MCR-1 is the first plasmid-borne (transferable) determinant of colistin (polymyxin) resistance, reported from Enterobacteriaceae in China in 2015. It is a phosphoethanolamine (pEtN) transferase (EC 2.7.8.43) that transfers phosphoethanolamine from the head group of phosphatidylethanolamine onto the 4'- (and 1'-) phosphate of lipid A. This modification neutralises the negative charge of lipid A and reduces binding of the cationic polymyxins, conferring colistin resistance — a target-modification (not drug-inactivation) mechanism. MCR-1 is an integral inner-membrane protein with an N-terminal five-helix transmembrane domain that anchors a C-terminal periplasmic catalytic domain; the catalytic domain has the alkaline-phosphatase/sulfatase fold, binds zinc at the active site, and uses a threonine nucleophile (Thr285, which is phosphoethanolamine-modified during catalysis). Because colistin is a last-resort antibiotic for multidrug-resistant Gram-negative infections, the mobilisation of this chromosomal pEtN-transferase activity onto conjugative plasmids is of major clinical and public-health significance; mcr-1 and its many allelic variants have since disseminated worldwide.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: MCR-1 is an integral inner-membrane (bacterial plasma membrane) protein, with a five-helix transmembrane domain anchoring a periplasmic catalytic domain. UniProt records the subcellular location as cell inner membrane. Reason: Correct and specific cellular location; consistent with the experimental localization (PMID:27655155) and the UniProt 'Cell inner membrane' annotation. |
| GO:0009244 lipopolysaccharide core region biosynthetic process | IEA GO_REF:0000118 | MARK AS OVER ANNOTATED | Summary: This electronic (TreeGrafter/PANTHER) annotation is imprecise. MCR-1 modifies lipid A by adding phosphoethanolamine to its 4'/1' phosphate; it does not synthesise the LPS core oligosaccharide region. The relevant biological process is lipid A modification in the context of antibiotic resistance, not core-region biosynthesis. Reason: Mechanistically inaccurate over-propagation: a lipid A phosphoethanolamine transferase is binned under 'LPS core region biosynthetic process'. The accurate process is captured by the NEW 'response to antibiotic' annotation below; the molecular event is lipid A modification, not core biosynthesis. Supporting Evidence: PMID:27655155 modification of the 1' and 4' phosphate groups of lipid A to neutralize the negative charge and reduce binding of the positively charged colistin |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: MCR-1 is an integral bacterial inner-membrane protein. Reason: Membrane is a valid broad description of the experimentally supported plasma-membrane location. A more specific annotation does not make this InterPro annotation incorrect. |
| GO:0016772 transferase activity, transferring phosphorus-containing groups | IEA GO_REF:0000002 | ACCEPT | Summary: MCR-1 transfers a phosphorus-containing phosphoethanolamine group. Reason: This broad transferase activity is chemically entailed by the established lipid A modification reaction and is a current GO ancestor of GO:0043838. Retain it alongside the more specific function. Supporting Evidence: PMID:27655155 MCR-1 is a phosphoethanolamine transferase that catalyzes the addition of phosphoethanolamine to lipid A |
| GO:0016776 phosphotransferase activity, phosphate group as acceptor | IEA GO_REF:0000118 | MODIFY | Summary: MCR-1 transfers phosphoethanolamine to lipid A; the exact reaction term is preferable to the ambiguous broad phosphate-acceptor classification. Reason: Retain MODIFY as a refinement to GO:0043838, not a finding that phosphoethanolamine transfer is false. Existing reports disagree: Falcon treats the phosphate-acceptor wording as applicable, whereas OpenScientist emphasizes EC 2.7.8.43 and the substituted-phosphate branch. Current QuickGO places GO:0043838 under GO:0016780 and GO:0016772, not GO:0016776. The broad text alone does not establish a wrong substrate reaction or a wrong graft position. Proposed replacements: phosphatidylethanolamine:Kdo2-lipid A phosphoethanolamine transferase activity Supporting Evidence: PMID:29079699 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in file:ECOLX/mcr-1/mcr-1-hypotheses/function-hypothesis-go-0016776/openscientist.md The seed hypothesis that MCR-1 has phosphotransferase activity, phosphate group as acceptor (GO:0016776) is refuted - the propagated term is the wrong sibling GO term. file:ECOLX/mcr-1/mcr-1-hypotheses/function-hypothesis-go-0016776/openscientist.md MCR-1 is a well-characterized plasmid-encoded phosphoethanolamine (PEtN) transferase (EC 2.7.8.43) file:ECOLX/mcr-1/mcr-1-hypotheses/function-hypothesis-go-0016776/falcon.md MCR-1 uses Thr285-mediated nucleophilic attack on phosphatidylethanolamine to form a covalent pEtN-enzyme intermediate |
| GO:0005886 plasma membrane | EXP PMID:27655155 Structure of the catalytic domain of the colistin resistance... | ACCEPT | Summary: Experimentally supported inner-membrane localization. ACCEPT as the core location. Reason: Experimental evidence for the bacterial inner (plasma) membrane location; this is the core cellular component for the enzyme. Supporting Evidence: PMID:27655155 the PEA transferases have a membrane-spanning domain and a periplasmic catalytic domain |
| GO:0043838 phosphatidylethanolamine:Kdo2-lipid A phosphoethanolamine transferase activity | IDA PMID:27655155 Structure of the catalytic domain of the colistin resistance... | NEW | Summary: The specific, characterised molecular function of MCR-1 (EC 2.7.8.43): transfer of phosphoethanolamine from phosphatidylethanolamine to lipid A. Currently absent from GOA, which carries only the over-general parents GO:0016772/GO:0016776. This is the candidate annotation derived from the ARO->GO mapping (ARO:3004112 -> GO:0043838), here verified against the primary literature. Reason: Replaces the two over-general IEA MF terms with the specific, structurally and biochemically supported activity. Directly evidenced by the MCR-1 structure/mechanism papers and EC 2.7.8.43. Supporting Evidence: PMID:27655155 MCR-1 is a phosphoethanolamine transferase that catalyzes the addition of phosphoethanolamine to lipid A PMID:29079699 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in |
| GO:0046677 response to antibiotic | IMP PMID:26603172 Emergence of plasmid-mediated colistin resistance mechanism ... | NEW | Summary: MCR-1 confers resistance to colistin (polymyxin) by modifying the lipid A target; 'response to antibiotic' is the standard biological process for a resistance determinant. Absent from GOA. Reason: The biological process in which MCR-1 participates is antibiotic (colistin) resistance via target modification; this is the accurate BP, replacing the mis-propagated GO:0009244. Supporting Evidence: PMID:26603172 Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China PMID:27655155 modification of the 1' and 4' phosphate groups of lipid A to neutralize the negative charge and reduce binding of the positively charged colistin |
| GO:0008270 zinc ion binding | IDA PMID:27655155 Structure of the catalytic domain of the colistin resistance... | NEW | Summary: The MCR-1 catalytic domain binds zinc at a conserved active-site position; MCR-1 is a metal(zinc)-dependent transferase. UniProt carries the broader 'metal ion binding' keyword term. Reason: Structurally supported zinc binding at the active site; the zinc is mechanistically required and is more informative than the keyword-derived 'metal ion binding'. Supporting Evidence: PMID:27655155 a zinc is present at a conserved site in addition to three zincs more peripherally located in the active site |
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Download this section (compressed HTML)Q: Does the in vitro preference for the 4' vs 1' phosphate of lipid A matter for the level of colistin resistance conferred in clinical isolates?
Experiment: Reconstitute purified MCR-1 with lipid A and phosphatidylethanolamine and measure steady-state kinetics and zinc dependence; compare allelic variants (e.g. MCR-1 vs MCR-3/MCR-8) for catalytic efficiency and resistance level.
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Download this section (compressed HTML)Reviewed all nine rows, including three earlier NEW proposals. Accepted membrane and phosphorus-group transfer as valid broad annotations. Kept the lipid-A-versus-LPS-core distinction and exact lipid A transferase refinement. Current QuickGO GO:0043838 ancestors include GO:0016780 and GO:0016772 but not GO:0016776. Existing OpenScientist and Falcon reports disagree on the latter term; their common biochemical evidence is integrated without calling broad wording a biological refutation or asserting a wrong graft position. The antibiotic-response proposal describes direct resistance through target modification, supported by the original phenotype and structural studies; the zinc-binding proposal is supported by active-site structural evidence.
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