Beyond the 20 amino acids commonly discussed in biology, selenocysteine stands as a unique building block within the intricate machinery of living cells. This distinct component of proteins is found in all forms of life. Its existence highlights the sophisticated mechanisms cells employ to expand the genetic code and perform specialized biological functions.
Defining the 21st Amino Acid
Selenocysteine structurally resembles cysteine, but a single atomic difference sets it apart. Cysteine contains a sulfur atom in its side chain, while selenocysteine features a selenium atom, forming a selenol group (-SeH). This substitution imparts distinct chemical properties.
Selenocysteine has a significantly lower pKa value, around 5.2 to 5.3, compared to cysteine’s pKa of 8.3 to 8.5. This lower pKa means that at physiological pH, selenocysteine’s selenol group is more likely to be deprotonated, existing as a highly reactive selenolate anion. Consequently, selenocysteine functions as a much stronger nucleophile than cysteine.
A Special Genetic Code
The incorporation of selenocysteine into proteins relies on a specialized mechanism that overrides a universal genetic signal. In standard protein synthesis, the UGA codon acts as a “stop” signal. However, cells have developed a system to “recode” this UGA codon to insert selenocysteine instead.
This recoding process involves several dedicated molecular components. A specialized transfer RNA (tRNA[Ser]Sec) is central to this mechanism; it is initially charged with serine, which is then enzymatically converted to selenocysteine while still attached to the tRNA. In bacteria, selenocysteine synthase (SelA) performs this conversion. In eukaryotes, a two-step process involves O-phosphoseryl-tRNA[Ser]Sec kinase (PSTK) and O-phosphoserine tRNA[Ser]Sec: selenocysteine synthase (SepSecS).
A distinct mRNA hairpin structure, known as the Selenocysteine Insertion Sequence (SECIS) element, is essential. In bacteria, the SECIS element is located immediately downstream of the UGA codon. In archaea and eukaryotes, it resides in the 3′-untranslated region (3′ UTR) of the messenger RNA. This structural element recruits specific elongation factors: SelB in bacteria, or a complex of EFSec and Selenocysteine-binding protein 2 (SBP2) in eukaryotes. These factors deliver the selenocysteine-charged tRNA to the ribosome, allowing the UGA codon to be translated as selenocysteine rather than a stop signal.
The Role in Selenoproteins
The cell’s machinery for incorporating selenocysteine is due to its unique functional contributions to a specific class of proteins known as selenoproteins. Selenocysteine is often found in the active sites of these proteins, where its distinctive chemical properties, such as high reactivity and lower redox potential, are leveraged for catalytic activity. This allows selenoproteins to perform biological functions with enhanced efficiency compared to their sulfur-containing counterparts.
A prominent family of selenoproteins includes the glutathione peroxidases (GPx), with five human members containing selenocysteine. These enzymes are key to cellular antioxidant defense, reducing reactive oxygen species like hydrogen peroxide and lipid hydroperoxides. GPx4, for example, inhibits ferroptosis, a type of regulated cell death.
The thioredoxin reductases (TrxR) are another class of selenoproteins, with three human isoforms, that regulate cellular redox balance. These enzymes reduce thioredoxin using NADPH as an electron donor. The iodothyronine deiodinases (DIO), comprising three enzymes, are selenoproteins involved in thyroid hormone metabolism. DIO1 and DIO2 convert inactive thyroxine (T4) into active triiodothyronine (T3), while DIO3 inactivates thyroid hormones, collectively regulating thyroid function.
Connection to Dietary Selenium
The cellular synthesis of selenocysteine depends on the availability of selenium, a trace element obtained from our diet. Once absorbed, dietary selenium is metabolized into an intermediate used for selenocysteine synthesis.
Insufficient dietary selenium can lead to impaired selenoprotein function and contribute to certain health conditions. Keshan disease, an endemic cardiomyopathy, is identified in areas of China with low soil selenium levels. This condition primarily affects women of childbearing age and preschool children, and selenium supplementation reduces its incidence. Kashin-Beck disease, a type of osteoarthritis, is also associated with selenium deficiency in specific regions.
While selenium is necessary, excessive intake can lead to toxicity, known as selenosis. Symptoms include a garlicky breath odor, dermatitis, and the loss of hair and fingernails. The range between beneficial and toxic doses of selenium is narrow, highlighting the importance of maintaining appropriate dietary intake for optimal selenoprotein function and overall health.