Journal
NATURE
Volume 602, Issue 7896, Pages 343-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-04392-4
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [GM122595, GM119707, AI121072, GM080189]
- Eberly Family Distinguished Chair in Science
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- NIH [S10 OD012289]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- Howard Hughes Medical Institute
- Department of Energy Office of Science User Facility [DE-AC02-05CH11231]
- NIH, National Institute of General Medical Sciences [P30 GM124169]
Ask authors/readers for more resources
Carbapenems are potent and broad-spectrum antibiotics that are considered as the last line of defense in the clinic. Their vital role is highlighted in the treatment of hospital-acquired and ventilator-associated bacterial pneumonia during the COVID-19 pandemic. The unique C6 hydroxyethyl side chain distinguishes carbapenems from other beta-lactam antibiotics and protects them from inactivation by beta-lactamase. The construction of this side chain is mediated by cobalamin- or B-12-dependent radical S-adenosylmethionine (SAM) enzymes.
Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic(1). The C6 hydroxyethyl side chain distinguishes the clinically used carbapenems from the other classes of beta-lactam antibiotics and is responsible for their low susceptibility to inactivation by occluding water from the beta-lactamase active site(2). The construction of the C6 hydroxyethyl side chain is mediated by cobalamin- or B-12-dependent radical S-adenosylmethionine (SAM) enzymes(3). These radical SAM methylases (RSMTs) assemble the alkyl backbone by sequential methylation reactions, and thereby underlie the therapeutic usefulness of clinically used carbapenems. Here we present X-ray crystal structures of TokK, a B-12-dependent RSMT that catalyses three-sequential methylations during the biosynthesis of asparenomycin A. These structures, which contain the two metallocofactors of the enzyme and were determined in the presence and absence of a carbapenam substrate, provide a visualization of a B-12-dependent RSMT that uses the radical mechanism that is shared by most of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggest that substrate positioning governs the rate of each methylation event.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available