Structural highlights
Function[BLAN1_KLEPN] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. Publication Abstract from PubMedThe 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 beta-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 beta-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the beta-lactam ring through a proton shuttle. NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism.,Kim Y, Cunningham MA, Mire J, Tesar C, Sacchettini J, Joachimiak A FASEB J. 2013 May;27(5):1917-27. doi: 10.1096/fj.12-224014. Epub 2013 Jan 30. PMID:23363572[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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