Role of pH in Regulating Cancer Pyrimidine Synthesis

Abstract

Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.

Exploring monocarboxylate transporter inhibition for cancer treatment

“…Another pathway that would be inhibited by deep intracellular acidification is purine and pyrimidine biosynthesis. All the enzymes involved in this pathway have an optimum pH of around 8 [ 228 ]. Deep development of therapies combining intracellular acidification with monocarboxylate inhibitors may thus be a very useful method of curtailing tumor cell growth.…”

“…Phosphofructokinase 1 is a rate-limiting enzyme of the glycolytic pathway and its pH optimum is around 8 [226]. It is inhibited by low pH and is fully pH-dependent [227]. Another pathway that would be inhibited by deep intracellular acidification is purine and pyrimidine biosynthesis.…”

Exploring Lead-Like Molecules of Traditional Chinese Medicine for Treatment Quest against Aliarcobacter butzleri: In Silico Toxicity Assessment, Dynamics Simulation, and Pharmacokinetic Profiling

“…Ligand and protein structure was prepared before docking by assigning bond orders, protonating, and adding missing atoms and energy minimization [32]. Orotidylic acid, natural binder of ODCase [33], was taken as control for docking. TCM library of 36,000 molecules was filtered for drug-like candidates using Lipinski's 1), and to ensure consistency with the previous studies [24,37], the particle radius, dissolution model, and density were kept constant.…”