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Adenosine kinase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Adenosine kinase (ADK) deficiency was first described in 2011, the result of an exome sequencing study in six patients from three families with global retardation, epilepsy, hepatic dysfunction, dysmorphic features and hypermethioninemia [1]. Increased urinary concentration of adenosine was considered to confirm the diagnosis. Since then, eleven additional patients from eight families were published [2], and one report of a family (three girls) with previously undetermined hypermethioninemia [3] could be assigned as ADK deficiency [2], so in total 20 patients have been published. All patients share the clinical features of psychomotor retardation, muscular hypotonia, and frontal bossing. All but one family presented with hepatic disease and most patients developed severe epilepsy in infancy.
Composition of The Chromaffin Cell
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
The subcellular distribution of diadenosine tetraphosphate and diadenosine pentaphosphate was studied by Rodriguez del Castillo, Torres, Delicado et al. (1988). In bovine adrenal medullary tissue, these diadenosine polyphosphates were most concentrated within chromaffin vesicles. Enzymatic degradation with phosphodiesterase produced AMP as the final product. The diadenosine polyphosphates were potent inhibitors of adenosine kinase.
The Autacoid Functions of Adenosine in Asthma
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
R. Polosa, M. K. Church, S. T. Holgate
Adenosine is a naturally occurring purine nucleoside which promotes both intra- and extracellular physiological functions in a wide variety of different cell systems, the latter being effected through interaction with specific cell surface receptors (purinoceptors).1 The generation of adenosine within cells is closely linked to the synthesis and degradation of adenine nucleotides concerned with energy and nucleic acid metabolism. Adenosine production is greatly increased under conditions of energy deficit,2 or tissue hypoxia,3 and (where appropriate) following immunological activation.4,5 Adenosine 5′-monophosphate (AMP), being mostly derived from the degradation of adenosine 5′-triphosphate (ATP), leaves the cell by transport across the cell membrane, where it is metabozed to adenosine through the catalytic action of a membrane-linked enzyme, 5′-nucleotidase.6 Once released, adenosine is rapidly rescued by cells through a process of facilitated transport across membrane channels that are blocked by the drug dipyridamole.7,8 The further metabolism of adenosine, either intra- or extracellularly, occurs mostly through enzymatic hydrolysis to inosine and hypoxanthine and subsequent degradation to xanthine and uric acid. A proportion of intracellular adenosine may be salvaged by conversion to AMP in a reaction catalyzed by adenosine kinase (Figure 1). Adenosine at extracellular sites behaves as an autacoid since it produces its pharmacological effects by stimulating cell surface purinoceptors to either decrease (A1) or increase (A2) intracellular levels of cyclic 3′, 5′-AMP.1,9,10 A third adenosine receptor subtype (A3) controlling the function of calcium-related mechanisms has recently been proposed.11 These cell surface receptors are to be differentiated from an intracellular site on the catalytic subunit of adenylate cyclase which, in the presence of high concentrations of adenosine or ribose-modified analogues, reduces cyclic AMP formation.12
Approaches for designing and discovering purinergic drugs for gastrointestinal diseases
Published in Expert Opinion on Drug Discovery, 2020
Diego Dal Ben, Luca Antonioli, Catia Lambertucci, Andrea Spinaci, Matteo Fornai, Vanessa D’Antongiovanni, Carolina Pellegrini, Corrado Blandizzi, Rosaria Volpini
In parallel, under physiological conditions, the levels of purines are finely tuned also by the activity of the nucleoside transporters [47]. Nowadays, these transporters are classified as: (a) equilibrative nucleoside transporters (ENTs), designated as ENT1, ENT2, ENT3, and ENT4, which transport nucleosides across cell membranes in either directions, based on concentration gradients; (b) concentrative nucleoside transporters (CNTs), classified in CNT1, CNT2, and CNT3, promoting the intracellular influx of nucleosides against their concentration gradient, using the sodium ion gradient across cellular membranes as a source of energy [48]. Once transported intracellularly, Ado gets phosphorylated to AMP by the intracellular adenosine kinase (ADK) enzyme, which controls the poly-phosphorylation of Ado to ATP. Intracellular Ado may also be converted to inosine by the intracellular ADA [39].
Characteristics and the role of purinergic receptors in pathophysiology with focus on immune response
Published in International Reviews of Immunology, 2020
Marharyta Zyma, Rafał Pawliczak
Adenosine can regulate the innate immune system leading to prevention of inflammatory damage of tissue in patients with sepsis. Additionally, the adenosine kinase activity is inhibited, causing an increase of adenosine level [85]. Neutrophils have the ability to release AMP, arising the adenosine levels. This adenosine binds to A2A receptors on neutrophils and inhibits free radicals, cytokines, and leukotriene B4 production as well as adhesion molecules expression and increases the intracellular level of cAMP. On the other hand, binding of the adenosine to A1 receptors increases the inflammatory activity of neutrophils at sites with low concentration of adenosine [85]. Moreover, macrophages can express all adenosine receptors and have the ability to generate ATP leading to production of exogenous adenosine. This adenosine is able to inhibit the monocyte differentiation and, also, the macrophages phagocytic functions [85]. Furthermore, adenosine has the ability to boost the inflammatory activity of mast cells in human through the binding to A2A receptors in mast cells [85].
CD73 as a potential opportunity for cancer immunotherapy
Published in Expert Opinion on Therapeutic Targets, 2019
Ghasem Ghalamfarsa, Mohammad Hossein Kazemi, Sahar Raoofi Mohseni, Ali Masjedi, Mohammad Hojjat-Farsangi, Gholamreza Azizi, Mehdi Yousefi, Farhad Jadidi-Niaragh
The cooperative enzymatic function of CD39 and CD73 regulates purinergic signals through conversion of ATP/ADP/AMP to adenosine. This activity attenuates pro-inflammatory condition generated by ATP and converts it into an anti-inflammatory environment by adenosine. Regarding an important role of ATP metabolism in the physiologic processes and signaling and immune homeostasis, it is tightly regulated. While CD39 converts ATP into AMP with just trace levels of ADP, CD73 generates adenosine from AMP [68]. CD39 degrades ATP through phosphohydrolyzing in the presence of Ca2+ and Mg2+ to generate AMP [69]. Generation of AMP from ATP by CD39 is a reversible reaction by a function of two extracellular kinases including NDP kinase and adenylate kinase that facilitate the conversion of ADP to ATP and AMP to ADP, respectively. On the other hand, generation of adenosine from AMP by CD73 is irreversible. However, it can be reversible upon intracellular transport of adenosine via the action of adenosine kinase [52]. ATP and ADP are also competitive inhibitors of CD73 [70,71]. Therefore, it seems that CD73 is a key checkpoint in the metabolism of immune-stimulating ATP and its conversion into immune-regulatory adenosine.