Kinetics of adenylate metabolism in human and rat myocardium

Tavenier, Monique; Składanowski, Andrzej C.; Abreu, Ronney A. De; Jong, Jan Willem de

doi:10.1016/0304-4165(95)98595-c

Cited by 13 publications

(5 citation statements)

References 41 publications

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“…In both species ecto-5′-nucleotidase exceeds activity of cytosolic 5′-nucleotidases approximately tenfold. Although total 5′-nucleotidase activity of human myocardium was determined to be roughly half that of rat myocardium, the overall distribution of enzymatic activity is similar with the membrane fraction exceeding the soluble fraction 5.5-fold (Kochan et al 1994;Tavenier et al 1995).…”

Section: Estimates Of the Different Sources Of Adenosinementioning

confidence: 99%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

101

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The quantitatively most important source of adenosine under well-oxygenated conditions is 5'-AMP hydrolyzed by cytosolic 5'-nucleotidase N-I. Hydrolysis of S-adenosylhomocysteine and extracellular dephosphorylation of 5'-AMP further contribute to total production. More than 90% of the total production occur intracellularly under well-oxygenated conditions. Besides cardiomyocytes, endothelial cells and smooth muscle contribute significantly to total cardiac adenosine production. Rapid enzymatic conversion of adenosine is provided by adenosine kinase and adenosine deaminase, keeping the cytosolic adenosine concentration in the nanomolar range. Due to the high intracellular rates of adenosine rephosphorylation and deamination the cytosolic is normally below the extracellular adenosine concentration, making the cytosol to a sink rather than a source of adenosine. It is for this reason that blockers of membrane transport enhance the plasma adenosine concentration. With increasing catabolism of adenine nucleotides the rate of intracellular adenosine production exceeds the rate of adenosine deamination and rephosphorylation. Thus, this condition will result in a concentration gradient from intra- to extracellular. Thence, membrane transport blockers would be expected to increase the intracellular adenosine concentration. A considerable insecurity on the importance of experimental data results from species differences of purine metabolism. Cardiac adenosine metabolism has recently been described in quantitative terms using mathematical model analysis. This analysis tool may prove useful in future when (1) clarifying the importance of various regulatory actions described for the different pathways of adenosine metabolism, (2) making quantitative comparisons of different experimental models possible and (3) deepening the insight from experimental data.

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Section: Estimates Of the Different Sources Of Adenosinementioning

confidence: 99%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

101

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“…AdK and ADA were assayed according to Tavernier et al. [39]. MK was assayed according to Zhang et al.…”

Section: Methodsmentioning

confidence: 99%

“…Traces of ATP in the substrates and enzyme preparations were excluded using the ATP Bioluminescent Assay Kit CLS II (Roche Diagnostics GmbH, Mannheim, Germany; Sirius LuminometerBerthold GmbH, Pforzheim, Germany). AdK and ADA were assayed according to Tavernier et al [39]. MK was assayed according to Zhang et al [40].…”

Section: Enzyme Assaysmentioning

confidence: 99%

Evidence of a new phosphoryl transfer system in nucleotide metabolism

et al. 2008

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Purine nucleotides are precursors of nucleic acids and participate in many metabolic pathways as substrates, coenzymes and energy sources. Much attention has been focused on the roles and intracellular levels of AMP, ADP and ATP in various tissues under normal and pathological conditions [1][2][3]. Their relationships to genetic diseases, blood disorders, drugs, tumours and other pathologies have been studied extensively [4][5][6].Although ATP formation occurs via several wellknown mechanisms, ADP is thought to be formed only from ATP, either by the adenylate kinase reaction or by ATPase-mediated hydrolysis. The possibility that ADP can be formed by de novo synthesis from low-energy precursors has never been investigated fully. Even less studied is the possibility that ADP might be synthesized from low-energy precursors under special conditions, such as ischaemia and hypoxia, in which massive depletion of ATP and elevation of AMP are known to occur [7][8][9][10].In this article, it is shown that, under physiological conditions, ADP may be formed in mammalian tissues by the disproportionation of AMP, consistent with an AMP-AMP phosphotransferase reaction. This reaction is carried out by enzymes of purine metabolism which, under specific cellular conditions, associate in a biological network and cooperate in a reaction not reported previously. Crude rat liver extract showed AMP-AMP phosphotransferase activity which, on purification, was ascribed to a novel interaction between adenylate kinase, also known as myokinase (EC 2.7.4.3), and adenosine kinase (EC 2.7.1.20). The activity was duplicated using the same enzymes purified from recombinant sources. The reaction requires physical contact between myokinase and adenosine kinase, and the net reaction is aided by the presence of adenosine deaminase (EC 3.5.4.4), which fills the gap in the energy balance of the phosphoryl transfer and shifts the equilibrium towards ADP and inosine synthesis. The proposed mechanism involves the association of adenosine kinase and myokinase through non-covalent, transient interactions that induce slight conformational changes in the active site of myokinase, bringing two already bound molecules of AMP together for phosphoryl transfer to form ADP. The proposed mechanism suggests a physiological role for the enzymes and for the AMP-AMP phosphotransferase reaction under conditions of extreme energy drain (such as hypoxia or temporary anoxia, as in cancer tissues) when the enzymes cannot display their conventional activity because of substrate deficiency.

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“…It has been characterised in mammals (rat, pig, calf, and human), birds (chicken, goose) as well as a frog [3], the invertebrate Artemia [4] and three fish species [5]. It is best documented in mammals and birds where it has been described in various tissues [1,6], including human (placenta [7], heart [8], erythrocytes [9] and lymphoblasts). cN‐II has a particularly elevated activity in avian liver and in organs with a high turnover rate or DNA replication including human colon carcinoma [10].…”

Section: Introductionmentioning

confidence: 99%

Regulation and activity of cytosolic 5′‐nucleotidase II

et al. 2005

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In many vertebrate tissues, cytosolic 50 -nucleotidase II (cN-II) either hydrolyses or phosphorylates a number of purine (monophosphorylated) nucleosides through a scheme common to the Haloacid Dehalogenase superfamily members. It possesses a pivotal role in purine cellular metabolism and it acts on antitumoural and antiviral nucleoside analogues, thus being of potential therapeutic importance. cN-II is Mg 2+ -dependant, regulated and stabilised by several factors such as allosteric effectors ATP and 2,3-DPG, although these are not directly involved in the reaction stoichiometry. We review herein the experimental knowledge currently available about this remarkable enzymatic activity.

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Kinetics of adenylate metabolism in human and rat myocardium

Cited by 13 publications

References 41 publications

Metabolic flux rates of adenosine in the heart

Metabolic flux rates of adenosine in the heart

Evidence of a new phosphoryl transfer system in nucleotide metabolism

Regulation and activity of cytosolic 5′‐nucleotidase II

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