2.02012-05-31 14:37:31 -06002015-06-03 17:19:43 -0600ECMDB20290M2MDB001129N-Acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamineN-acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamine is an intermediate in peptidoglycan synthesis. It is a substrate for the enzyme undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase (murG). Peptidoglycan can be described as a fisherman's net that encloses bacteria. The mesh of the net is made of two segments of parallel, somewhat inextensible glycan threads, held together by two small elastic peptide crosslinks allowing the net to expand or shrink. The glycan moiety of the peptidoglycan is very uniform among all bacteria, and is made up of alternating β-1,4-linked N-acetylglucosamine and N-acetyl muramate residues, with an average chain lengthof 10 to 65 disaccharide units (depending on the organism). The peptidoglycan synthesis pathway starts in the cytoplasm, where in six steps the peptidoglycan precursor a UDP-N-acetylmuramoyl-pentapeptide is synthesized. This precursor is then attached to the memberane acceptor all-trans-undecaprenyl phosphate, generating a N-acetylmuramoyl-pentapeptide-diphosphoundecaprenol, also known as lipid I. Another transferase then adds UDP-N-acetyl-α-D-glucosamine, yielding the complete monomeric unit a lipid II, also known as lipid II. This final lipid intermediate is transferred by an as yet unknown mechanism through the membrane. The peptidoglycan monomers are then polymerized on the outside surface by glycosyltransferases, which form the linear glycan chains, and transpeptidases, which catalyze the formation of peptide crosslinks. Peptide crosslinks form between different parts of the peptides depending on the organism. For example, in Mycobacteria and in E. coli most links form between the carboxyl group of the penultimate D-alanine (residue 4) of one peptide to the amino group at the D-center of meso-diaminopimelate (residue 3) of an adjacent peptide of a second glycan chain (as in E. coli). The crosslinking reaction is catalyzed by transpeptidases and involves the cleavage of the D-alanyl-D-alanine bond of the donor peptide, providing the energy to drive the reaction. As a result, the peptides in the peptidoglycan polymers are one or two amino acids shorter than the peptides in the monomers.<i>N</i>-acetyl-muramoyl-(pentapeptide)-<i>N</i>-acetylglucosamine-diphosphoundecaprenol<i>N</i>-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminoheptane-D-alanyl-D-alanine-diphosphoundecaprenyl-<i>N</i>-acetylglucosamineDiphosphoundecaprenyl-[GlcNAc-MurNAc-pentapeptide]<sub>n</sub>Diphosphoundecaprenyl-[GlcNAc-MurNAc-pentapeptide]NGlcNAc-(1->4)-MurNAc-pentapeptide-diphosphoundecaprenolLipid IILipid intermediate IILipid intermediic acid IIN-Acetyl-muramoyl-(pentapeptide)-N-acetylglucosamine-diphosphoundecaprenolN-Acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminoheptane-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamineUndecaprenyl-diphospho-N-acetylmuramoyl-(N-acetylglucosamine)-L-ala-D-glu-meso-2,6-diaminopimeloyl-D-ala-D-alaUndecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-<i>N</i>-acetylglucosamineUndecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-N-acetylglucosamineC94H156N8O26P21876.231875.060600228(4R)-4-{[(1S)-5-amino-1-{[(1R)-1-{[(1R)-1-carboxyethyl]-C-hydroxycarbonimidoyl}ethyl]-C-hydroxycarbonimidoyl}pentyl]-C-hydroxycarbonimidoyl}-4-{[(2S)-2-{[(2R)-2-{[(2R,3S,4R,5R,6R)-3-{[(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-[(1-hydroxyethylidene)amino]-6-(hydroxymethyl)oxan-2-yl]oxy}-6-{[hydroxy({hydroxy[(3,7,11,15,19,23,27,31,35,39,43-undecamethyltetratetraconta-2,6,10,14,18,22,26,30,34,38,42-undecaen-1-yl)oxy]phosphoryl}oxy)phosphoryl]oxy}-5-[(1-hydroxyethylidene)amino]-2-(hydroxymethyl)oxan-4-yl]oxy}-1-hydroxypropylidene]amino}-1-hydroxypropylidene]amino}butanoic acid(4R)-4-{[(1S)-5-amino-1-{[(1R)-1-{[(1R)-1-carboxyethyl]-C-hydroxycarbonimidoyl}ethyl]-C-hydroxycarbonimidoyl}pentyl]-C-hydroxycarbonimidoyl}-4-{[(2S)-2-{[(2R)-2-{[(2R,3S,4R,5R,6R)-3-{[(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-[(1-hydroxyethylidene)amino]-6-(hydroxymethyl)oxan-2-yl]oxy}-6-({hydroxy[hydroxy(3,7,11,15,19,23,27,31,35,39,43-undecamethyltetratetraconta-2,6,10,14,18,22,26,30,34,38,42-undecaen-1-yl)oxyphosphoryl]oxyphosphoryl}oxy)-5-[(1-hydroxyethylidene)amino]-2-(hydroxymethyl)oxan-4-yl]oxy}-1-hydroxypropylidene]amino}-1-hydroxypropylidene]amino}butanoic acid[H][C@](C)(O[C@@]1([H])[C@]([H])(O[C@@]2([H])O[C@]([H])(CO)[C@@]([H])(O)[C@]([H])(O)[C@@]2([H])N=C(C)O)[C@@]([H])(CO)O[C@]([H])(OP(O)(=O)OP(O)(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)[C@]1([H])N=C(C)O)C(O)=N[C@@]([H])(C)C(O)=N[C@]([H])(CCC(O)=O)C(O)=N[C@@]([H])(CCCCN)C(O)=N[C@]([H])(C)C(O)=N[C@]([H])(C)C(O)=OInChI=1S/C94H156N8O26P2/c1-59(2)31-21-32-60(3)33-22-34-61(4)35-23-36-62(5)37-24-38-63(6)39-25-40-64(7)41-26-42-65(8)43-27-44-66(9)45-28-46-67(10)47-29-48-68(11)49-30-50-69(12)54-56-122-129(118,119)128-130(120,121)127-94-82(100-75(18)106)86(85(79(58-104)125-94)126-93-81(99-74(17)105)84(110)83(109)78(57-103)124-93)123-73(16)89(113)96-71(14)88(112)101-77(52-53-80(107)108)91(115)102-76(51-19-20-55-95)90(114)97-70(13)87(111)98-72(15)92(116)117/h31,33,35,37,39,41,43,45,47,49,54,70-73,76-79,81-86,93-94,103-104,109-110H,19-30,32,34,36,38,40,42,44,46,48,50-53,55-58,95H2,1-18H3,(H,96,113)(H,97,114)(H,98,111)(H,99,105)(H,100,106)(H,101,112)(H,102,115)(H,107,108)(H,116,117)(H,118,119)(H,120,121)/t70-,71+,72-,73-,76+,77-,78-,79-,81-,82-,83-,84-,85-,86-,93-,94-/m1/s1MYJUVRULDQURQG-OCYHILAXSA-NInner membraneMembraneOuter membranelogp3.42logs-5.62solubility4.47e-03 g/llogp14.53pka_strongest_acidic1.71pka_strongest_basic10.21iupac(4R)-4-{[(1S)-5-amino-1-{[(1R)-1-{[(1R)-1-carboxyethyl]-C-hydroxycarbonimidoyl}ethyl]-C-hydroxycarbonimidoyl}pentyl]-C-hydroxycarbonimidoyl}-4-{[(2S)-2-{[(2R)-2-{[(2R,3S,4R,5R,6R)-3-{[(2R,3R,4R,5S,6R)-4,5-dihydroxy-3-[(1-hydroxyethylidene)amino]-6-(hydroxymethyl)oxan-2-yl]oxy}-6-{[hydroxy({hydroxy[(3,7,11,15,19,23,27,31,35,39,43-undecamethyltetratetraconta-2,6,10,14,18,22,26,30,34,38,42-undecaen-1-yl)oxy]phosphoryl}oxy)phosphoryl]oxy}-5-[(1-hydroxyethylidene)amino]-2-(hydroxymethyl)oxan-4-yl]oxy}-1-hydroxypropylidene]amino}-1-hydroxypropylidene]amino}butanoic acidaverage_mass1876.23mono_mass1875.060600228smiles[H][C@](C)(O[C@@]1([H])[C@]([H])(O[C@@]2([H])O[C@]([H])(CO)[C@@]([H])(O)[C@]([H])(O)[C@@]2([H])N=C(C)O)[C@@]([H])(CO)O[C@]([H])(OP(O)(=O)OP(O)(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)[C@]1([H])N=C(C)O)C(O)=N[C@@]([H])(C)C(O)=N[C@]([H])(CCC(O)=O)C(O)=N[C@@]([H])(CCCCN)C(O)=N[C@]([H])(C)C(O)=N[C@]([H])(C)C(O)=OformulaC94H156N8O26P2inchiInChI=1S/C94H156N8O26P2/c1-59(2)31-21-32-60(3)33-22-34-61(4)35-23-36-62(5)37-24-38-63(6)39-25-40-64(7)41-26-42-65(8)43-27-44-66(9)45-28-46-67(10)47-29-48-68(11)49-30-50-69(12)54-56-122-129(118,119)128-130(120,121)127-94-82(100-75(18)106)86(85(79(58-104)125-94)126-93-81(99-74(17)105)84(110)83(109)78(57-103)124-93)123-73(16)89(113)96-71(14)88(112)101-77(52-53-80(107)108)91(115)102-76(51-19-20-55-95)90(114)97-70(13)87(111)98-72(15)92(116)117/h31,33,35,37,39,41,43,45,47,49,54,70-73,76-79,81-86,93-94,103-104,109-110H,19-30,32,34,36,38,40,42,44,46,48,50-53,55-58,95H2,1-18H3,(H,96,113)(H,97,114)(H,98,111)(H,99,105)(H,100,106)(H,101,112)(H,102,115)(H,107,108)(H,116,117)(H,118,119)(H,120,121)/t70-,71+,72-,73-,76+,77-,78-,79-,81-,82-,83-,84-,85-,86-,93-,94-/m1/s1inchikeyMYJUVRULDQURQG-OCYHILAXSA-Npolar_surface_area548.88refractivity507.48polarizability208.6rotatable_bond_count63acceptor_count31donor_count16physiological_charge-4formal_charge0peptidoglycan biosynthesis I 2Peptidoglycan is a net-like polymer which surrounds the cytoplasmic membrane of most bacteria and functions to maintain cell shape and prevent rupture due to the internal turgor.In E. coli K-12, the peptidoglycan consists of glycan strands of alternating subunits of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) which are cross-linked by short peptides. The pathway for constructing this net involves two cell compartments: cytoplasm and periplasmic space. The pathway starts with a beta-D-fructofuranose going through a mannose PTS permease, phosphorylating the compund and producing a beta-D-fructofuranose 6 phosphate. This compound can be obtained from the glycolysis and pyruvate dehydrogenase or from an isomerization reaction of Beta-D-glucose 6-phosphate through a glucose-6-phosphate isomerase.The compound Beta-D-fructofuranose 6 phosphate and L-Glutamine react with a glucosamine fructose-6-phosphate aminotransferase, thus producing a glucosamine 6-phosphate and a l-glutamic acid. The glucosamine 6-phosphate interacts with phosphoglucosamine mutase in a reversible reaction producing glucosamine-1P. Glucosamine-1p and acetyl coa undergo acetylation throuhg a bifunctional protein glmU releasing Coa and a hydrogen ion and producing a N-acetyl-glucosamine 1-phosphate. Glmu, being a bifunctional protein, follows catalyze the interaction of N-acetyl-glucosamine 1-phosphate, hydrogen ion and UTP into UDP-N-acetylglucosamine and pyrophosphate. UDP-N-acetylglucosamine then interacts with phosphoenolpyruvic acid and a UDP-N acetylglucosamine 1- carboxyvinyltransferase realeasing a phosphate and the compound UDP-N-acetyl-alpha-D-glucosamine-enolpyruvate. This compound undergoes a NADPH dependent reduction producing a UDP-N-acetyl-alpha-D-muramate through a UDP-N-acetylenolpyruvoylglucosamine reductase. UDP-N-acetyl-alpha-D-muramate and L-alanine react in an ATP-mediated ligation through a UDP-N-acetylmuramate-alanine ligase releasing an ADP, hydrogen ion, a phosphate and a UDP-N-acetylmuramoyl-L-alanine. This compound interacts with D-glutamic acid and ATP through UDP-N-acetylmuramoylalanine-D-glutamate ligase releasing ADP, A phosphate and UDP-N-acetylmuramoyl-L-alanyl-D-glutamate. The latter compound then interacts with meso-diaminopimelate in an ATP mediated ligation through a UDP-N-acetylmuramoylalanine-D-glutamate-2,6-diaminopimelate ligase resulting in ADP, phosphate, hydrogen ion and UDP-N-Acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminopimelate. This compound in turn with D-alanyl-D-alanine react in an ATP-mediated ligation through UDP-N-Acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase to produce UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine and hydrogen ion, ADP, phosphate. UDP-N-acetyl-alpha-D-muramoyl-L-alanyl-gama-D-glutamyl-meso-2,6-diaminopimeloyl-Dalanyl-D-alanine interacts with di-trans,octa-cis-undecaprenyl phosphate through a phospho-N-acetylmuramoyl-pentapeptide-transferase, resulting in UMP and N-Acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelyl-D-alanyl-D-alanine-diphosphoundecaprenol which in turn reacts with a UDP-N-acetylglucosamine through a N-acetylglucosaminyl transferase to produce a hydrogen, UDP and Undecaprenyl-diphospho-N-acetylmuramoyl-(N-acetylglucosamine)-L-alanyl-D-glutaminyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine. This compound ends the cytoplasmic part of the pathway. Undecaprenyl-diphospho-N-acetylmuramoyl-(N-acetylglucosamine)-L-alanyl-D-glutaminyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine is transported through a lipi II flippase. Once in the periplasmic space, the compound reacts with a penicillin binding protein 1A prodducing a peptidoglycan dimer, a hydrogen ion, and UDP. The peptidoglycan dimer then reacts with a penicillin binding protein 1B producing a peptidoglycan with D,D, cross-links and a D-alanine.PW002062Metabolicpeptidoglycan biosynthesis I (<I>meso</I>-diaminopimelate containing)PEPTIDOGLYCANSYN-PWYSpecdb::MsMs26369Specdb::MsMs26370Specdb::MsMs26371Specdb::MsMs32927Specdb::MsMs32928Specdb::MsMs3292925203452C6Keseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590.21097882van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25.17765195Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948.18331064Barneoud-Arnoulet, A., Barreteau, H., Touze, T., Mengin-Lecreulx, D., Lloubes, R., Duche, D. (2010). "Toxicity of the colicin M catalytic domain exported to the periplasm is FkpA independent." J Bacteriol 192:5212-5219.20675494Gerard, F., Brooks, M. A., Barreteau, H., Touze, T., Graille, M., Bouhss, A., Blanot, D., van Tilbeurgh, H., Mengin-Lecreulx, D. (2011). "X-ray structure and site-directed mutagenesis analysis of the Escherichia coli colicin M immunity protein." J Bacteriol 193:205-214.21037007Phospho-N-acetylmuramoyl-pentapeptide-transferaseP0A6W3MRAY_ECOLImraYhttp://ecmdb.ca/proteins/P0A6W3.xmlUDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligaseP11880MURF_ECOLImurFhttp://ecmdb.ca/proteins/P11880.xmlUDP-N-acetylglucosamine--N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferaseP17443MURG_ECOLImurGhttp://ecmdb.ca/proteins/P17443.xmlPenicillin-binding protein 1CP76577PBPC_ECOLIpbpChttp://ecmdb.ca/proteins/P76577.xmlVirulence factor mviN homologP0AF16MVIN_ECOLImviNhttp://ecmdb.ca/proteins/P0AF16.xmlVirulence factor mviN homologP0AF16MVIN_ECOLImviNhttp://ecmdb.ca/proteins/P0AF16.xmlN-Acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelyl-D-alanyl-D-alanine-diphosphoundecaprenol + Uridine diphosphate-N-acetylglucosamine <> Hydrogen ion + N-Acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamine + Uridine 5'-diphosphateNACGLCTRANS-RXNN-Acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamine > Hydrogen ion + a peptidoglycan dimer (<I>meso</I>-diaminopimelate containing) + Undecaprenyl diphosphateRXN0-5405UDP-N-Acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminopimelate + D-Alanyl-D-alanine + Adenosine triphosphate > N-Acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamine + ADP + Phosphate + Hydrogen ionPW_R006023N-Acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine-diphosphoundecaprenyl-N-acetylglucosamine + di-trans,octa-cis-undecaprenyl phosphate > N-Acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelyl-D-alanyl-D-alanine-diphosphoundecaprenol + Uridine 5'-monophosphatePW_R006022