pyrrolysine

Pyrrolysine is a genetically encoded amino acid that represents the 22nd amino acid incorporated into proteins in a subset of organisms. It occurs in certain methanogenic archaea and a few bacteria, where the amber stop codon (UAG) is repurposed to specify pyrrolysine. Its incorporation relies on a dedicated translation system, including a specific tRNA (tRNA^Pyl) and the enzyme pyrrolysyl-tRNA synthetase (PylRS) that charges tRNA^Pyl with pyrrolysine.

Biosynthesis and decoding of pyrrolysine involve a pyl gene cluster that encodes enzymes PylB, PylC, and PylD, which convert a lysine-derived precursor into pyrrolysine. The charged tRNA^Pyl recognizes UAG as a sense codon, enabling the ribosome to insert pyrrolysine at designated positions rather than terminating translation. This system is largely orthogonal to the standard translation machinery.

Structure and properties: The side chain of pyrrolysine is a pyrroline-containing moiety linked to the lysine backbone, making it a bulky, unique residue distinct from the 20 canonical amino acids. Its chemical features enable specific catalytic or binding roles in certain enzymes.

Distribution and significance: Pyrrolysine is found in enzymes involved in methane metabolism, notably methylamine methyltransferases in Methanosarcina species. The natural reassignment of UAG to pyrrolysine is a notable example of genetic code expansion in nature, and the PylRS/tRNA^Pyl system has been adapted for genetic code expansion in laboratory settings to incorporate noncanonical amino acids.