Nucleoside

Nucleosides are a class of biomolecules composed of a nitrogenous base linked to a five-carbon sugar, either ribose or 2-deoxyribose. They are structurally similar to nucleotides but lack the phosphate group. The glycosidic bond connecting the sugar to the base forms between the anomeric carbon of the sugar and either the N9 position of a purine or the N1 position of a pyrimidine. Nucleosides and their phosphorylated counterparts, nucleotides, form the essential building blocks of DNA and RNA, enabling the storage and transmission of genetic information.

Structure and Classification

A nucleoside consists of two main components:

• Nitrogenous base: Purine (adenine, guanine) or pyrimidine (cytosine, thymine, uracil).
• Pentose sugar: Ribose in RNA nucleosides, or 2-deoxyribose in DNA nucleosides.

The absence of phosphate distinguishes nucleosides from nucleotides, though both families share identical bases and sugars. When nucleosides are phosphorylated at the 5′ carbon of the sugar, they form nucleotides, which participate in nucleic acid polymerisation, cellular signalling and energy metabolism.
In biochemical contexts, nucleosides and nucleotides are frequently abbreviated using established symbols. For instance, adenosine (Ado) corresponds to adenine, and cytidine (Cyd) to cytosine. Long nucleotide sequences in genomics are typically denoted by the base symbols A, C, G and T (or U in RNA).

Sources and Metabolism

Nucleosides arise through several metabolic and dietary pathways. They are synthesised de novo within the body, particularly in the liver, via nucleotide breakdown pathways. Dietary nucleic acids are degraded by nucleotidases in the digestive tract, generating free nucleosides, which are subsequently cleaved by nucleosidases into nitrogenous bases and ribose or deoxyribose. Within cells, nucleotides may also be degraded into ribose-1-phosphate or deoxyribose-1-phosphate and free bases. These products feed into salvage pathways that recycle components for renewed nucleotide synthesis.

Medical and Biotechnological Applications

Numerous nucleoside analogues play critical roles in modern medicine, particularly in antiviral and anticancer treatments. These modified nucleosides possess altered bases or sugars that allow them to be incorporated by viral polymerases or rapidly dividing cancer cells. Once inside the cell, they are phosphorylated into nucleotides, enabling them to interfere with nucleic acid synthesis. Because charged nucleotides cannot readily cross cell membranes, drugs are administered in their nucleoside form for effective uptake.
In molecular biology, analogues of the sugar–phosphate backbone are used to improve stability or binding specificity. RNA’s susceptibility to hydrolysis renders alternative structures beneficial for research and therapeutic applications. Examples include:

• Locked nucleic acids (LNA), in which the ribose ring is conformationally constrained for enhanced binding affinity.
• Morpholinos, which replace the ribose–phosphate backbone with a morpholine ring and phosphorodiamidate linkages.
• Peptide nucleic acids (PNA), which employ a peptide-like backbone and bind strongly to complementary nucleic acids.

During DNA sequencing, dideoxynucleotides play an essential role. Their sugar, dideoxyribose, lacks the 3′ hydroxyl group required for phosphodiester bond formation. DNA polymerases incorporate these analogues without distinction, but once added, they terminate chain elongation, enabling precise determination of nucleotide positions.

Prebiotic Synthesis and the Origins of Life

Understanding how nucleosides could form under prebiotic conditions is a central question in origins-of-life research. The RNA world hypothesis suggests that early life relied on RNA molecules capable of both storing information and catalysing reactions. This implies that free ribonucleosides and ribonucleotides existed in the primordial environment.
Research has demonstrated plausible routes for their formation. Experiments by Nam and colleagues showed that ribonucleosides can form directly from nucleobases and ribose within aqueous microdroplets, facilitating condensation reactions under mild conditions. Further studies by Becker and others reported that alternating wet–dry cycles, common in early Earth environments, could yield both purine and pyrimidine ribonucleosides and corresponding nucleotides. These findings contribute to the growing body of evidence supporting natural synthesis of RNA precursors without the need for sophisticated catalytic systems.