In Gavin's class we discussed the mechanism and promiscuity of the thioesterase domain from tyrocidine A biosynthesis. Chris suggested that only N-terminal D-Phe and Orn amino acid residues are important for cyclization activity of TycC because it might be that only these residues are accommodated into the active site of the TycC, with the rest of the polypeptide chain looping out of the enzyme. This review paper provides some insights into the mechanism of TE-catalized macrocyclization. Based on crystal structure solved for SrfTE, it has been determined that only two Leu residues were important for cyclization, with the rest of the peptide sequence less well coordinated. This agrees with what Chris suggested and explains the promiscuity of these NRPSs.Friday, October 7, 2011
Learning from Nature's Drug Factories: Nonribosomal Synthesis of Macrocyclic Peptides
In Gavin's class we discussed the mechanism and promiscuity of the thioesterase domain from tyrocidine A biosynthesis. Chris suggested that only N-terminal D-Phe and Orn amino acid residues are important for cyclization activity of TycC because it might be that only these residues are accommodated into the active site of the TycC, with the rest of the polypeptide chain looping out of the enzyme. This review paper provides some insights into the mechanism of TE-catalized macrocyclization. Based on crystal structure solved for SrfTE, it has been determined that only two Leu residues were important for cyclization, with the rest of the peptide sequence less well coordinated. This agrees with what Chris suggested and explains the promiscuity of these NRPSs.
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Sweet! It would be cool if one of these enzymes could be evolved to cyclize lots of different peptides or non peptides as long as the end terminal recognition peptides were present. It would be more promiscuous than the enzyme we discussed in class.
ReplyDeleteThat would allow for a large number of macrocycles to be produced and even be screened for antibiotic activity.
Chris, I have thought about this too. Marahiel reported a FRET based screen for evolving a TE domain in Chemistry & Biology a few years ago, but it was never used in an actual directed evolution experiment...
ReplyDeleteIrina, thanks for posting nice review article. Perhaps you could post the original article which describes the structural studies you are referring too?
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