Precursor Manipulation in Glycopeptide Antibiotic Biosynthesis: Are β-Amino Acids Compatible with the Oxidative Cyclization Cascade?
- Melanie Schoppet
Melanie SchoppetEMBL Australia and The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, GermanyMore by Melanie Schoppet
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- Julien Tailhades
Julien TailhadesEMBL Australia and The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, AustraliaMore by Julien Tailhades
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- Ketav Kulkarni
Ketav KulkarniThe Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, AustraliaMore by Ketav Kulkarni
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- Max J. Cryle*
Max J. Cryle*E-mail: [email protected]EMBL Australia and The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, GermanyMore by Max J. Cryle
Abstract
Natural products such as the glycopeptide antibiotics (GPAs, including vancomycin and teicoplanin) are of great pharmaceutical importance due to their use against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus. GPAs are assembled in a complex process based on nonribosomal peptide synthesis and late-stage, multistep cross-linking of the linear heptapeptide performed by cytochrome P450 monooxygenases. These P450 enzymes demonstrate varying degrees of substrate selectivity toward the linear peptide precursor, with limited information available about their tolerance regarding modifications to amino acid residues within the essential antibiotic core of the GPA. In order to test the acceptance of altered residues by the P450-catalyzed cyclization cascade, we have explored the use of β-amino acids in both variable and highly conserved positions within GPA peptides. Our results indicate that the incorporation of β-amino acids at the C-terminus of the peptide leads to a dramatic reduction in the efficiency of peptide cyclization by the P450s during GPA biosynthesis, whereas replacement of residue 3 is well tolerated by the same enzymes. These results show that maintaining the C-terminal 3,5-dihydroxyphenylglycine residue is of key importance to maintain the efficiency of this complex and essential enzymatic cross-linking process.
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This article is cited by 12 publications.
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- Mohammad Movassaghi, (Guest Editor), Wilfred A. van der Donk (Guest Editor). Synthesis of Antibiotics and Related Molecules. The Journal of Organic Chemistry 2018, 83 (13) , 6826-6828. https://doi.org/10.1021/acs.joc.8b01330
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- Y. T. Candace Ho, Ralf B. Schittenhelm, Dumitrita Iftime, Evi Stegmann, Julien Tailhades, Max J. Cryle. Exploring the Flexibility of the Glycopeptide Antibiotic Crosslinking Cascade for Extended Peptide Backbones. ChemBioChem 2023, 24 (6) https://doi.org/10.1002/cbic.202200686
- Y. T. Candace Ho, Yongwei Zhao, Julien Tailhades, Max J. Cryle. A Chemoenzymatic Approach to Investigate Cytochrome P450 Cross-Linking in Glycopeptide Antibiotic Biosynthesis. 2023, 187-206. https://doi.org/10.1007/978-1-0716-3214-7_9
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- Yongwei Zhao, Y. T. Candace Ho, Julien Tailhades, Max Cryle. Understanding the Glycopeptide Antibiotic Crosslinking Cascade: In Vitro Approaches Reveal the Details of a Complex Biosynthesis Pathway. ChemBioChem 2021, 22 (1) , 43-51. https://doi.org/10.1002/cbic.202000309
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