Escherichia coli K-12 substr. MG1655 Pathway: UDP-N-acetylmuramoyl-pentapeptide biosynthesis I (meso-diaminopimelate containing)
Inferred from experimentTraceable author statement to experimental support

Pathway diagram: UDP-N-acetylmuramoyl-pentapeptide biosynthesis I (meso-diaminopimelate containing)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Locations of Mapped Genes:

Schematic showing all replicons, marked with selected genes

Genetic Regulation Schematic

Genetic regulation schematic for UDP-N-acetylmuramoyl-pentapeptide biosynthesis I (meso-diaminopimelate containing)

Superclasses: BiosynthesisCell Structures BiosynthesisCell Wall BiosynthesisUDP-N-Acetylmuramoyl-Pentapeptide Biosynthesis

Synthesis of peptidoglycan in E. coli K-12 is a complex process which occurs across two cell compartments. This pathway describes the first stage of this process - the cytoplasmic synthesis of UDP-N-acetylmuramoyl-pentapeptide (a nucleotide activated monosaccharide-peptide) from the essential peptidoglycan precursor UDP-N-acetyl-α-D-glucosamine.

The first reaction of this pathway, an enolpyruvyl transfer from phosphoenolpyruvate (PEP) to the C3-hydroxyl group of UDP-N-acetylglucosamine, is catalysed by MurA [Marquardt92]. The product of this reaction, UDP-N-acetylglucosamine-enolpyruvate, is then reduced to UDP-N-acetyl-muramate (UDP-MurNAc) in a reaction catalysed by the NADPH dependent flavoprotein MurB [Benson93]. The final 4 steps of the pathway result in attachment of a pentapeptide stem to the lactyl group of UDP-MurNAc to form a UDP-MurNAc-pentapeptide (specifically UDP-N-acetyl-α-D-muramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine). The composition of the pentapeptide stem varies within bacterial species (see [Vollmer08]); in E. coli K-12 the pentapeptide is formed by successive addition of L-alanine, D-glutamate, meso-diaminopimelic acid (m-A2pm) and a D-alanyl-alanine dipeptide catalysed by the MurC, MurD, MurE and MurF ligases respectively [Liger95, PratvielSosa91, Michaud90, Duncan90]. The pentapeptide stem contains several rare D-amino acids formed from their corresponding L-enantiomers through the action of amino acid racemases - alanine racemase I and II and glutamate racemase.

In a subsequent pathway (see peptidoglycan biosynthesis I (meso-diaminopimelate containing)), the UDP-MurNAC-pentapeptide is transformed by the addition of N-acetylglucosamine and a lipid carrier molecule to form Lipid II (ditrans,octacis-undecaprenyldiphospho-N-acetyl-(N-acetylglucosaminyl)muramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminopimeloyl-D-alanyl-D-alanine) which is the monomer unit transported across the inner membrane for peptidoglycan maturation (described in peptidoglycan maturation (meso-diaminopimelate containing)).

The enzymes of this pathway are essential for growth and are thus attractive targets for antibacterial drug development (see for example reviews by [El03, Kotnik07, Fisher08, Gautam11]).

Review: [Barreteau08]

Citations: [Delcour99]

Superpathways: peptidoglycan biosynthesis I (meso-diaminopimelate containing)

Created 20-Nov-2009 by Caspi R, SRI International
Revised 23-Apr-2015 by Mackie A, Macquarie University
Last-Curated 23-Apr-2015 by Mackie A, Macquarie University


Barreteau08: Barreteau H, Kovac A, Boniface A, Sova M, Gobec S, Blanot D (2008). "Cytoplasmic steps of peptidoglycan biosynthesis." FEMS Microbiol Rev 32(2);168-207. PMID: 18266853

Benson93: Benson TE, Marquardt JL, Marquardt AC, Etzkorn FA, Walsh CT (1993). "Overexpression, purification, and mechanistic study of UDP-N-acetylenolpyruvylglucosamine reductase." Biochemistry 1993;32(8);2024-30. PMID: 8448160

Delcour99: Delcour J, Ferain T, Deghorain M, Palumbo E, Hols P (1999). "The biosynthesis and functionality of the cell-wall of lactic acid bacteria." Antonie Van Leeuwenhoek 76(1-4);159-84. PMID: 10532377

Duncan90: Duncan K, van Heijenoort J, Walsh CT (1990). "Purification and characterization of the D-alanyl-D-alanine-adding enzyme from Escherichia coli." Biochemistry 1990;29(9);2379-86. PMID: 2186811

El03: El Zoeiby A, Sanschagrin F, Levesque RC (2003). "Structure and function of the Mur enzymes: development of novel inhibitors." Mol Microbiol 47(1);1-12. PMID: 12492849

Fisher08: Fisher SL (2008). "Glutamate racemase as a target for drug discovery." Microb Biotechnol 1(5);345-60. PMID: 21261855

Gautam11: Gautam A, Rishi P, Tewari R (2011). "UDP-N-acetylglucosamine enolpyruvyl transferase as a potential target for antibacterial chemotherapy: recent developments." Appl Microbiol Biotechnol 92(2);211-25. PMID: 21822642

Kotnik07: Kotnik M, Anderluh PS, Prezelj A (2007). "Development of novel inhibitors targeting intracellular steps of peptidoglycan biosynthesis." Curr Pharm Des 13(22);2283-309. PMID: 17692001

Liger95: Liger D, Masson A, Blanot D, van Heijenoort J, Parquet C (1995). "Over-production, purification and properties of the uridine-diphosphate-N-acetylmuramate:L-alanine ligase from Escherichia coli." Eur J Biochem 1995;230(1);80-7. PMID: 7601127

Marquardt92: Marquardt JL, Siegele DA, Kolter R, Walsh CT (1992). "Cloning and sequencing of Escherichia coli murZ and purification of its product, a UDP-N-acetylglucosamine enolpyruvyl transferase." J Bacteriol 1992;174(17);5748-52. PMID: 1512209

Michaud90: Michaud C, Mengin-Lecreulx D, van Heijenoort J, Blanot D (1990). "Over-production, purification and properties of the uridine-diphosphate-N-acetylmuramoyl-L-alanyl-D-glutamate: meso-2,6-diaminopimelate ligase from Escherichia coli." Eur J Biochem 1990;194(3);853-61. PMID: 2269304

PratvielSosa91: Pratviel-Sosa F, Mengin-Lecreulx D, van Heijenoort J (1991). "Over-production, purification and properties of the uridine diphosphate N-acetylmuramoyl-L-alanine:D-glutamate ligase from Escherichia coli." Eur J Biochem 1991;202(3);1169-76. PMID: 1765076

Sheng14: Sheng J, Huang L, Zhu X, Cai J, Xu Z (2014). "Reconstitution of the peptidoglycan cytoplasmic precursor biosynthetic pathway in cell-free system and rapid screening of antisense oligonucleotides for Mur enzymes." Appl Microbiol Biotechnol 98(4);1785-94. PMID: 24389752

Vollmer08: Vollmer W, Blanot D, de Pedro MA (2008). "Peptidoglycan structure and architecture." FEMS Microbiol Rev 32(2);149-67. PMID: 18194336

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

AboGhalia85: Abo-Ghalia M, Michaud C, Blanot D, van Heijenoort J (1985). "Specificity of the uridine-diphosphate-N-acetylmuramyl-L-alanyl-D-glutamate: meso-2,6-diaminopimelate synthetase from Escherichia coli." Eur J Biochem 1985;153(1);81-7. PMID: 3905407

AboGhalia88: Abo-Ghalia M, Flegel M, Blanot D, Van Heijenoort J (1988). "Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli." Int J Pept Protein Res 32(3);208-22. PMID: 3072305

alBar92: al-Bar OA, O'Connor CD, Giles IG, Akhtar M (1992). "D-alanine: D-alanine ligase of Escherichia coli. Expression, purification and inhibitory studies on the cloned enzyme." Biochem J 282 ( Pt 3);747-52. PMID: 1554356

Anderson96: Anderson MS, Eveland SS, Onishi HR, Pompliano DL (1996). "Kinetic mechanism of the Escherichia coli UDPMurNAc-tripeptide D-alanyl-D-alanine-adding enzyme: use of a glutathione S-transferase fusion." Biochemistry 35(50);16264-9. PMID: 8973200

Anwar79: Anwar RA, Vlaovic M (1979). "Purification of UDP-N-acetylenolpyruvoylglucosamine reductase from Escherichia coli by affinity chromatography, its subunit structure and the absence of flavin as the prosthetic group." Can J Biochem 1979;57(2);188-96. PMID: 36973

Ashiuchi02: Ashiuchi M, Kuwana E, Yamamoto T, Komatsu K, Soda K, Misono H (2002). "Glutamate racemase is an endogenous DNA gyrase inhibitor." J Biol Chem 277(42);39070-3. PMID: 12213801

Ashiuchi95: Ashiuchi M, Yoshimura T, Kitamura T, Kawata Y, Nagai J, Gorlatov S, Esaki N, Soda K (1995). "In vivo effect of GroESL on the folding of glutamate racemase of Escherichia coli." J Biochem 117(3);495-8. PMID: 7629013

Auger96: Auger G, van Heijenoort J, Vederas JC, Blanot D (1996). "Effect of analogues of diaminopimelic acid on the meso-diaminopimelate-adding enzyme from Escherichia coli." FEBS Lett 391(1-2);171-4. PMID: 8706910

Auger98: Auger G, Martin L, Bertrand J, Ferrari P, Fanchon E, Vaganay S, Petillot Y, van Heijenoort J, Blanot D, Dideberg O (1998). "Large-scale preparation, purification, and crystallization of UDP-N-acetylmuramoyl-L-alanine: D-glutamate ligase from Escherichia coli." Protein Expr Purif 13(1);23-9. PMID: 9631510

Axley97: Axley MJ, Fairman R, Yanchunas J, Villafranca JJ, Robertson JG (1997). "Spectroscopic properties of Escherichia coli UDP-N-acetylenolpyruvylglucosamine reductase." Biochemistry 36(4);812-22. PMID: 9020779

Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554

Bachelier06: Bachelier A, Mayer R, Klein CD (2006). "Sesquiterpene lactones are potent and irreversible inhibitors of the antibacterial target enzyme MurA." Bioorg Med Chem Lett 16(21);5605-9. PMID: 16945528

Baliko88: Baliko G, Raukas A, Boros I, Venetianer P (1988). "An Escherichia coli gene in search of a function." Mol Gen Genet 211(2);326-31. PMID: 2832706

Baliko93: Baliko G, Venetianer P (1993). "An Escherichia coli gene in search of a function: phenotypic effects of the gene recently identified as murI." J Bacteriol 175(20);6571-7. PMID: 8407834

Barbosa02: Barbosa MD, Yang G, Fang J, Kurilla MG, Pompliano DL (2002). "Development of a whole-cell assay for peptidoglycan biosynthesis inhibitors." Antimicrob Agents Chemother 46(4);943-6. PMID: 11897573

Barreteau12: Barreteau H, Sosič I, Turk S, Humljan J, Tomašić T, Zidar N, Herve M, Boniface A, Peterlin-Mašič L, Kikelj D, Mengin-Lecreulx D, Gobec S, Blanot D (2012). "MurD enzymes from different bacteria: evaluation of inhibitors." Biochem Pharmacol 84(5);625-32. PMID: 22705647

Batson10: Batson S, Rea D, Fulop V, Roper DI (2010). "Crystallization and preliminary X-ray analysis of a D-alanyl-D-alanine ligase (EcDdlB) from Escherichia coli." Acta Crystallogr Sect F Struct Biol Cryst Commun 66(Pt 4);405-8. PMID: 20383009

Baum01: Baum EZ, Montenegro DA, Licata L, Turchi I, Webb GC, Foleno BD, Bush K (2001). "Identification and characterization of new inhibitors of the Escherichia coli MurA enzyme." Antimicrob Agents Chemother 45(11);3182-8. PMID: 11600375

Baum06: Baum EZ, Crespo-Carbone SM, Abbanat D, Foleno B, Maden A, Goldschmidt R, Bush K (2006). "Utility of muropeptide ligase for identification of inhibitors of the cell wall biosynthesis enzyme MurF." Antimicrob Agents Chemother 50(1);230-6. PMID: 16377691

Baum07: Baum EZ, Crespo-Carbone SM, Klinger A, Foleno BD, Turchi I, Macielag M, Bush K (2007). "A MurF inhibitor that disrupts cell wall biosynthesis in Escherichia coli." Antimicrob Agents Chemother 51(12);4420-6. PMID: 17908943

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Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
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