Pyrrolysine

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Pyrrolysine is a naturally-occurring genetically-coded amino acid used by some methanogenic archaea in enzymes that are part of their methane-producing metabolism. Its structure is N6-[(2R,3R)-3-methyl-3,4-dihydro-2H-pyrrol-2-ylcarbonyl]-L-lysine.

Ball-and-stick model of pyrrolysine

This lysine derivative is encoded by the UAG codon (normally the 'amber' stop codon), possibly modified by the presence of a specific downstream sequence, named PYLIS, which forms a stem-loop in the mRNA, forcing the incorporation of pyrrolysine instead of terminating translation. It is also of interest to note that UAG appears to be used much less often than other stop codons and whenever it is found in an open reading frame it is always followed by one or more of the other two stop codons shortly after.

Near a methyltransferase gene cluster of Methanosarcina barkeri is the pylT gene, which encodes an unusual transfer RNA (tRNA) with a CUA anticodon. The adjacent pylS gene encodes a class II aminoacyl-tRNA synthetase that charges the pylT-derived tRNA with pyrrolysine. The operon containing pylT and pylS are also found in the genomes of other sequenced members of the Methanosarcinaceae family. Homologs of pylS and pylT are found in a Gram-positive bacterium, Desulfitobacterium hafniense, although the function of these putative genes in this organism is unknown. It was initially shown that pylT encoded tRNA (CUA) can be charged with lysine by PylS. Recently, it has been shown that the tRNA(CUA) can be charged with lysine in vitro by the concerted action of the M. barkeri Class I and Class II Lysyl-tRNA synthetases. Charging a tRNA(CUA) with lysine was originally hypothesized to be the first step in translating UAG amber codons as pyrrolysine in certain methanogens. The current model based on in vitro and in vivo data favors direct charging of pyrrolysine on to the tRNA(CUA) by the protein product of the pylS gene. This makes Pyrrolysine the 22nd genetically encoded natural amino acid. The mechanism of encoding makes it the 21st natural directly encoded amino acid.

The joint nomenclature committee of the IUPAC/IUBMB has officially recommended the three-letter symbol Pyl and the one-letter symbol O for pyrrolysine.