Biochemical mechanisms in nucleotide repair

Abstract

Background. Nucleotides are stable monomers of nucleic acids. They are required for a wide variety of biological processes and are constantly synthesized in all the cells. As cells proliferate, increased nucleotide synthesis is required for DNA replication and RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore, the synthesis of previous nucleotides is also strongly regulated at several levels. Case report. In order to keep the quantity of nucleotides constant, the cell uses two important pathways: 1. novo synthesis 2. nucleotide repair with reuse of metabolic residues from preexisting nucleotides. However, despite the existence of different repair pathways, most proliferative cells synthesize nucleotides and de novo nucleic acids, mainly from glucose, glutamine and CO2. This was observed by using C13 and N15 labeled isotopes. Different parts of nucleotides come from different sources of carbon and nitrogen in the cell, and the RNTP (ribo-nucleotide-triphosphate) assembly requires a great amount of energy. Thus, starting from glucose, three equivalents of ATP are required to make activated ribose-5'-phosphoribosyl pyrophosphate (PRPP), which is produced by the reaction between 5'-phosphoribose with ATP, caused by the release of the 5'-AMP group. Pyrimidine rings are first synthesized in the form of uracil from aspartate, CO2 (or bicarbonate) and glutamine, which require two ATP. Metabolic requirements for nucleotides and their bases can be met either by energy input or by de novo synthesis from precursors with low molecular weight. The ability to save nucleotides in the body alleviates any significant nutritional needs for nucleotides, so purine and pyrimidine bases are not required as part of the diet. The repair pathways are a major source for DNA, RNA and enzyme co-factors synthesis. Inside the body, the main system for de novo nucleotide synthesis, for the renewal and maintenance of intracellular pools, is the liver. After their synthesis in the liver, the nucleotides are dephosphorylated, next partially phosphorylated in nucleobases and ribose-1-phosphate for transport to the blood and subsequently uptake by the other cells. These processes are regulated at transcription level by a set of main transcription factors, but also at the level of the enzyme by allosteric regulation and feedback inhibition. Studies based on labeled isotopes provide important information on nucleotide biosynthesis, such as the preference for endogenously synthesized precursors, such as glycine and aspartate, compared to those provided externally, and how resources are re-allocated based on environmental conditions, particularly pathological conditions such as cancers ("metabolic reprogramming"). Conclusions. Almost all cells in the body are capable of synthesizing de novo nucleotides. The source of these molecules may be nucleic acids of their own tissues and foods, but these sources have only a secondary, auxiliary value.