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An Investigation into the Extended Coordination Network of Catalytic Zinc Ions in a Class B β‐lactamase
Author(s) -
Caruso Alessio,
Eberhardt Eric
Publication year - 2016
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/fasebj.30.1_supplement.605.2
Subject(s) - zinc , chemistry , antibiotics , asparagine , penicillin , catalysis , hydroxide , residue (chemistry) , enzyme , stereochemistry , microbiology and biotechnology , combinatorial chemistry , biochemistry , biology , inorganic chemistry , organic chemistry
Antibiotics have a long history as essential tools in fighting bacterial infections. The β‐lactam subgroup of antibiotics has been widely and successfully used since the identification of penicillin in the early 20th century. In recent years, β‐lactamases have been responsible for an alarming increase of bacterial resistance to many β‐lactam antibiotics. Our study gains insight into the mechanism of action of New Delhi Metallo β‐lactamase (NDM‐1 EC: 3.5.2.6) to facilitate the development of mechanism‐based inhibitors to metallo β‐lactamases. NDM1 is a dinuclear zinc‐containing enzyme that demonstrates higher catalytic efficiency than its mono‐zinc counterparts. High‐resolution crystal structures of NDM‐1 by Zhang and Hao reveal insight into the role zinc ions play in the formation of a catalytic hydroxide as well as additional stabilization of the leaving group. Our inquiry explores the role of a key residue of NDM‐1: in particular, Asp‐223 that may play a role in the extended coordination network of the catalytic metals. Asparagine and alanine mutants have been generated, and the steady‐state kinetic parameters are being evaluated.