Oral Presentation 13th Australian Peptide Conference 2019

Mechanisms of nonribosomal peptide diversification  (#32)

Gregory Challis 1 2
  1. Department of Chemistry, University of Warwick, Coventry, UK
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

Nonribosomal peptide synthetases (NRPSs) assemble a remarkably diverse array of peptide-based natural products. Several different strategies are employed by Nature for nonribosomal peptide diversification, including the biosynthesis and incorporation of non-proteinogenic amino acids, conjugation with fatty acid and polyketide chains, promiscuous NRPS subunit recognition, and a various on- and post-NRPS modifying enzymes. In this lecture, I will describe efforts to understand diversification mechanisms in the biosynthesis of several unusual nonribosomal peptides, including the EPA-approved herbicide thaxtomin A,1,2 the epoxyketone proteasome inhibitors TMC-86A and eponemycin,3 FR-901375 and related histone deactylase inhibitors, and icosalide A1.4 

  1. S.M. Barry, J.A. Kers, E.G. Johnson, L. Song, P.R. Aston, B. Patel, S.B. Krasnoff, B.R. Crane, D.M. Gibson, R. Loria and G.L. Challis. Cytochrome P450–catalyzed L-tryptophan nitration in thaxtomin phytotoxin biosynthesis. Nat. Chem. Biol. 2012, 8, 814-816.
  2. L.M. Alkhalaf, S.M. Barry, D. Rea, A. Gallo, D. Griffths, J.R. Lewandoswki, V. Fulop and G.L. Challis. Binding of distinct substrate conformations enables hydroxylation of remote sites in thaxtomin D by cytochrome P450 TxtC. J. Am. Chem. Soc. 2019, 141, 216-222.
  3. D. Zabala, J.W. Cartwright, D.M. Roberts, B.J.C. Law, L. Song, M. Samborskyy, P.F. Leadlay, J. Micklefield, and G.L. Challis. A flavin-dependent decarboxylase-dehydrogenase-monooxygenase assembles the warhead of α, β-epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 2016, 138, 4342-4345.
  4. M. Jenner, X. Jian, Y. Dashti, J. Masschelein, C. Hobson, D. Roberts, C. Jones, S. Harris, J. Parkhill, H. Raja, N. Oberlies, C. Pearce, E. Mahenthiralingam and G.L. Challis. An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles ‘fungal’ icosalide antibiotics. Chem. Sci. 2019, 10, 5489-5494.