Purine-Metabolising Enzymes and Apoptosis in Cancer

Abstract

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

“…To examine other potential mechanisms, we performed immunoprecipitation (IP) with the ARL13B antibody, followed by liquid chromatography-mass spectrometry (LC-MS). This analysis identified inosine monophosphate dehydrogenase 2 (IMPDH2), a key ratelimiting enzyme for purine biosynthesis 44,45 , as a novel interacting partner of ARL13B ( Fig. 4D; p<.0001 calculated by Scaffold Viewer software n=2 replicates).…”

Guanosine-Based Nucleotides, the Sons of a Lesser God in the Purinergic Signal Scenario of Excitable Tissues

“…In addition, other studies showed that guanosine would also modulate glutamate transporter activity and that guanine nucleotides are able to displace glutamate from its receptors [32]. As postulated by Tasca et al (2018), "the identification of the extracellular actions of GBPs as intercellular messengers was possible due to five pieces of evidences: (1) GBPs can be found in the extracellular space, where they are released upon certain harmful conditions; (2) hydrolization of extracellular guanine nucleotides leads to the formation of guanosine and guanine; (3) GTP is stored in synaptic vesicles; (4) glutamate binding is displaced by guanine nucleotides; and (5) GBPs modulate glutamate transporter activity. Based on these findings, it can be concluded that GBPs act as endogenous modulators of glutamatergic transmission, and it might result in the potentially critical role that these molecules play in neuroprotection."…”

“…Purines are endogenous organic molecules that are essential for all cells. Purines, adenine-based purines (ABPs) and guanine-based purines (GBPs), are composed of two fused linked rings containing five carbon and four nitrogen atoms as well as their derivatives: nucleosides (nitrogenous bases plus a pentose sugar, commonly ribose); and nucleotides (nitrogenous bases plus ribose and phosphate) that are mono-, di-or tri-phosphorylated [1]. Adenine and guanine are very commonly found in nature, mostly as nucleoside and nucleotide derivatives, i.e., phosphorylates (Adenosine monophosphate, AMP; Adenosine diphosphate ADP; Adenosine triphosphate, ATP; Guanosine monophosphate, GMP; Guanosine diphosphate, GDP; Guanosine triphosphate, GTP).…”

“…In addition to synaptic transmission, intracellular nucleotides can be released by non-specific mechanisms in response to various conditions of cellular stress due to alterations of cell membrane permeability. The nucleotides released from damaged cells act as chemotaxis signals that guide the migration of phagocytes to the injury sites leading to the removal of necrotic debris [1]. On the other hand, the increase in the extracellular pool of nucleotides and nucleosides may also be due to the existence of specific mechanisms of transport through the cell membrane essentially consisting of processes of vesicular exocytosis, opening of specific channels and the activation of transporters [22].…”

“…GBPs exert several extracellular trophic effects on neural and/or glial cells not related to G proteins and having a multiple consequences on development and reparative mechanisms of nervous system [1]. Thus, nowadays it is possible to propose a specific guanine-based purinergic system in addition to the well-characterized adenine-based purinergic system [28].…”