NDM‐1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism Academic Article uri icon

abstract

  • 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.

altmetric score

  • 0.5

author list (cited authors)

  • Kim, Y., Cunningham, M. A., Mire, J., Tesar, C., Sacchettini, J., & Joachimiak, A.

citation count

  • 74

complete list of authors

  • Kim, Youngchang||Cunningham, Mark A||Mire, Joseph||Tesar, Christine||Sacchettini, James||Joachimiak, Andrzej

publication date

  • January 2013

publisher