ArticleProceedings of the National Academy of Sciences of the United States of America2021
Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, ᴅ-amino acid, and dehydroamino acid synthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Structure of a stand-alone homodimeric nonribosomal peptide synthetase condensation domain reveals occlusion of the canonical carrier-protein interface.The Journal of biological chemistry · 2026Article
- Structure of a Stand-Alone Homodimeric NRPS Condensation Domain Reveals Occlusion of the Canonical Carrier-Protein Interface.bioRxiv : the preprint server for biology · 2026Article
- Complete genome sequence and mass spectrometry assist mining siderophore turnerbactin analogs in a non-modelFrontiers in microbiology · 2026Article
- Discovery of Fusadapamides, Accessory Chromosome-Associated Metabolites Incorporating l-2,3-Diaminopropionic Acid inJournal of natural products · 2025Article
- Mammalian Tolerance to Amino Acid Heterochirality.Chembiochem : a European journal of chemical biology · 2025Review
- Computational Insights into Amide Bond Formation Catalyzed by the Condensation Domain of Nonribosomal Peptide Synthetases.ACS omega · 2024Article
- PEARL-Catalyzed Peptide Bond Formation after Chain Reversal by Ureido-Forming Condensation Domains.ACS central science · 2024Article
- High-throughput reprogramming of an NRPS condensation domain.Nature chemical biology · 2024Article
- Identification of an Optimized Clinical Development Candidate from Cilagicin, an Antibiotic That Evades Resistance by Dual Polyprenyl Phosphate Binding.ACS infectious diseases · 2024Article
- TheiScience · 2024Article
- Controlling Substrate- and Stereospecificity of Condensation Domains in Nonribosomal Peptide Synthetases.ACS chemical biology · 2024Article
- Dehydroamino acid residues in bioactive natural products.Natural product reports · 2024Review
- Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases.Natural product reports · 2023Review
- Stereomeric Lipopeptides from a Single Non-Ribosomal Peptide Synthetase as an Additional Source of Structural and Functional Diversification inInternational journal of molecular sciences · 2023Article
- Tistrellabactins A and B Are PhotoreactiveJournal of natural products · 2023Article
- Knowledge-guided data mining on the standardized architecture of NRPS: Subtypes, novel motifs, and sequence entanglements.PLoS computational biology · 2023Article
- Biosynthesis of Lyngbyastatins 1 and 3, Cytotoxic Depsipeptides from anJournal of natural products · 2023Article
- Emulating nonribosomal peptides with ribosomal biosynthetic strategies.RSC chemical biology · 2023Review
- Structure modification of an antibiotic: by engineering the fusaricidin bio-synthetase A inFrontiers in microbiology · 2023Article
- Accurate Substrate-Like Probes for Trapping Late-Stage Intermediates in Nonribosomal Peptide Synthetase Condensation Domains.ACS chemical biology · 2022Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Nonribosomal peptide synthetases (NRPSs) are large, multidomain biosynthetic enzymes involved in the assembly-line-like synthesis of numerous peptide natural products. Among these are clinically useful antibiotics including three classes of β-lactams: the penicillins/cephalosporins, the monobactams, and the monocyclic nocardicins, as well as the vancomycin family of glycopeptides and the depsipeptide daptomycin. During NRPS synthesis, peptide bond formation is catalyzed by condensation (C) domains, which couple the nascent peptide with the next programmed amino acid of the sequence. A growing number of additional functions are linked to the activity of C domains. In the biosynthesis of the nocardicins, a specialized C domain prepares the embedded β-lactam ring from a serine residue. Here, we examine the evolutionary descent of this unique β-lactam-synthesizing C domain. Guided by its ancestry, we predict and demonstrate in vitro that this C domain alternatively performs peptide bond formation when a single stereochemical change is introduced into its peptide starting material. Remarkably, the function of the downstream thioesterase (TE) domain also changes. Natively, the TE directs C terminus epimerization prior to hydrolysis when the β-lactam is made but catalyzes immediate release of the alternative peptide. In addition, we investigate the roles of C-domain histidine residues in light of clade-specific sequence motifs, refining earlier mechanistic proposals of both β-lactam formation and canonical peptide synthesis. Finally, expanded phylogenetic analysis reveals unifying connections between β-lactam synthesis and allied C domains associated with the appearance of ᴅ-amino acid and dehydroamino acid residues in other NRPS-derived natural products.
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