Dodging the Central Dogma of Molecular Biology

Hopefully, you’re perplexed, because the Central Dogma of Molecular Biology implies that all peptides must be encoded by the genome. Nobel laureate Edward Tatum was just as confused, and in 1963, he devised an ingenious experiment.

Protein translation

Protein translation is carried out by a molecular machine called a ribosome, and so Tatum reasoned that if he inhibited the ribosome, all protein production in Bacillus brevis should grind to a halt. To his amazement, all proteins did indeed shut down — except for tyrocidines and gramicidins! His experiment led Tatum to hypothesize that some yet unknown non-ribosomal mechanism must assemble these peptides.

In 1969, Fritz Lipmann (another Nobel laureate) demonstrated that tyrocidines and gramicidins are non-ribosomal peptides (NRPs), synthesized not by the ribosome, but by a giant protein called NRP synthetase. This enzyme pieces together antibiotic peptides without any reliance on RNA or the genetic code! We now know that every NRP synthetase assembles peptides by growing them one amino acid at a time, as shown in the figure below.