Regulation of Adenine Nucleotide Metabolism by Adenylate Kinase Isozymes: Physiological Roles and Diseases

Abstract

Adenylate kinase (AK) regulates adenine nucleotide metabolism and catalyzes the ATP + AMP ⇌ 2ADP reaction in a wide range of organisms and bacteria. AKs regulate adenine nucleotide ratios in different intracellular compartments and maintain the homeostasis of the intracellular nucleotide metabolism necessary for growth, differentiation, and motility. To date, nine isozymes have been identified and their functions have been analyzed. Moreover, the dynamics of the intracellular energy metabolism, diseases caused by AK mutations, the relationship with carcinogenesis, and circadian rhythms have recently been reported. This article summarizes the current knowledge regarding the physiological roles of AK isozymes in different diseases. In particular, this review focused on the symptoms caused by mutated AK isozymes in humans and phenotypic changes arising from altered gene expression in animal models. The future analysis of intracellular, extracellular, and intercellular energy metabolism with a focus on AK will aid in a wide range of new therapeutic approaches for various diseases, including cancer, lifestyle-related diseases, and aging.

Keywords: ATP; adenine nucleotides; adenylate kinase; energy metabolism; enzyme.

Figure 1

Model for high-energy phosphoryl transfer via adenylate kinase. As energy is transported from the mitochondria to the sites of utilization such as proton pumps or motors, the intracellular system supports an energy network of creatine kinase (CK), adenylate kinase (AK), and the localization or transport of the mitochondria themselves, in addition to simple diffusion. The presence of extracellular secretory AKs outside the cells suggests the existence of extracellular energy metabolism. In addition, intercellular energy networks, such as extracellular vesicles (EVs) are thought to exist.