Interplay between adenylate metabolizing enzymes and AMP‐activated protein kinase

Abstract

Purine nucleotides are involved in a variety of cellular functions, such as energy storage and transfer, and signalling, in addition to being the precursors of nucleic acids and cofactors of many biochemical reactions. They can be generated through two separate pathways, the de novo biosynthesis pathway and the salvage pathway. De novo purine biosynthesis leads to the formation of IMP, from which the adenylate and guanylate pools are generated by two additional steps. The salvage pathways utilize hypoxanthine, guanine and adenine to generate the corresponding mononucleotides. Despite several decades of research on the subject, new and surprising findings on purine metabolism are constantly being reported, and some aspects still need to be elucidated. Recently, purine biosynthesis has been linked to the metabolic pathways regulated by AMP-activated protein kinase (AMPK). AMPK is the master regulator of cellular energy homeostasis, and its activity depends on the AMP : ATP ratio. The cellular energy status and AMPK activation are connected by AMP, an allosteric activator of AMPK. Hence, an indirect strategy to affect AMPK activity would be to target the pathways that generate AMP in the cell. Herein, we report an up-to-date review of the interplay between AMPK and adenylate metabolizing enzymes. Some aspects of inborn errors of purine metabolism are also discussed.

AMPK: a balancer of the renin–angiotensin system

“…The phosphorylation of AMPK is largely dependent on the AMP and ATP ratio [43,[46][47][48][49]. After AMP binding to the AMPK γ-subunit, the allosteric structure will change.…”

“…Through AMP binding to site 1, the enzyme is activated. At site 3, binding of either AMP or ADP will suppress the ability of phosphatases to remove the phosphate from Thr 172 and inhibit the enzyme [9,43].The phosphorylation of AMPK is largely dependent on the AMP and ATP ratio [43,[46][47][48][49]. After AMP binding to the AMPK γ-subunit, the allosteric structure will change.…”

Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors

“…De novo synthesis is feedback regulated by its final products adenosine 5′-monophosphate (AMP), inosine 5′-monophosphate (IMP) and guanosine 5′-monophosphate (GMP), which are allosteric inhibitors of 5-phosphoribosyl-1-pyrophosphate (PRPP) amidotransferase (PPAT) [ 5 ], while it is increased in the presence of PRPP which is both substrate and allosteric activator of the same enzyme [ 6 ] ( Figure 1 ). Conversely, the purine salvage pathway is mainly regulated by the level of expression of enzymes and their kinetic characteristics and substrate concentrations, particularly of PRPP, which is a cosubstrate for adenine, hypoxanthine, and guanine salvage [ 7 ] ( Figure 2 ). Therefore, PRPP appears to be an important regulator in common to both pathways [ 6 , 7 ].…”

“…Conversely, the purine salvage pathway is mainly regulated by the level of expression of enzymes and their kinetic characteristics and substrate concentrations, particularly of PRPP, which is a cosubstrate for adenine, hypoxanthine, and guanine salvage [ 7 ] ( Figure 2 ). Therefore, PRPP appears to be an important regulator in common to both pathways [ 6 , 7 ]. As shown in Figure 2 , the purine salvage pathway and purine catabolism are strictly correlated.…”

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…137,138 More importantly, phosphorylating of AMPK signaling depends on adenosine triphosphate ATP/AMP ratio to a great extent. 139,140 Interestingly, AMPK signaling expressed a dual role to protect normal brain cells from energy stress while repressing the tumor cells. 141 It has been reported that activities of glycolysis including glucose uptake, ATP levels, and lactate production were regulated by AMPK signaling in glioma cells.…”