implicated in metabolic signal transduction (12,15,27). Indeed, phosphoryl flux through adenylate kinase has been shown to correlate with functional recovery in the metabolically compromised heart (30) and to facilitate intracellular energetic communication (3,9,13

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“…However, spatially arranged intracellular enzymatic networks are necessitated, because it seems to be insufficient to fulfill all cellular energetic needs (Dzeja et al 2000). Thereby to support high-energy phosphoryltransfer and signal communication between ATP-generating and ATP-consuming/ATP-sensing processes, these networks need to be catalyzed by CK, AK and enzymes of the glycolysis pathway, in especial PK (Dzeja et al 1998), (Dzeja and Terzic 2003), (Wallimann et al 1992). For maintaining the cellular energy homeostasis is indispensable the network between the enzymatic capacities, isoform distribution and the dynamics of phosphoryl flux through the integrated phosphoryltransfer systems tightly correlate with cellular functions, thus indicating a critical role of such networks in efficient energy transfer and distribution (Dzeja and Terzic 2003).…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

Ianiski

Rech

Nishihira

et al. 2016

An. Acad. Bras. Ciênc.

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Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease.

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Adenylate kinase: Kinetic behavior in intact cells indicates it is integral to multiple cellular processes

Cited by 87 publications

References 62 publications

Metabolic consequences of functional complexes of mitochondria,myofibrils and sarcoplasmic reticulum in muscle cells

Metabolic consequences of functional complexes of mitochondria,myofibrils and sarcoplasmic reticulum in muscle cells

Adenylate kinase AK1 knockout heart: energetics and functional performance under ischemia-reperfusion

Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex

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