Cyclodipeptide synthases : towards understanding their catalytic mechanism and the molecular bases of their specificity

• Main Author: Li, Yan
• Language: ENG
• Published: Université Paris Sud - Paris XI 2012
• Subjects: [SDV:SA] Life Sciences/Agricultural sciences; [SDV:SA] Sciences du Vivant/Sciences agricoles; [SDV:MHEP] Life Sciences/Human health and pathology; [SDV:MHEP] Sciences du Vivant/Médecine humaine et pathologie; Cyclodipeptide synthase (CDPS); Diketopiperazine (DKP); Nonribosomal biosynthesis; Peptide bond; Aminoacyl-tRNA; Secondary metabolite
• Online Access: http://tel.archives-ouvertes.fr/tel-00868787; http://tel.archives-ouvertes.fr/docs/00/86/87/87/PDF/VA_LI_-_Yan_26092012.pdf; http://tel.archives-ouvertes.fr/docs/00/86/87/87/ANNEX/VA_Li_Yan_26092012_annexe-1.pdf

Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of secondary metabolites with noteworthy biological activities that are mainly synthesized by microorganisms. The biosynthetic pathways of some DKPs contain cyclodipeptide synthases (CDPSs), a newly defined family of enzymes. CDPSs hijack aminoacyl-tRNAs from their essential role in ribosomal protein synthesis to catalyze the formation of the two peptide bonds of various cyclodipeptides. The aim of the work presented in this thesis manuscript is to characterize the CDPS family. At first, the structural and mechanistic characterization of the first identified CDPS, AlbC of Streptomyces noursei, is presented. Then, the results obtained with three other CDPSs, each of which having suitable properties to increase our understanding of the CDPS family, are described. The CDPS Ndas_1148 of Nocardiopsis dassonvillei extends our knowledge of the molecular bases of the CDPS specificity. The CDPS AlbC-IMI of S. sp. IMI 351155 is a good model to analyze the interaction of each of the two substrates required for the formation of a cyclodipeptide. Finally, the characterization of the CDPS Nvec-CDPS2 from Nematostella vectensis provides the first example of enzymes of animal origin involved in nonribosomal peptide synthesis.