Lesson 4.3
Dodging the Central Dogma of Molecular Biology
Hopefully, you are 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 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.
Figure: NRP synthetase is a giant multi-module protein that assembles a cyclic peptide in steps, one amino acid at a time. Each of ten different modules (shown by different colors) adds a single amino acid to the peptide, which in the figure is one of many tyrocidines produced by Bacilus brevis. In a final step, the peptide is circularized.
The reason why many NRPs have pharmaceutical applications is that they have been optimized by eons of evolution as "molecular bullets" that bacteria and fungi use to kill their enemies. If these enemies happen to be pathogens, researchers are eager to borrow these bullets as antibacterial drugs. However, NRPs are not limited to antibiotics: many of them represent anti-tumor agents and immunosuppressors, while others are used by bacteria to communicate with other cells. For more details, see "DETOUR: Quorum Sensing" in the print companion or at Cogniterra.