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NDM‐1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism
Author(s) -
Kim Youngchang,
Cunningham Mark A.,
Mire Joseph,
Tesar Christine,
Sacchettini James,
Joachimiak Andrzej
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-224014
Subject(s) - enzyme , chemistry , substrate (aquarium) , active site , antibiotics , klebsiella pneumoniae , combinatorial chemistry , stereochemistry , biochemistry , biology , escherichia coli , gene , ecology
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