Abstract
Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors. A network of adenylate kinase isoforms (AK1-AK7) are distributed throughout intracellular compartments, interstitial space and body fluids to regulate energetic and metabolic signaling circuits, securing efficient cell energy economy, signal communication and stress response. The dynamics of adenylate kinase-catalyzed phosphotransfer regulates multiple intracellular and extracellular energy-dependent and nucleotide signaling processes, including excitation-contraction coupling, hormone secretion, cell and ciliary motility, nuclear transport, energetics of cell cycle, DNA synthesis and repair, and developmental programming. Metabolomic analyses indicate that cellular, interstitial and blood AMP levels are potential metabolic signals associated with vital functions including body energy sensing, sleep, hibernation and food intake. Either low or excess AMP signaling has been linked to human disease such as diabetes, obesity and hypertrophic cardiomyopathy. Recent studies indicate that derangements in adenylate kinase-mediated energetic signaling due to mutations in AK1, AK2 or AK7 isoforms are associated with hemolytic anemia, reticular dysgenesis and ciliary dyskinesia. Moreover, hormonal, food and antidiabetic drug actions are frequently coupled to alterations of cellular AMP levels and associated signaling. Thus, by monitoring energy state and generating and distributing AMP metabolic signals adenylate kinase represents a unique hub within the cellular homeostatic network.
Highlights
Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors
Adenylate kinase generated AMP is emerging as a potential metabolic signal whose intracellular and circulatory levels determine the balance of peripheral organ energy supply between glucose, glycogen and fat, regulating food intake, hormonal state, sleep, hibernation and body energy sensing in conjunction with hypothalamic AMP-activated protein kinase (AMPK), K-ATP
Mononuclear cells obtained from bone marrow of healthy donors lacked adenylate kinase 1 (AK1), whereas adenylate kinase 2 (AK2) was readily detectable. These results indicate that leukocytes may be susceptible to defects caused by the lack of AK2, as they do not express AK1 in sufficient amounts to compensate for AK2 functional deficits
Summary
The existence of multiple isoforms of an enzyme usually relates to their different intracellular distribution and kinetic properties according to the local metabolic requirements (Figure 2). 57], three major isoforms, AK1, AK2 and AK3 have been identified, which are localized in the cytosol, mitochondrial intermembrane space and matrix, respectively [13,14,73] They differ in molecular weight, structure, kinetic properties and nucleotide specificity [19,25,74]. Corresponding proteins AK1 – AK7 define separate adenylate kinase isoforms with different molecular weights, kinetic properties and intracellular localization. AK1 gene product, the p53-inducible membrane-bound myristoylated AK1β, has been reported and implicated in p53-dependent cell-cycle arrest and nucleotide exchange in the submembrane space [51,73,87] In this context, the gene encoding AK1 is down-regulated during tumor development, which could be associated with lower AK1β levels and cell cycle disturbances [88]. AK1β has been demonstrated to be associated with the nuclear envelope [73] and proteomic studies have identified AK1β in epithelium microvilli [89], suggesting a role in energy support of nuclear and epithelia transport processes
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