NDM‐1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism

The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a...

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Bibliographic Details
Published in:The FASEB journal 2013-05, Vol.27 (5), p.1917-1927
Main Authors: Kim, Youngchang, Cunningham, Mark A., Mire, Joseph, Tesar, Christine, Sacchettini, James, Joachimiak, Andrzej
Format: Article
Language:English
Subjects:
antibiotic resistance
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Catalytic Domain
Humans
Hydrogen-Ion Concentration
Hydrolysis
Kinetics
Klebsiella pneumoniae - enzymology
metallo‐β‐lactamase
Metals - chemistry
Molecular Dynamics Simulation
pH dependence
Quantum Theory
Research Communications
Zinc - chemistry
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Summary:The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a new enzyme, first identified in Klebsiella pneumoniae from a patient from New Delhi and denoted as NDM‐1, represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known β‐lactam‐based antibiotics with startling efficiency. NDM‐1 can utilize different metal cofactors and seems to exploit an alternative mechanism based on the reaction conditions. Here we report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. We utilize structures obtained through X‐ray crystallography, biochemical assays, and numerical simulation to construct a model of the enzyme catalytic pathway. The NDM‐1 enzyme interacts with the substrate solely through zinc, or other metals, bound in the active site, explaining the observed lack of specificity against a broad range of β‐lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the β‐lactam ring through a proton shuttle.—Kim, Y., Cunningham, M. A.; Mire, J., Tesar, C., Sacchettini, J., Joachimiak, A. NDM‐1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism. FASEB J. 27, 1917–1927 (2013). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.12-224014