The question of whether sulfur is a component of nucleic acids like DNA and RNA has a nuanced answer. In their fundamental, naturally occurring structures, sulfur is not typically present in the core sugar-phosphate backbone or the primary nitrogenous bases. However, sulfur can be found in modified forms of nucleic acids, both those occurring naturally in living organisms and those created synthetically for research or therapeutic purposes. This distinction highlights the adaptable nature of these molecules beyond their well-known canonical structures.
The Fundamental Components of DNA and RNA
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are composed of repeating monomer units called nucleotides. Each nucleotide consists of three main parts: a five-carbon sugar, a phosphate group, and a nitrogenous base. In DNA, the sugar is deoxyribose, while in RNA, it is ribose.
The backbone of both DNA and RNA molecules is formed by alternating sugar and phosphate groups linked together. These connections are known as phosphodiester bonds, which are strong covalent bonds that provide structural integrity. The phosphate group forms the link between the 3′ carbon of one sugar and the 5′ carbon of the next. The nitrogenous bases — adenine, guanine, cytosine, and thymine (in DNA) or uracil (in RNA) — attach to the sugar component from this sugar-phosphate framework.
Sulfur’s Role in Modified Nucleic Acids
While not a part of the standard DNA or RNA backbone, sulfur is incorporated into nucleic acids through specific modifications. Naturally occurring sulfur-containing nucleosides are found primarily in transfer RNAs (tRNAs). These modified nucleosides, such as 4-thiouridine (s4U) and 2-thiouridine (s2U) derivatives, involve the substitution of an oxygen atom with a sulfur atom on certain nucleobases. These modifications are introduced post-transcriptionally by specific enzymes and are important for the proper function of tRNAs, including their role in protein synthesis and the regulation of gene expression. For instance, 4-thiouridine at position 8 of bacterial and archaeal tRNAs helps protect cells from near-UV radiation.
In addition to natural modifications, sulfur is deliberately introduced into nucleic acid analogs for synthetic and therapeutic applications, most notably in phosphorothioate oligonucleotides. In these modified molecules, an oxygen atom in the phosphate backbone is replaced by a sulfur atom. This modification enhances the stability of these synthetic nucleic acids by making them more resistant to degradation by cellular enzymes called nucleases. Phosphorothioates are widely utilized in antisense oligonucleotides (ASOs), which are short synthetic strands of DNA or RNA designed to bind to specific messenger RNA (mRNA) sequences to block protein production or correct genetic defects. This increased stability allows therapeutic oligonucleotides to remain active longer within the body, improving their effectiveness in treating various conditions.
Why Sulfur is Excluded from the Primary Nucleic Acid Backbone
The absence of sulfur from the primary nucleic acid backbone is due to chemical stability and evolutionary selection. The phosphodiester bonds that form the backbone of DNA and RNA are stable under physiological conditions, which is important for maintaining genetic integrity over long periods.
Oxygen forms stronger and more stable bonds within the phosphodiester linkage than sulfur. While sulfur-containing bonds can offer advantages in synthetic contexts, they are generally more reactive or less stable than their oxygen counterparts under the conditions required for genetic information storage and transmission. Life evolved with phosphorus and oxygen forming the structural framework of nucleic acids, and this specific chemical arrangement proved effective and robust for the storage and transfer of genetic information.