1. Cyclodipeptide synthases, a family of class-I aminoacyl-tRNA synthetase-like enzymes involved in non-ribosomal peptide synthesis
- Author
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Yan Li, Muriel Gondry, Mireille Moutiez, Jean-Luc Pernodet, Ludovic Sauguet, Robert Thai, Matthieu Fonvielle, Jérôme Seguin, Cédric Masson, Marie-Hélène Le Du, Jean-Baptiste Charbonnier, Pascal Belin, Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Enzymologie et Biosynthèse Peptidique Non Ribosomale (BIOSYN), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de Bioénergétique, Biologie Stucturale, et Mécanismes (SB2SM), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Models, Molecular ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,MESH: Sequence Homology, Amino Acid ,MESH: Streptomyces ,MESH: Catalytic Domain ,MESH: Amino Acid Sequence ,RNA, Transfer, Amino Acyl ,01 natural sciences ,Peptide Synthases ,chemistry.chemical_compound ,MESH: Dipeptides ,Structural Biology ,Catalytic Domain ,MESH: Peptide Biosynthesis, Nucleic Acid-Independent ,Peptide synthesis ,Peptide bond ,Peptide sequence ,MESH: Bacterial Proteins ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,Crystallography ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,MESH: Crystallography ,Dipeptides ,MESH: Peptide Synthases ,Streptomyces ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Biochemistry ,Transfer RNA ,Peptide Biosynthesis, Nucleic Acid-Independent ,MESH: Biocatalysis ,MESH: Models, Molecular ,Molecular Sequence Data ,Biology ,Peptides, Cyclic ,Amino Acyl-tRNA Synthetases ,03 medical and health sciences ,Bacterial Proteins ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,MESH: RNA, Transfer, Amino Acyl ,Genetics ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Amino Acid Sequence ,Peptide Biosynthesis ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,MESH: Amino Acyl-tRNA Synthetases ,MESH: Peptides, Cyclic ,030304 developmental biology ,Binding Sites ,MESH: Molecular Sequence Data ,Sequence Homology, Amino Acid ,010405 organic chemistry ,Aminoacyl tRNA synthetase ,0104 chemical sciences ,chemistry ,MESH: Binding Sites ,Biocatalysis - Abstract
International audience; Cyclodipeptide synthases (CDPSs) belong to a newly defined family of enzymes that use aminoacyl-tRNAs (aa-tRNAs) as substrates to synthesize the two peptide bonds of various cyclodipeptides, which are the precursors of many natural products with noteworthy biological activities. Here, we describe the crystal structure of AlbC, a CDPS from Streptomyces noursei. The AlbC structure consists of a monomer containing a Rossmann-fold domain. Strikingly, it is highly similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs), especially class-Ic TyrRSs and TrpRSs. AlbC contains a deep pocket, highly conserved among CDPSs. Site-directed mutagenesis studies indicate that this pocket accommodates the aminoacyl moiety of the aa-tRNA substrate in a way similar to that used by TyrRSs to recognize their tyrosine substrates. These studies also suggest that the tRNA moiety of the aa-tRNA interacts with AlbC via at least one patch of basic residues, which is conserved among CDPSs but not present in class-Ic aaRSs. AlbC catalyses its two-substrate reaction via a ping-pong mechanism with a covalent intermediate in which L-Phe is shown to be transferred from Phe-tRNA(Phe) to an active serine. These findings provide insight into the molecular bases of the interactions between CDPSs and their aa-tRNAs substrates, and the catalytic mechanism used by CDPSs to achieve the non-ribosomal synthesis of cyclodipeptides.
- Published
- 2011