l-2,3-Diaminopropionate Binding Mode of the SulM Adenylation Domain Limits Engineering Monobactam Analogue Biosynthesis with Larger Substrates DOI Creative Commons
Lukas Kahlert, Ketan D. Patel, Michael S. Lichstrahl

et al.

JACS Au, Journal Year: 2025, Volume and Issue: 5(4), P. 1992 - 2003

Published: April 16, 2025

The simple but essential azetidinone core of the β-lactam antibiotics is uniquely N-sulfonated in monobactam subfamily. This feature confers both target binding specificity to inactivate bacterial cell wall biosynthesis (antibiosis) and structural differentiation elude destruction by metallo-β-lactamases (MBLs). recent FDA approval Emblaveo treat serious infections combines an established synthetic aztreonam avibactam, which additionally blocks serine β-lactamases, create a broadly effective antibacterial therapeutic. Here we report experiments capture native biosynthetic steps natural product sulfazecin with aim accessing new monobactams reprogramming its machinery. In biosynthesis, ring formed nonribosomal peptide synthetase SulM that incorporates l-2,3-diaminopropionate (Dap), then trans efficiently cyclized fully elaborated unusual thioesterase (TE) domain. We describe improved synthesis (2S,3R)-vinylDap support rational structure-based engineering obtain corresponding (4R)-vinyl sulfazecin. While these were initially based on AlphaFold model adenylation domain Dap (SulM A3), further high-resolution X-ray crystal structures l-Dap substrate accurate analogue activated (3R)-methyl-Dap adenylate bound. ligand-bound rationalize inability SulA3 incorporate larger substrates. Comparisons other diamino acid-activating domains identify alternate modes may be more suitable for production analogues. impact relation recently structurally characterized SulTE are discussed.

Language: Английский

The Structural Basis of Substrate Selectivity of the Acinetobactin Biosynthetic Adenylation Domain, BasE DOI Creative Commons
Syed Fardin Ahmed, Andrew M. Gulick

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108413 - 108413

Published: March 1, 2025

Language: Английский

Citations

1
l-2,3-Diaminopropionate Binding Mode of the SulM Adenylation Domain Limits Engineering Monobactam Analogue Biosynthesis with Larger Substrates DOI Creative Commons
Lukas Kahlert, Ketan D. Patel, Michael S. Lichstrahl

et al.

JACS Au, Journal Year: 2025, Volume and Issue: 5(4), P. 1992 - 2003

Published: April 16, 2025

The simple but essential azetidinone core of the β-lactam antibiotics is uniquely N-sulfonated in monobactam subfamily. This feature confers both target binding specificity to inactivate bacterial cell wall biosynthesis (antibiosis) and structural differentiation elude destruction by metallo-β-lactamases (MBLs). recent FDA approval Emblaveo treat serious infections combines an established synthetic aztreonam avibactam, which additionally blocks serine β-lactamases, create a broadly effective antibacterial therapeutic. Here we report experiments capture native biosynthetic steps natural product sulfazecin with aim accessing new monobactams reprogramming its machinery. In biosynthesis, ring formed nonribosomal peptide synthetase SulM that incorporates l-2,3-diaminopropionate (Dap), then trans efficiently cyclized fully elaborated unusual thioesterase (TE) domain. We describe improved synthesis (2S,3R)-vinylDap support rational structure-based engineering obtain corresponding (4R)-vinyl sulfazecin. While these were initially based on AlphaFold model adenylation domain Dap (SulM A3), further high-resolution X-ray crystal structures l-Dap substrate accurate analogue activated (3R)-methyl-Dap adenylate bound. ligand-bound rationalize inability SulA3 incorporate larger substrates. Comparisons other diamino acid-activating domains identify alternate modes may be more suitable for production analogues. impact relation recently structurally characterized SulTE are discussed.

Language: Английский

Citations

0