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Redesign of substrate selection in glycopeptide antibiotic biosynthesis enables effective formation of alternate peptide backbones

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Kittilä,  Tiia
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Kaniusaite, M., Kittilä, T., Goode, R. J. A., Schittenhelm, R. B., & Cryle, M. J. (2020). Redesign of substrate selection in glycopeptide antibiotic biosynthesis enables effective formation of alternate peptide backbones. ACS Chemical Biology, 15(9), 2444-2455. doi:10.1021/acschembio.0c00435.


Cite as: http://hdl.handle.net/21.11116/0000-0006-DF8E-0
Abstract
Nonribosomal peptide synthesis is capable of utilizing a wide range of amino acid residues due to the selectivity of adenylation (A)-domains. Changing the selectivity of A-domains could lead to new bioactive nonribosomal peptides, although remodeling efforts of A-domains are often unsuccessful. Here, we explored and successfully reengineered the specificity of the module 3 A-domain from glycopeptide antibiotic biosynthesis to change the incorporation of 3,5-dihydroxyphenylglycine into 4-hydroxyphenylglycine. These engineered A-domains remain selective in a functioning peptide assembly line even under substrate competition conditions and indicate a possible application of these for the future redesign of GPA biosynthesis.