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oai:docta.ucm.es:20.500.14352/943212025-09-18T16:43:14Zcom_20.500.14352_14col_20.500.14352_15

Catalytic Mechanism of the Colistin Resistance Protein MCR-1 Suardíaz Delrío, Reynier Lythell, Emily Hinchliffe, Philip Van der Kamp, Marc Spencer, James Fey, Natalie Mulholland, Adrian Química 23 Química 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. Royal Society of Chemistry (Reino Unido) Biotechnology and Biological Sciences Research Council (Reino Unido) Engineering and Physical Sciences Research Council (Reino Unido) Medical Research Council (Reino Unido) Depto. de Química Física Fac. de Ciencias Químicas TRUE pub 2024-01-22T11:26:47Z 2024-01-22T11:26:47Z 2020 journal article VoR https://hdl.handle.net/20.500.14352/94321 1477-0520 10.1039/d0ob02566f eng R19-3409 R20-6912 EP/M013219/1 EP/M022609/1 MR/P007295/1 MR/T016035/1 BB/J014400/1 BB/M026280/1 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. Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ open access application/pdf Royal Society of Chemistry