4.6 Article

Use of ferrous iron by metallo-β-lactamases

期刊

JOURNAL OF INORGANIC BIOCHEMISTRY
卷 163, 期 -, 页码 185-193

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2016.07.013

关键词

Antibiotic resistance; beta-Lactam antibiotics; Metallo-beta-lactamase; Zinc hydrolase; Metalloenzyme; Carbapenem

资金

  1. Biotechnology and Biological Sciences Research Council [BB/J014427/1]
  2. Medical Research Council/Canadian [G1100135]
  3. MRC [MR/L007665/1] Funding Source: UKRI
  4. Biotechnology and Biological Sciences Research Council [1360493] Funding Source: researchfish
  5. Cancer Research UK [16466] Funding Source: researchfish
  6. Medical Research Council [MR/L007665/1] Funding Source: researchfish

向作者/读者索取更多资源

Metallo-beta-lactamases (MBLs) catalyse the hydrolysis of almost all beta-lactam antibacterials including the latest generation carbapenems and are a growing worldwide clinical problem. It is proposed that MBLs employ one or two zinc ion cofactors in vivo. Isolated MBLs are reported to use transition metal ions other than zinc, including copper, cadmium and manganese, with iron ions being a notable exception. We report kinetic and biophysical studies with the di-iron(II)-substituted metallo-beta-lactamase II from Bacillus cereus (di-Fe(II) BcII) and the clinically relevant Bl subclass Verona integron-encoded metallo-p-lactamase 2 (di-Fe(II) VIM-2). The results reveal that MBLs can employ ferrous iron in catalysis, but with altered kinetic and inhibition profiles compared to the zinc enzymes. A crystal structure of di-Fe(11) BcII reveals only small overall changes in the active site compared to the di-Zn(II) enzyme including retention of the di-metal bridging water; however, the positions of the metal ions are altered in the di-Fe(II) compared to the di-Zn(II) structure. Stopped-flow analyses reveal that the mechanism of nitrocefin hydrolysis by both di-Fe(II) BcII and di-Fe(II) VIM-2 is altered compared to the diZn(Il) enzymes. Notably, given that the MBLs are the subject of current medicinal chemistry efforts, the results raise the possibility the Fe(II)-substituted MBLs may be of clinical relevance under conditions of low zinc availability, and reveal potential variation in inhibitor activity against the differently metallated MBLs. (C) 2016 The Authors. Published by Elsevier Inc.

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