Cyclodipeptides and biosynthesis
Cyclic dipeptides, or cyclodipeptides, are small, highly stable molecules primarily synthesized by microorganisms. They exhibit a wide range of biological activities of interest for drug development, including antibacterial, antifungal, antiviral, and anticancer properties.
In bacteria, the first step of their synthesis is catalyzed by cyclodipeptide synthases (CDPS). These enzymes sequentially use two amino acid substrates charged on transfer RNA (AA-tRNA) to catalyze the formation of cyclodipeptides. The reaction proceeds through the formation of successive aminoacyl-enzyme and dipeptidyl-enzyme intermediates.
Analogs and structures
In a study published in Nucleic Acids Research, the "Enzymology and non ribosomal peptide biosynthesis " team, in collaboration with the "Nuclear envelope, Telomeres and DNA repair " team (I2BC) and the ICSN (Gif-sur-Yvette), generated a series of CDPS substrate analogs. These analogs combine an amino acid linked to a microhelix mimicking the acceptor arm of a tRNA. The researchers analyzed their interactions with the CDPS from Nocardia brasiliensis, which synthesizes an alanine-glutamate cyclodipeptide, and measured the catalytic activity of this CDPS for several of these analogs. Additionally, they determined the three-dimensional structure of the CDPS in interaction with three analogs of either the first or second substrate.
Their results reveal that both substrates adopt nearly the same binding mode within the active site of the CDPS, despite differences in their sequences.
Furthermore, the study demonstrates that these microhelices are versatile tools for studying the function of CDPS and, more broadly, that of other enzymes dependent on aminoacylated tRNAs.
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