Open AccessEvolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, ᴅ-amino acid, and dehydroamino acid synthesis
Author(s) -
Michael J. Wheadon,
Craig A. Townsend
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2026017118
Subject(s) - nonribosomal peptide , peptide , stereochemistry , chemistry , lactam , peptide sequence , biosynthesis , amino acid , biochemistry , biology , enzyme , gene
Significance By applying phylogenetic tools, we infer the ancestral origins of a nonribosomal peptide synthetase (NRPS) condensation (C) domain responsible for β-lactam (antibiotic) synthesis. Subsequent in vitro experiments suggest a mechanism for how this unique synthetic function likely evolved. β-Lactam synthesizing ability appears to have emerged along with an adjacent epimerization (E) domain deletion and in parallel with other C domains whose catalysis presumably share intermediates with β-lactam synthesis, including ᴅ-amino acid and dehydroamino acid synthesis. The implied mechanistic link between β-lactam formation and the latter two C-domain functions can be experimentally tested in the future to discern how evolutionary differences dictate synthetic outcome. These insights may constructively guide protein engineering efforts to introduce potentially valuable structural elements into NPRS products.