Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules Journal Article
| Authors: | Cisar, J. S.; Ferreras, J. A.; Soni, R. K.; Quadri, L. E. N.; Tan, D. S. |
| Article Title: | Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules |
| Abstract: | Macrocyclic aminoacyl-AMP analogs have been developed to inhibit non-ribosomal peptide synthetase amino acid adenylation domains selectively by mimicking a cisoid ligand binding conformation observed in crystal structures. In contrast, these macrocycles do not inhibit aminoacyl-tRNA synthetases, which are mechanistically closely related, but bind their ligands in a distinct transoid conformation. The macrocycles contain a two- or three-carbon linker between Cβ of the amino acid moiety and C8 of the adenine ring and a sulfamate in place of the phosphate group. These compounds are potent inhibitors of the cysteine adenylation domain activity of the yersiniabactin siderophore synthetase HMWP2 and, unlike the corresponding linear aminoacyl-AMP analogs, do not inhibit protein translation in vitro. Selective small molecule inhibitors of non-ribosomal peptide synthesis should provide a powerful means to study the biological functions of non-ribosomal peptide natural products and a potential avenue to develop novel antibiotics. Copyright © 2007 American Chemical Society. |
| Keywords: | enzyme inhibition; ligand; ligands; amino acid; crystal structure; protein structure, tertiary; molecular structure; amino acids; conformation; ligand binding; macrocyclic compound; macrocyclic compounds; cross coupling reaction; adenylation; deprotection reaction; peptide synthase; peptide synthases |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 129 |
| Issue: | 25 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2007-06-27 |
| Start Page: | 7752 |
| End Page: | 7753 |
| Language: | English |
| DOI: | 10.1021/ja0721521 |
| PUBMED: | 17542590 |
| PROVIDER: | scopus |
| PMCID: | PMC2565600 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "CODEN: JACSA" - "Source: Scopus" |
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