ArticleOrganic & biomolecular chemistry2021
Catalytic mechanism of the colistin resistance protein MCR-1.
Article in Organic & biomolecular chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Methods for the establishment of enzymatic mechanisms - from QM to ML.Chemical science · 2026Review
- Adaptive colistin resistance dynamics inMicrobiology spectrum · 2026Article
- mcr gene family evolution and structural mechanisms of colistin resistance: from mcr-1 to emerging variants.Archives of microbiology · 2026Review
- Solvent Channels and Electric Fields Guide Proton Delivery to the Active Site of Heme Peroxidases.Angewandte Chemie (International ed. in English) · 2025Article
- Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1.Nature communications · 2025Article
- Dynamic Behavior and Substrate Interactions of the Polymyxin Resistance Determinant MCR-1 Investigated by Molecular Dynamics Simulations in the Membrane Environment.Journal of chemical information and modeling · 2025Article
- The multifaceted roles of phosphoethanolamine-modified lipopolysaccharides: from stress response and virulence to cationic antimicrobial resistance.Microbiology and molecular biology reviews : MMBR · 2024Review
- Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions.The Biochemical journal · 2024Article
- Bacteria carrying mobile colistin resistance genes and their control measures, an updated review.Archives of microbiology · 2024Review
- Structure-based targeting of the lipid A-modifying enzyme PmrC to contrast colistin resistance inFrontiers in microbiology · 2024Article
- Structural biology of MCR-1-mediated resistance to polymyxin antibiotics.Current opinion in structural biology · 2023Review
- Phosphoethanolamine Transferases as Drug Discovery Targets for Therapeutic Treatment of Multi-Drug Resistant Pathogenic Gram-Negative Bacteria.Antibiotics (Basel, Switzerland) · 2023Review
- Tautomer-Specific Deacylation and Ω-Loop Flexibility Explain the Carbapenem-Hydrolyzing Broad-Spectrum Activity of the KPC-2 β-Lactamase.Journal of the American Chemical Society · 2023Article
- Computational Study Reveals the Role of Water Molecules in the Inhibition Mechanism of LAT1 by 1,2,3-Dithiazoles.Journal of chemical information and modeling · 2021Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
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.
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