The many isoforms of human adenylate kinases

Panayiotou, Christakis; Solaroli, Nicola; Karlsson, Anna

doi:10.1016/j.biocel.2014.01.014

Cited by 120 publications

(145 citation statements)

References 62 publications

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“…Adenylate kinases are interesting enzymes in that there are nine isoforms, several of which are found in brain and localised to the cytosol [82]. Moreover, most isoforms possess both nucleoside monophosphate (eg AMP→ADP) and nucleoside diphosphate (eg ADP→ATP) kinase activity and are capable of utilising phosphate donors other than ATP.…”

Section: The Purine Salvage Pathway As the Vehicle For Atp Replenishmentmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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Section: The Purine Salvage Pathway As the Vehicle For Atp Replenishmentmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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“…Ribose-5-phosphate is then incorporated into the phosphoribosyl pyrophosphate pool, from which a phosphoribose group is used by cytosolic APRT and HPRT to generate purine mononucleotides, including AMP (Figure 1). Through the actions of adenylate kinase, several isoforms of which are cytosolic and found in brain, AMP can be converted to ATP (Panayiotou et al, 2014). Importantly, adenylate kinases are promiscuous in that they can utilise nucleotide triphosphate donors other than ATP, such as GTP, which are largely preserved during cerebral ischaemia (Hagberg et al, 1987); this avoids the futile cycle of robbing ATP to pay ADP.…”

Section: Therapies To Restore Ischaemia-depleted Atp: Lessons From Thmentioning

confidence: 99%

Proof of concept and feasibility studies examining the influence of combination ribose, adenine and allopurinol treatment on stroke outcome in the rat

Faller

Leach

Johnston

et al. 2017

Brain and Neuroscience Advances

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Background: Cerebral ischaemia results in a rapid and profound depletion of adenosine triphosphate (ATP), the energy currency of the cell. This depletion leads to disruption of cellular homeostasis and cell death. Early replenishment of ATP levels might therefore have a neuroprotective effect in the injured brain. We have previously shown that the ATP precursors, D-ribose and adenine (RibAde), restored the reduced ATP levels in rat brain slices to values similar to those measured in the intact rodent brain. The aim of this study was to assess whether RibAde, either alone or in combination with the xanthine oxidase inhibitor allopurinol (RibAdeAll; to further increase the availability of ATP precursors), could improve outcome in an in vivo rodent model of transient cerebral ischaemia. Methods: After 60 min occlusion of the middle cerebral artery, and upon reperfusion, rats were administered saline, RibAde, or RibAdeAll for 6 h. Baseline lesion volume was determined by diffusion-weighted MRI prior to reperfusion and final infarct volume determined by T2-weighted MRI at Day 7. Neurological function was assessed at Days 1, 3 and 7. Results: Ischaemic lesion volume decreased between Days 1 and 7: a 50% reduction was observed for the RibAdeAll group, 38% for the RibAde group and 18% in the animals that received saline. Reductions in lesion size in treatment groups were accompanied by a trend for faster functional recovery. Conclusion: These data support the potential use of ribose, adenine and allopurinol in the treatment of cerebral ischaemic injury, especially since all compounds have been used in man.

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“…Compared to ecto-nucleotidases, the physiological significance of AK1 in the plasma is less clear. AK1 is a ubiquitous cytosolic protein most abundantly expressed in muscle cells [33]. Its role is largely linked to intracellular signaling, such as those through AMP sensitive protein kinase, ATP-sensitive potassium channel, and AMP-sensitive metabolic enzymes [34].…”

Section: Discussionmentioning

confidence: 99%

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

Jiang

Wu²,

Csizmadia³

et al. 2014

Purinergic Signalling

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Phosphohydrolysis of extracellular ATP and ADP is an essential step in purinergic signaling that regulates key pathophysiological processes, such as those linked to inflammation. Classically, this reaction has been known to occur in the pericellular milieu catalyzed by membrane bound cellular ecto-nucleotidases, which can be released in the form of both soluble ecto-enzymes as well as being associated with exosomes. Circulating ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1/CD39) and adenylate kinase 1 (AK1) activities have been shown to be present in plasma. However, other ecto-nucleotidases have not been characterized in depth. An in vitro ADPase assay was developed to probe the ecto-enzymes responsible for the ectonucleotidase activity in human platelet-free plasma, in combination with various specific biochemical inhibitors. Identities of ecto-nucleotidases were further characterized by chromatography, immunoblotting, and flow cytometry of circulating exosomes. We noted that microparticle-bound ENTPDases and soluble AK1 constitute the highest levels of ecto-nucleotidase activity in human plasma. All four cell membrane expressed E-NTPDases are also found in circulating microparticles in human plasma, inclusive of: CD39, NTPDase 2 (CD39L1), NTPDase 3 (CD39L3), and NTPDase 8. CD39 family members and other ecto-nucleotidases are found on distinct microparticle populations. A significant proportion of the microparticle-associated ecto-nucleotidase activity is sensitive to POM6, inferring the presence of NTPDases, either −2 or/and −3. We have refined ADPase assays of human plasma from healthy volunteers and have found that CD39, NTPDases 2, 3, and 8 to be associated with circulating microparticles, whereas soluble AK1 is present in human plasma. These ecto-enzymes constitute the bulk circulating ADPase activity, suggesting a broader implication of CD39 family and other ecto-enzymes in the regulation of extracellular nucleotide metabolism.

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The many isoforms of human adenylate kinases

Cited by 120 publications

References 62 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Proof of concept and feasibility studies examining the influence of combination ribose, adenine and allopurinol treatment on stroke outcome in the rat

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

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