Selenocysteine (21st amino acid)

Discovered in the late 1980s, selenocysteine broke the dogma that only 20 amino acids existed. Its synthesis is unique: it is not charged from a free selenocysteine but assembled directly on a dedicated tRNA (tRNA[Sec]) that recognizes the UGA codon. For the ribosome to read UGA as an amino acid rather than a stop signal, the selenoprotein mRNA carries a SECIS element (Selenocysteine Insertion Sequence) — a stem-loop in the 3' untranslated region — which, together with factors such as SBP2 and EFSec, recruits the recoding machinery.

The biochemical advantage of selenium is decisive: the selenol has a lower pKa than the thiol of cysteine, so at physiological pH it is ionized and more nucleophilic and reactive. This multiplies the catalytic efficiency of selenoproteins and, crucially, makes them resistant to the irreversible over-oxidation that inactivates cysteine-based enzymes.

In longevity this matters because selenocysteine-dependent selenoproteins — glutathione peroxidase (neutralizes peroxides), thioredoxin reductase (regenerates antioxidants), and GPX4 (restrains ferroptosis) — form a central line of defense against oxidative stress. Their synthesis is limited by dietary selenium supply, which links selenium status to endogenous antioxidant capacity.