Redesign of Substrate Selection in Glycopeptide Antibiotic Biosynthesis Enables Effective Formation of Alternate Peptide Backbones.

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.

Citation

Milda Kaniusaite, Tiia Kittilä, Robert J A Goode, Ralf B Schittenhelm, Max J Cryle. Redesign of Substrate Selection in Glycopeptide Antibiotic Biosynthesis Enables Effective Formation of Alternate Peptide Backbones. ACS chemical biology. 2020 Sep 18;15(9):2444-2455

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PMID: 32794694

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