RT Journal Article
T1 Catalytic Mechanism of the Colistin Resistance Protein MCR-1
A1 Suardíaz Delrío, Reynier
A1 Lythell, Emily
A1 Hinchliffe, Philip
A1 Van der Kamp, Marc
A1 Spencer, James
A1 Fey, Natalie
A1 Mulholland, Adrian
AB The mcr-1 gene encodes a membrane-bound Zn2+-metalloenzyme, MCR-1, which catalyses phosphoethanolamine transfer onto bacterial lipid A, making bacteria resistant to colistin, a last-resort antibiotic. Mechanistic understanding of this process remains incomplete. Here, we investigate possible catalytic pathways using DFT and ab initio calculations on cluster models and identify a complete two-step reaction mechanism. The first step, formation of a covalent phosphointermediate via transfer of phosphoethanolamine from a membrane phospholipid donor to the acceptor Thr285, is rate-limiting and proceeds with a single Zn2+ ion. The second step, transfer of the phosphoethanolamine group to lipid A, requires an additional Zn2+. The calculations suggest the involvement of the Zn2+ orbitals directly in the reaction is limited, with the second Zn2+ acting to bind incoming lipid A and direct phosphoethanolamine addition. The new level of mechanistic detail obtained here, which distinguishes these enzymes from other phosphotransferases, will aid in the development of inhibitors specific to MCR-1 and related bacterial phosphoethanolamine transferases.
PB Royal Society of Chemistry
SN 1477-0520
YR 2020
FD 2020
LK https://hdl.handle.net/20.500.14352/94321
UL https://hdl.handle.net/20.500.14352/94321
LA eng
NO Suardíaz, Reynier, et al. «Catalytic Mechanism of the Colistin Resistance Protein MCR-1». Organic & Biomolecular Chemistry, vol. 19, n.o 17, 2021, pp. 3813-19. https://doi.org/10.1039/D0OB02566F.
NO Royal Society of Chemistry (Reino Unido)
NO Biotechnology and Biological Sciences Research Council (Reino Unido)
NO Engineering and Physical Sciences Research Council (Reino Unido)
NO Medical Research Council (Reino Unido)
DS Docta Complutense
RD 9 abr 2025