Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.


Issue 10, 2014
Previous Article Next Article

Exploring the substrate promiscuity of an antibiotic inactivating enzyme

Author affiliations

Abstract

Peptide–nucleotide conjugates have been extensively studied as scaffolds for the development of new antibiotics. However, in vivo, the efficacy of such compounds is limited by various detoxicants, such as aminoacyl-nucleotide hydrolase MccF. MccF cleaves the amide bond between amino acid and phosphoramine–adenylate of the aspartyl tRNA synthetase inhibitor microcin C7, providing self-immunity to the producing strains. However, MccF orthologs are also found in strains that do not produce microcin C7, suggesting a broader role in detoxification. Here, we demonstrate that MccF has no specificity for the nucleotide moiety of the antibiotic and can accept amino acids linked to any purine nucleobase as substrates. Biochemical characterization of synthetic substrate analogs and the co-crystal structure of these compounds with MccF provide a rationale for understanding this promiscuity. These findings have implications for the design of antibiotics that can avert MccF-mediated inactivation and for understanding the function of homologs that may play roles in the metabolism of other cellular intermediates.

Graphical abstract: Exploring the substrate promiscuity of an antibiotic inactivating enzyme

Back to tab navigation

Supplementary files

Article information


Submitted
08 May 2014
Accepted
28 Jul 2014
First published
30 Jul 2014

Med. Chem. Commun., 2014,5, 1567-1570
Article type
Concise Article
Author version available

Exploring the substrate promiscuity of an antibiotic inactivating enzyme

V. Agarwal, G. Vondenhoff, B. Gadakh, K. Severinov, A. Van Aerschot and S. K. Nair, Med. Chem. Commun., 2014, 5, 1567
DOI: 10.1039/C4MD00204K

Search articles by author

Spotlight

Advertisements