A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.079 Immunity
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: Article No. eaas8667 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260240
• Chủ đề: 1. 60 applied life sciences; 2. Science & technology - other topics

Tóm tắt

One group of enzymes that confer resistance to aminoglycoside antibiotics through covalent modification belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily. We show how a unique GNAT subfamily member uses a previously unidentified noncanonical catalytic triad, consisting of a glutamic acid, a histidine, and the antibiotic substrate itself, which acts as a nucleophile and attacks the acetyl donor molecule. Neutron diffraction studies allow for unambiguous identification of a low-barrier hydrogen bond, predicted in canonical catalytic triads to increase basicity of the histidine. This work highlights the role of this unique catalytic triad in mediating antibiotic resistance while providing new insights into the design of the next generation of aminoglycosides.