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Editing of non-cognate aminoacyl adenylates by peptide synthetases

, : Editing of non-cognate aminoacyl adenylates by peptide synthetases. Biochemical Journal 342 Pt 3: 715-719

Non-ribosomally formed peptides display both highly conserved and variable amino acid positions, the variations leading to a wide range of peptide families. Activation of the amino acid substrate proceeds in analogy to the ribosomal biosynthetic mechanism generating aminoacyl adenylate and acyl intermediates. To approach the mechanism of fidelity of amino acid selection, the stability of the aminoacyl adenylates was studied by employing a continuous coupled spectrophotometric assay. The apo-form of tyrocidine synthetase 1 (apo-TY1) was used, generating an L-phenylalanyl-adenylate intermediate stabilized by the interaction of two structural subdomains of the adenylation domain. Adenylates of substrate analogues have shown variable and reduced degrees of stability, thus leading to an enhanced generation of pyrophosphate due to hydrolysis and continuous adenylate formation. Discrimination of the non-aromatic amino acids L-Leu and L-Met, or L-Phe analogues such as p-amino- and p-chloro-L-Phe derivatives, as well as the stereospecific selection of L-Phe, is supported by less-stable adenylate intermediates exhibiting elevated susceptibility to hydrolysis. Breakdown of the L-phenylalanyl intermediate utilizing 2'-deoxy-ATP as the nucleotide substrate was significantly enhanced compared with the natural analogue. Apo-TY1 engineered at positions involved in adenylate formation showed variable protection against hydrolysis. The results imply that stability of the aminoacyl intermediates may act as an essential factor in substrate selection and fidelity of non-ribosomal-peptide-forming systems.


PMID: 10477284

DOI: 10.1042/0264-6021:3420715

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