Professor Ken Houk has collaborated with the Professor Martin Schmeing (McGill University) group to reveal a novel mechanism for peptide biosynthesis. In an accelerated publication in Nature, the Schmeing group’s crystal structures and the Houk group’s computations are reported that explain how a critical step occurs in the biosynthesis of the antibiotic peptide, gramicidin.
Non-ribosomal peptide synthases (NRPS) are mega-enzymes that biosynthesize many chemically important natural products, from penicillin through vancomycin and beyond. The key amide bond formation between aminoacyl units has been studied previously by some of the greats of enzymology, with various controversies about details of the mechanism. Through a masterpiece of substrate engineering and crystallography, the Schmeing group produced a 3D picture of the enzyme C of the mega-enzyme with bound substrate analogs (see Figure) and also the product.
Houk’s calculations, with postdoc Pengchen Ma, who is now at Xi’an Jiaotong University, showed how the reaction happens, and produced a 3D view of the transition state. Surprisingly, the amide formation is concerted, with the histidine 908 that could serve as base acting instead to stabilize the developing ammonium formed from the attacking nucleophilic amine. The concerted mechanism occurs instead of the more usual stepwise mechanism involving in a tetrahedral intermediate. The results are being employed for further engineering of peptide-linking enzymes.
Contact: Professor Ken Houk, UCLA Department of Chemistry & Biochemistry, houk@chem.ucla.edu
