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Pathway Description
Polymyxin Resistance
Escherichia coli
Metabolic Pathway
UDP-glucuronic acid compound undergoes a NAD dependent reaction through a bifunctional polymyxin resistance protein to produce UDP-Beta-L-threo-pentapyranos-4-ulose. This compound then reacts with L-glutamic acid through a UDP-4-amino-4-deoxy-L-arabinose--oxoglutarate aminotransferase to produce an oxoglutaric acid and UDP-4-amino-4-deoxy-beta-L-arabinopyranose The latter compound interacts with a N10-formyl-tetrahydrofolate through a bifunctional polymyxin resistance protein ArnA, resulting in a tetrahydrofolate, a hydrogen ion and a UDP-4-deoxy-4-formamido-beta-L-arabinopyranose, which in turn reacts with a product of the methylerythritol phosphate and polysoprenoid biosynthesis pathway, di-trans,octa-cis-undecaprenyl phosphate to produce a 4-deoxy-4-formamido-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate.
The compound 4-deoxy-4-formamido-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate hypothetically reacts with water and results in the release of a formic acid and 4-amino-4-deoxy-α-L-arabinopyranosyl ditrans,octacis-undecaprenyl phosphate which in turn reacts with a KDO2-lipid A through a 4-amino-4-deoxy-L-arabinose transferase resulting in the release of a di-trans,octa-cis-undecaprenyl phosphate and a L-Ara4N-modified KDO2-Lipid A
References
Polymyxin Resistance References
Barchiesi J, Espariz M, Checa SK, Soncini FC: Downregulation of RpoN-controlled genes protects Salmonella cells from killing by the cationic antimicrobial peptide polymyxin B. FEMS Microbiol Lett. 2009 Feb;291(1):73-9. doi: 10.1111/j.1574-6968.2008.01437.x. Epub 2008 Dec 3.
Pubmed: 19076233
Bretscher LE, Morrell MT, Funk AL, Klug CS: Purification and characterization of the L-Ara4N transferase protein ArnT from Salmonella typhimurium. Protein Expr Purif. 2006 Mar;46(1):33-9. doi: 10.1016/j.pep.2005.08.028. Epub 2005 Sep 28.
Pubmed: 16226890
Fu W, Yang F, Kang X, Zhang X, Li Y, Xia B, Jin C: First structure of the polymyxin resistance proteins. Biochem Biophys Res Commun. 2007 Oct 5;361(4):1033-7. doi: 10.1016/j.bbrc.2007.07.144. Epub 2007 Aug 2.
Pubmed: 17686460
Gatzeva-Topalova PZ, May AP, Sousa MC: Structure and mechanism of ArnA: conformational change implies ordered dehydrogenase mechanism in key enzyme for polymyxin resistance. Structure. 2005 Jun;13(6):929-42. doi: 10.1016/j.str.2005.03.018.
Pubmed: 15939024
Groisman EA, Kayser J, Soncini FC: Regulation of polymyxin resistance and adaptation to low-Mg2+ environments. J Bacteriol. 1997 Nov;179(22):7040-5.
Pubmed: 9371451
Gunn JS: The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends Microbiol. 2008 Jun;16(6):284-90. doi: 10.1016/j.tim.2008.03.007. Epub 2008 May 6.
Pubmed: 18467098
Kline T, Trent MS, Stead CM, Lee MS, Sousa MC, Felise HB, Nguyen HV, Miller SI: Synthesis of and evaluation of lipid A modification by 4-substituted 4-deoxy arabinose analogs as potential inhibitors of bacterial polymyxin resistance. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1507-10. doi: 10.1016/j.bmcl.2007.12.061. Epub 2007 Dec 27.
Pubmed: 18187325
Kox LF, Wosten MM, Groisman EA: A small protein that mediates the activation of a two-component system by another two-component system. EMBO J. 2000 Apr 17;19(8):1861-72. doi: 10.1093/emboj/19.8.1861.
Pubmed: 10775270
Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A 3rd, Forrest A, Bulitta JB, Tsuji BT: Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010 Dec;30(12):1279-91. doi: 10.1592/phco.30.12.1279.
Pubmed: 21114395
Nummila K, Kilpelainen I, Zahringer U, Vaara M, Helander IM: Lipopolysaccharides of polymyxin B-resistant mutants of Escherichia coli are extensively substituted by 2-aminoethyl pyrophosphate and contain aminoarabinose in lipid A. Mol Microbiol. 1995 Apr;16(2):271-8.
Pubmed: 7565089
Pilonieta MC, Erickson KD, Ernst RK, Detweiler CS: A protein important for antimicrobial peptide resistance, YdeI/OmdA, is in the periplasm and interacts with OmpD/NmpC. J Bacteriol. 2009 Dec;191(23):7243-52. doi: 10.1128/JB.00688-09. Epub 2009 Sep 18.
Pubmed: 19767429
Raetz CR, Whitfield C: Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635-700. doi: 10.1146/annurev.biochem.71.110601.135414. Epub 2001 Nov 9.
Pubmed: 12045108
Trent MS, Ribeiro AA, Doerrler WT, Lin S, Cotter RJ, Raetz CR: Accumulation of a polyisoprene-linked amino sugar in polymyxin-resistant Salmonella typhimurium and Escherichia coli: structural characterization and transfer to lipid A in the periplasm. J Biol Chem. 2001 Nov 16;276(46):43132-44. doi: 10.1074/jbc.M106962200. Epub 2001 Sep 4.
Pubmed: 11535605
Wosten MM, Kox LF, Chamnongpol S, Soncini FC, Groisman EA: A signal transduction system that responds to extracellular iron. Cell. 2000 Sep 29;103(1):113-25.
Pubmed: 11051552
Yan A, Guan Z, Raetz CR: An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli. J Biol Chem. 2007 Dec 7;282(49):36077-89. doi: 10.1074/jbc.M706172200. Epub 2007 Oct 10.
Pubmed: 17928292
Zhou Z, Lin S, Cotter RJ, Raetz CR: Lipid A modifications characteristic of Salmonella typhimurium are induced by NH4VO3 in Escherichia coli K12. Detection of 4-amino-4-deoxy-L-arabinose, phosphoethanolamine and palmitate. J Biol Chem. 1999 Jun 25;274(26):18503-14.
Pubmed: 10373459
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