What Amino Acid Does the UGA Codon Code For?

The genetic information that builds an organism is written in a four-letter alphabet, assembled into three-letter “words” called codons. The cell’s ribosome reads these codons along a messenger RNA (mRNA) molecule to assemble a chain of amino acids into proteins. The set of rules dictating which codon corresponds to which amino acid is the genetic code. While this code is highly consistent, certain codons have complex roles. The UGA codon, in particular, reveals the genetic code is more flexible than once thought.

The Canonical Role of the UGA Codon

In the standard genetic code, the UGA codon is one of three sequences, alongside UAA and UAG, that act as termination or “stop” signals. When the ribosome encounters a stop codon, it signals that the protein is complete. This termination process is mediated by specialized proteins called release factors. When a stop codon like UGA enters the ribosome’s active site, release factors bind to it. This binding triggers the cleavage of the newly synthesized protein from the final transfer RNA (tRNA), releasing the completed polypeptide chain.

The Exception to the Rule: Selenocysteine

The designation of UGA as a stop signal is not absolute. In an exception to the standard genetic code, this codon can direct the incorporation of an amino acid called selenocysteine (Sec). Often called the 21st proteinogenic amino acid, selenocysteine is an important building block of proteins. It is an analog of the more common amino acid cysteine, but with a selenium atom in place of the usual sulfur atom. This dual meaning depends on specific signals within the mRNA molecule, a reinterpretation process known as translational recoding.

The Molecular Switch for UGA Recoding

The cell’s ability to distinguish between UGA’s two roles hinges on a structural element within the mRNA molecule known as a Selenocysteine Insertion Sequence (SECIS) element. This element is a sequence of nucleotides that folds into a distinct hairpin-loop structure. Its location relative to the UGA codon differs between organisms, but its presence acts as a recruitment signal for specialized molecular machinery.

A unique elongation factor binds to both the SECIS structure and a specialized tRNA molecule carrying selenocysteine (Sec-tRNASec). This complex then delivers the selenocysteine to the ribosome. When the ribosome encounters the UGA codon, the SECIS-bound complex overrides the binding of termination factors, allowing the ribosome to insert selenocysteine. If the SECIS element is absent, the UGA codon is simply read as a stop signal and protein synthesis terminates.

The Significance of Selenoproteins

Proteins that incorporate selenocysteine residues are called selenoproteins. The properties of selenocysteine make it highly effective in enzymes involved in antioxidant defense and redox regulation. These proteins protect cells from damage caused by reactive oxygen species, which are byproducts of metabolism. Prominent examples include glutathione peroxidases, which neutralize harmful molecules, and thyroid hormone deiodinases, which activate hormones that regulate metabolism. The synthesis of these functional selenoproteins is dependent on the body’s supply of selenium, as translation terminates prematurely at the UGA codon without it.