Lipid A phosphoethanolamine transferase
| Lipid A phosphoethanolamine transferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 2.7.8.43 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
| Lipid A phosphoethanolamine transferase | |
|---|---|
| Identifiers | |
| Symbol | PEA_transferase |
| InterPro | IPR040423 |
| Phosphoethanolamine transferase, N-terminal | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | EptA-like_N | ||||||||
| Pfam | PF08019 | ||||||||
| InterPro | IPR012549 | ||||||||
| |||||||||
Lipid A phosphoethanolamine transferase (EC 2.7.8.43, lipid A PEA transferase, LptA, formerly EC 2.7.4.30) is an enzyme that modifies Lipid A by linkage to a phosphoethanolamine moiety. Doing so at some positions reduces the affinity to colistin and related polymyxins, resulting in reduced activity of the antimicrobial. This type of resistance is known as target modification.[1] This type of enzyme is of special medical note, as it offers resistance to a last-resort antibiotic.[2] The modifications also provide cross-resistance to host immunity factors, specifically antimicrobial peptides and lysozyme.[3][4] EC 2.7.8.43 catalyzes one of the following three reactions:[5]
- a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A (E. coli) a 1,2-diacyl-sn-glycerol + lipid A hexaacyl 1-(2-aminoethyl diphosphate)
- a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A (E. coli) a 1,2-diacyl-sn-glycerol + lipid A 4'-(2-aminoethyl diphosphate) (E. coli)
- a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A hexaacyl 1-(2-aminoethyl diphosphate) a 1,2-diacyl-sn-glycerol + lipid A 1,4'-bis(2-aminoethyl diphosphate)
Enzyme databases may list a very long list of synonyms for this enzyme. Many of these names, such as mcr-1, do not refer to this type of enzyme in general, but only to a specific member of the family.[6] There are many non-mobile (chromosomal) versions of this enzyme scattered all around the evolutionary tree, but mcr-1 was notable because it was found on a plasmid, therefore capable of horizontal gene transfer.[7] Only one family of protein is currently known to perform the activity described by the EC number.
Structure
[edit]The enzyme is composed of two domains. The N-terminal part (about 1/3 of the length) is a transmembrane domain, while the rest is catalytic. Both domains contribute to the phosphoethanolamine substrate cavity. The C-terminal domain binds zinc as a cofactor.[7]
Function
[edit]Polymyxins and other cationic antimicrobial peptides attach to the LPS cell walls of bacteria by virtue of the highly negatively-charged groups in LPS such as Lipid A and Kdo. Modification of LPS with positively-charged PEA shields these sites from binding.[8]
Not all members of this family perform the same reaction, contrary to the EC classification framework. For example, E. coli naturally has three related genes all from this family, EptA through C, all with different preferences for where to attach PEA. Addition of PEA can happen on Lipid A (this EC entry), on Kdo (EC 2.7.8.42), or on Heptose 1 (no EC number), the latter two being parts of the core oligosaccharide. In the case of EptC, addition of PEA to Heptose compacts the LPS by forming a network of hydrogen bonds.[9]
Regulation
[edit]In chromosomal versions of this enzyme, the gene is regulated by a two-component regulatory system termed PmrAB or BasRS. The PmrA or BasS is the histidine kinase sensor, which activates the DNA-binding response regulator BasR or PmrB. The sensor triggers in a variety of dangerous situations, such as metal ions and being ingested by a phagocyte, helping the bacterium build a stronger cell wall to survive. The PhoPQ system, which detects similar situations and the presence of antimicrobial peptides, can also cross-trigger PmrA via a PmrD connector. Antibiotic resistance can occur when this system, or its upstream signals, mutates to become constitutively active.[10]
In plasmid versions, the gene is simply constitutively activated by an upstream promoter.[10] The extra metabolic resources diverted means that the resistant trait is disadvantageous in environments without antibiotic or antimicrobial peptide threats, specifically by about 3%.[4]
See also
[edit]References
[edit]- ^ Hinchliffe P, Yang QE, Portal E, Young T, Li H, Tooke CL, Carvalho MJ, Paterson NG, Brem J, Niumsup PR, Tansawai U, Lei L, Li M, Shen Z, Wang Y, Schofield CJ, Mulholland AJ, Shen J, Fey N, Walsh TR, Spencer J (January 2017). "Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1". Scientific Reports. 7: 39392. Bibcode:2017NatSR...739392H. doi:10.1038/srep39392. PMC 5216409. PMID 28059088.
- ^ Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (February 2016). "Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study". The Lancet. Infectious Diseases. 16 (2): 161–8. doi:10.1016/S1473-3099(15)00424-7. PMID 26603172.
- ^ Napier BA, Burd EM, Satola SW, Cagle SM, Ray SM, McGann P, Pohl J, Lesho EP, Weiss DS (21 May 2013). "Clinical Use of Colistin Induces Cross-Resistance to Host Antimicrobials in Acinetobacter baumannii". mBio. 4 (3): e00021–13–e00021–13. doi:10.1128/mBio.00021-13. PMC 3663567. PMID 23695834.
- ^ a b Jangir, Pramod K; Ogunlana, Lois; Szili, Petra; Czikkely, Marton; Shaw, Liam P; Stevens, Emily J; Yang, Yu; Yang, Qiue; Wang, Yang; Pál, Csaba; Walsh, Timothy R; MacLean, Craig R (25 April 2023). "The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence". eLife. 12: e84395. doi:10.7554/eLife.84395. PMC 10129329. PMID 37094804.
- ^ "ENZYME - 2.7.8.43 lipid A phosphoethanolamine transferase". enzyme.expasy.org.
- ^ "2.7.8.43: lipid A phosphoethanolamine transferase - BRENDA Enzyme Database". www.brenda-enzymes.org.
- ^ a b Xu Y, Wei W, Lei S, Lin J, Srinivas S, Feng Y (April 2018). "An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance". mBio. 9 (2). doi:10.1128/mBio.02317-17. PMC 5893884. PMID 29636432.
- ^ Anaya-López, José Luis; López-Meza, Joel Edmundo; Ochoa-Zarzosa, Alejandra (May 2013). "Bacterial resistance to cationic antimicrobial peptides". Critical Reviews in Microbiology. 39 (2): 180–195. doi:10.3109/1040841x.2012.699025. PMID 22799636. S2CID 35828720.
- ^ Salazar, Javier; Alarcón, Mackarenna; Huerta, Jaime; Navarro, Belén; Aguayo, Daniel (April 2017). "Phosphoethanolamine addition to the Heptose I of the Lipopolysaccharide modifies the inner core structure and has an impact on the binding of Polymyxin B to the Escherichia coli outer membrane". Archives of Biochemistry and Biophysics. 620: 28–34. doi:10.1016/j.abb.2017.03.008. PMID 28342805.
- ^ a b Poirel, L; Jayol, A; Nordmann, P (April 2017). "Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes". Clinical Microbiology Reviews. 30 (2): 557–596. doi:10.1128/CMR.00064-16. PMC 5355641. PMID 28275006.
