The complete biosynthesis of the genetically encoded amino acid pyrrolysine from lysine

Biosynthesis of the twenty-second amino acid Pyrrolysine, the latest addition to the ranks of the genetically encoded amino acids, is found in methanogenic archaea and bacteria, in which it is a necessary component of the enzymes involved in the formation of methane from methylamines. Its biosynthetic pathway remains poorly characterized. Joseph Krzycki and colleagues now show that lysine is the sole precursor for the pyrrolysine synthesis system of Methanosarcina sp. Archaea. The radical S-adenosyl-L-methionine protein PylB converts lysine to 3-methylornithine, which then undergoes a PylC-catalysed condensation with a second lysine to generate a product that is oxidized by PylD to generate pyrrolysine. The authors suggest that synthetic analogues of intermediates in this pathway may provide useful pyrrolysine derivatives that could be incorporated into tailored recombinant proteins.