A nucleoside always consists of a nucleic base linked to the monosaccharide ribose or deoxyribose by an N-glycosidic bond. All 5 nucleic bases – the building blocks of DNA and RNA double and single helices – can be enzymatically converted into nucleosides. Some glycosides have physiological significance such as adenosine, which is the basic building block for ADP and ATP in cellular energy metabolism.
What are nucleosides?
The double helices of DNA and the single helices of RNA are formed from sequences of only five different nucleic bases in the form of nucleotides. All five nucleic bases, of which adenine and guanine are the basic structure based on the five- and six-membered rings of purine, and cytosine, thymine, and uracil are based on the aromatic six-membered ring of pyrimidine, can combine N-glycosidically with the monosaccharide ribose and deoxyribose, respectively. The hydroxyl group (-OH) on C atom 1 of pentose reacts with the amino group (-NH2) of the nucleic base to form and split off an H2O molecule. When a ribose or deoxyribose residue is attached, adenine is converted to adenosine or deoxyadenosine, respectively. Similarly, the purine base guanine is converted to guanosine and deoxyguanosine, respectively. The three purine bases thymine, cytosine and uracil are transformed into thymidine, cytidine and uridine by the addition of the ribose residue, or receive the prefix “deoxy-” if the added sugar residue consists of deoxyribose. In addition, a large number of modified nucleosides exist, some of which play a role in transfer DNA (tDNA) and ribosomal RNA (rRNA). Artificially produced, modified, nucleosides, so-called nucleoside analogues act in part as antivirals and are used specifically to combat retroviruses. Some nucleoside analogs exhibit cytostatic activity, so they are used to fight certain cancer cells.
Function, action, and roles
One of the most important functions of the five basic nucleosides is to be converted into nucleotides with the addition of a phosphate group to the pentose and, as nucleotides, to form the building blocks of DNA and RNA. In modified form, some nucleosides also perform tasks in the catalysis of certain metabolic processes. For example, the so-called “active methionine” (S-adenosyl-methionine) serves as a donor of methyl groups. In some cases, nucleosides also function in their nucleotide form as building blocks of group-transferring coenzymes. Examples include riboflavin (vitamin B2), which serves as a precursor for many coenzymes and thus plays a central role in many metabolic processes. In the energy supply of cells, adenosine plays a very important role as adensine diphosphate (ADP) and as adenosine triphosphate (ATP). ATP can be described as a universal energy carrier and also serves as a phosphate donor in very many metabolic processes that involve phosphorylation. Guanosine triphosphate (GTP) is the energy carrier in the so-called citrate cycle in mitochondria. Nucleotides are also components of coenzyme A and vitamin B12. The nucleosides uridine and cytidine are used in combination as drugs to treat nerve inflammation and muscle diseases. For example, the drug is used for nerve root inflammation of the spine and lumbago. Modified nucleosides, so-called nucleoside analogues, show virostatic effects against retroviruses in some cases. They are used in drugs against, for example, herpes simplex virus and HIV viruses. Other nucleoside analogues with cytostatic activity play a role in cancer treatment.
Formation, occurrence, properties, and optimal values
Nucleosides are composed entirely of carbon, hydrogen, oxygen, and nitrogen. All substances are abundant virtually everywhere on Earth. Trace elements and rare minerals are not needed to build nucleosides. Nevertheless, the body does not synthesize nucleosides from scratch because the synthesis is complex and energy consuming. Therefore, the human body takes the opposite path, obtaining nucleosides mainly from degradation processes in intermediate purine and pyrimidine metabolism (salvage pathway). Nucleosides participate in a variety of enzymatic-catalytic metabolic processes in the pure form or in the phosphorylated form as nucleotides. Of particular note is the function of adenosine in the form of ATP and ADP in the so-called respiratory chain.The nucleotide guanine triphosphate plays a crucial role in the so-called citrate cycle. In cycles, processes take place within the mitochondria of cells. Since nucleosides are almost always present in large quantities in bound form or as functional carriers in practically all body cells, there is no general limit or guideline value for an optimal concentration. Determination of the concentration of specific nucleosides or nucleotides in blood plasma can be helpful for diagnoses and differential diagnoses.
Diseases and disorders
Nucleosides are an active part of many metabolic processes and their functions can rarely be considered in isolation. Disorders usually involve complex enzymatic-catalytic processes that are interrupted or inhibited at specific sites, leading to corresponding symptoms. Diseases that cause metabolic abnormalities of nucleosides usually also involve purine or pyrimidine metabolism because the five basic nucleosides carry either a purine or a pyrimidine backbone. A known disorder in purine metabolism is caused by the well-known Lesch-Nyhan syndrome, a hereditary disease that causes a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The enzyme deficiency prevents the recycling of certain nucleic bases, resulting in a cumulative accumulation of hypoxanthine and guanine. This in turn triggers hyperuricemia, an elevated uric acid level, which leads to gout. The elevated uric acid level leads to deposits on joints and tendon sheaths, which can cause painful symptoms. A very rare hereditary disease manifests itself in adenylosuccinate lyase deficiency, which leads to problems in purine metabolism. The disease causes muscle twitching and delayed fetal development with a severe course.
