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Amino acid-loaded transfer RNAs, best known for delivering amino acids for protein synthesis, play a role in secondary metabolism of some microorganisms, French researchers report (Nat. Chem. Biol., DOI: 10.1038/nchembio.175).
Jean-Luc Pernodet of the National Center for Scientific Research and the University of Paris South, in Orsay; Muriel Gondry of the Atomic Energy Commission, in Gif-sur-Yvette; and coworkers find that a family of enzymes called cyclodipeptide synthases surprisingly use aminoacylated tRNAs as their substrates to make cyclodipeptides.
The study "opens the way for the rational engineering of the diketopiperazine biosynthetic pathway" to make useful new compounds, comments Wolfgang Maison, an organic chemistry professor at the University of Giessen, in Germany. Cyclodipeptides, which act as scaffolds for the assembly of other natural products, belong to the family of diketopiperazines.
Cyclodipeptides are usually made with large, modular, multifunctional enzymes called nonribosomal peptide synthetases. In 2002, Pernodet, Gondry, and coworkers showed that the bacterium Streptomyces noursei makes cyclo(L-phenylalanine-L-leucine), the precursor to the antibiotic dipeptide albonoursin, using a 239-residue enzyme not related to nonribosomal peptide synthetases. The enzyme, called AlbC, catalyzes the formation of two peptide bonds despite not having an adenosine triphosphate-binding site, necessary to activate amino acids.
The researchers now find that AlbC uses tRNAs already loaded with activated amino acids in the reaction. "Now, it seems logical to think that they were using already-activated amino acids," Pernodet says, "but it came as quite a surprise to us."
Searching through DNA sequences, they found eight proteins in other microorganisms that also catalyze the synthesis of cyclodipeptides. Gondry's group reports that one of these proteins, made by Mycobacterium tuberculosis, catalyzes the synthesis of a cyclodipeptide that is the substrate for a cytochrome P450 essential for the mycobacterium's survival (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0812191106).
The researchers want to find out how widespread this family of enzymes is. "We are wondering if some enzymes from this family could be present in eukaryotes, because in some cases you also have the production of cyclodipeptides in yeast or other eukaryotes," Pernodet says.
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