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Escherichia coli K-12 substr. MG1655 Enzyme: UDP-N-acetylmuramoylalanyl-D-glutamate 2,6-diaminopimelate ligase



Gene: murE Accession Numbers: EG10621 (EcoCyc), b0085, ECK0086

Regulation Summary Diagram: ?

Summary:
UDP-N-acetylmuramoylalanyl-D-glutamate 2,6-diaminopimelate ligase (MurE) catalyzes the addition of the third amino acid, meso-diaminopimelate, to the peptide moiety of the monomer unit of peptidoglycan [Michaud90]. The enzyme's ability to use the LL-DAP isomer at a low level leads to the incorporation of LL-DAP into peptidoglycan in a DapF (dapF) mutant [MenginLecreulx88].

A crystal structure of the enzyme has been solved at 2Å resolution, allowing the identification of residues involved in catalysis. The Lys224 residue within the active site is carbamylated [Gordon01], and this modification appears to be required for enzymatic activity [Dementin01].

Temperature-sensitive murE mutants have been isolated [Lugtenberg72], and the genetic defects of the murE1 allele has been identified [Eveland97]. In a dapA mutant, cystathionine or lanthionine will substitute for diaminopimelate [MenginLecreulx94]. Repression of murE expression with a synthetic small RNA leads to increased production of cadaverine in an engineered strain [Na13].

MurE is a potential antimicrobial drug target; inhibitors of MurE activity have been identified [AboGhalia88, Auger96, Bratkovic08, Sova09].

Reviews: [El03a, Typas12]

Citations: [Maruyama88, Tao89, Michaud90a]

Gene Citations: [Vicente98, MenginLecreulx98, Hara97]

Locations: cytosol

Map Position: [93,166 -> 94,653] (2.01 centisomes)
Length: 1488 bp / 495 aa

Molecular Weight of Polypeptide: 53.344 kD (from nucleotide sequence), 55.0 kD (experimental) [MenginLecreulx89 ]

pI: 5.74

Unification Links: ASAP:ABE-0000311 , CGSC:475 , DIP:DIP-10280N , EchoBASE:EB0616 , EcoGene:EG10621 , EcoliWiki:b0085 , Mint:MINT-1230964 , ModBase:P22188 , OU-Microarray:b0085 , PortEco:murE , PR:PRO_000023316 , Pride:P22188 , Protein Model Portal:P22188 , RefSeq:NP_414627 , RegulonDB:EG10621 , SMR:P22188 , String:511145.b0085 , UniProt:P22188

Relationship Links: InterPro:IN-FAMILY:IPR000713 , InterPro:IN-FAMILY:IPR004101 , InterPro:IN-FAMILY:IPR005761 , InterPro:IN-FAMILY:IPR013221 , PDB:Structure:1E8C , Pfam:IN-FAMILY:PF01225 , Pfam:IN-FAMILY:PF02875 , Pfam:IN-FAMILY:PF08245

In Paralogous Gene Group: 32 (3 members) , 407 (2 members)

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

GO Terms:

Biological Process: GO:0009252 - peptidoglycan biosynthetic process Inferred from experiment Inferred by computational analysis [UniProtGOA12, UniProtGOA11a, GOA06, Lugtenberg72]
GO:0007049 - cell cycle Inferred by computational analysis [UniProtGOA11a]
GO:0008360 - regulation of cell shape Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0009058 - biosynthetic process Inferred by computational analysis [GOA01a]
GO:0051301 - cell division Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0071555 - cell wall organization Inferred by computational analysis [UniProtGOA11a]
Molecular Function: GO:0008765 - UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase activity Inferred from experiment Inferred by computational analysis [GOA06, GOA01, Gordon01, Michaud90]
GO:0000166 - nucleotide binding Inferred by computational analysis [UniProtGOA11a]
GO:0005524 - ATP binding Inferred by computational analysis [UniProtGOA11a, GOA06, GOA01a]
GO:0016874 - ligase activity Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0016881 - acid-amino acid ligase activity Inferred by computational analysis [GOA01a]
Cellular Component: GO:0005829 - cytosol Inferred from experiment Inferred by computational analysis [DiazMejia09, Ishihama08]
GO:0005737 - cytoplasm Inferred by computational analysis [UniProtGOA11, UniProtGOA11a, GOA06, GOA01a]

MultiFun Terms: cell structure murein
metabolism biosynthesis of macromolecules (cellular constituents) murein (peptidoglycan)

Essentiality data for murE knockouts: ?

Growth Medium Growth? T (°C) O2 pH Osm/L Growth Observations
LB Lennox No 37 Aerobic 7   No [Baba06, Comment 1]

Credits:
Last-Curated ? 25-Jul-2013 by Keseler I , SRI International


Enzymatic reaction of: UDP-N-acetylmuramoylalanyl-D-glutamate 2,6-diaminopimelate ligase

Synonyms: UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelate synthetase, UDP-N-acetylmuramyl-tripeptide synthetase, meso-2,6-diaminopimelate-adding enzyme, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:meso-2,6-diaminoheptanedioate ligase (ADP-forming), UDP-MurNac-tripeptide synthetase

EC Number: 6.3.2.13

meso-diaminopimelate + UDP-N-acetylmuramoyl-L-alanyl--D-glutamate + ATP <=> UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminopimelate + ADP + phosphate + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction of enzyme catalysis.

The reaction is physiologically favored in the direction shown.

Alternative Substrates for meso-diaminopimelate: L,L-diaminopimelate [MenginLecreulx88 ] , meso-lanthionine [MenginLecreulx94 ] , L-allocystathionine [MenginLecreulx94 ] , D-cystathionine [MenginLecreulx94 ]

Alternative Substrates for UDP-N-acetylmuramoyl-L-alanyl--D-glutamate: DDP-N-acetylmuramoyl-L-alanyl-D-glutamate [AboGhalia85 ]

In Pathways: peptidoglycan biosynthesis I (meso-diaminopimelate containing) , UDP-N-acetylmuramoyl-pentapeptide biosynthesis I (meso-DAP-containing)

Summary:
The reaction can be measured in the reverse direction in vitro [Michaud90], but it is likely not reversible in vivo.

Several analogs of meso-diaminopimelate can serve as substrates/inhibitors of the enzyme [Michaud90]. The enzyme prefers the meso isomer [Auger96].

Activators (Unknown Mechanism): phosphate [Michaud90, Comment 2] , K+ [Michaud90, Comment 2]

Inhibitors (Unknown Mechanism): 1-phospho-N-acetylmuramoyl-L-alanyl-D-glutamate [AboGhalia85] , N-acetylmuramate(beta-methyl)-L-alanyl-D-glutamate [AboGhalia85] , N-acetylmuramate(alpha-methyl)-L-alanyl-D-glutamate [AboGhalia85] , UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminopimelate [AboGhalia85] , UDP-N-acetylmuramoyl-L-alanine [AboGhalia85] , UDP-N-α-D-acetylmuramate [AboGhalia85] , UDP-N-acetyl-α-D-glucosamine [AboGhalia85] , UDP [AboGhalia85]

Kinetic Parameters:

Substrate
Km (μM)
Citations
L,L-diaminopimelate
36000.0
[MenginLecreulx88]
L-allocystathionine
3900.0
[MenginLecreulx94]
DDP-N-acetylmuramoyl-L-alanyl-D-glutamate
97.0
[AboGhalia85]
UDP-N-acetylmuramoyl-L-alanyl--D-glutamate
76.0
[Michaud90]
ATP
620.0
[Michaud90, BRENDA14]
D-cystathionine
10000.0
[MenginLecreulx94]
meso-diaminopimelate
40.0
[MenginLecreulx94, BRENDA14]
meso-diaminopimelate
36.0
[Michaud90, BRENDA14]
meso-lanthionine
1500.0
[MenginLecreulx94]

pH(opt): 8 [Michaud90]


Sequence Features

Feature Class Location Citations Comment
Cleavage-of-Initial-Methionine 1
[Michaud90, Michaud90a, UniProt11, Michaud90]
UniProt: Removed.
Chain 2 -> 495
[UniProt09]
UniProt: UDP-N-acetylmuramoyl-L-alanyl-D- glutamate--2,6-diaminopimelate ligase;
Amino-Acid-Sites-That-Bind 27
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu; via carbonyl oxygen;
Amino-Acid-Sites-That-Bind 29
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu;
Protein-Segment 44 -> 46
[UniProt10a]
UniProt: UDP-MurNAc-L-Ala-D-Glu binding; Sequence Annotation Type: region of interest;
Nucleotide-Phosphate-Binding-Region 116 -> 122
[UniProt10a]
UniProt: ATP; Non-Experimental Qualifier: potential;
Amino-Acid-Sites-That-Bind 157
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu;
Protein-Segment 158 -> 159
[UniProt10a]
UniProt: UDP-MurNAc-L-Ala-D-Glu binding; Sequence Annotation Type: region of interest;
Amino-Acid-Sites-That-Bind 185
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu;
Amino-Acid-Sites-That-Bind 191
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu;
Amino-Acid-Sites-That-Bind 193
[UniProt10]
UniProt: UDP-MurNAc-L-Ala-D-Glu;
N6-carboxylysine-Modification 225
[UniProt11a]
UniProt: N6-carboxylysine.
Extrinsic-Sequence-Variant 344
[UniProt10]
Alternate sequence: E → K; UniProt: (in murE1);
Amino-Acid-Sites-That-Bind 390
[UniProt10]
UniProt: Meso-diaminopimelate;
Protein-Segment 414 -> 417
[UniProt10]
UniProt: Meso-diaminopimelate binding; Sequence Annotation Type: region of interest;
Amino-Acid-Sites-That-Bind 465
[UniProt10]
UniProt: Meso-diaminopimelate; via carbonyl oxygen;
Amino-Acid-Sites-That-Bind 469
[UniProt10]
UniProt: Meso-diaminopimelate;
Extrinsic-Sequence-Variant 495
[UniProt10]
Alternate sequence: A → S; UniProt: (in murE1);


Gene Local Context (not to scale): ?

Transcription Units:

Notes:

History:
10/20/97 Gene b0085 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10621; confirmed by SwissProt match.


References

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

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

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

Bratkovic08: Bratkovic T, Lunder M, Urleb U, Strukelj B (2008). "Peptide inhibitors of MurD and MurE, essential enzymes of bacterial cell wall biosynthesis." J Basic Microbiol 48(3);202-6. PMID: 18506905

BRENDA14: BRENDA team (2014). "Imported from BRENDA version existing on Aug 2014." http://www.brenda-enzymes.org.

Dementin01: Dementin S, Bouhss A, Auger G, Parquet C, Mengin-Lecreulx D, Dideberg O, van Heijenoort J, Blanot D (2001). "Evidence of a functional requirement for a carbamoylated lysine residue in MurD, MurE and MurF synthetases as established by chemical rescue experiments." Eur J Biochem 268(22);5800-7. PMID: 11722566

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

El03a: 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

Eveland97: Eveland SS, Pompliano DL, Anderson MS (1997). "Conditionally lethal Escherichia coli murein mutants contain point defects that map to regions conserved among murein and folyl poly-gamma-glutamate ligases: identification of a ligase superfamily." Biochemistry 36(20);6223-9. PMID: 9166795

GOA01: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

Gordon01: Gordon E, Flouret B, Chantalat L, van Heijenoort J, Mengin-Lecreulx D, Dideberg O (2001). "Crystal structure of UDP-N-acetylmuramoyl-L-alanyl-D-glutamate: meso-diaminopimelate ligase from Escherichia coli." J Biol Chem 276(14);10999-1006. PMID: 11124264

Hara97: Hara H, Yasuda S, Horiuchi K, Park JT (1997). "A promoter for the first nine genes of the Escherichia coli mra cluster of cell division and cell envelope biosynthesis genes, including ftsI and ftsW." J Bacteriol 179(18);5802-11. PMID: 9294438

Ishihama08: Ishihama Y, Schmidt T, Rappsilber J, Mann M, Hartl FU, Kerner MJ, Frishman D (2008). "Protein abundance profiling of the Escherichia coli cytosol." BMC Genomics 9;102. PMID: 18304323

Lugtenberg72: Lugtenberg EJ, v Schijndel-van Dam A (1972). "Temperature-sensitive mutants of Escherichia coli K-12 with low activity of the diaminopimelic acid adding enzyme." J Bacteriol 110(1);41-6. PMID: 4553000

Lugtenberg72a: Lugtenberg EJ (1972). "Studies on Escherichia coli enzymes involved in the synthesis of uridine diphosphate-N-acetyl-muramyl-pentapeptide." J Bacteriol 110(1);26-34. PMID: 4552992

Maruyama88: Maruyama IN, Yamamoto AH, Hirota Y (1988). "Determination of gene products and coding regions from the murE-murF region of Escherichia coli." J Bacteriol 170(8);3786-8. PMID: 2841306

MenginLecreulx82: Mengin-Lecreulx D, Flouret B, van Heijenoort J (1982). "Cytoplasmic steps of peptidoglycan synthesis in Escherichia coli." J Bacteriol 151(3);1109-17. PMID: 6125497

MenginLecreulx88: Mengin-Lecreulx D, Michaud C, Richaud C, Blanot D, van Heijenoort J (1988). "Incorporation of LL-diaminopimelic acid into peptidoglycan of Escherichia coli mutants lacking diaminopimelate epimerase encoded by dapF." J Bacteriol 170(5);2031-9. PMID: 3283102

MenginLecreulx89: Mengin-Lecreulx D, Parquet C, Desviat LR, Pla J, Flouret B, Ayala JA, van Heijenoort J (1989). "Organization of the murE-murG region of Escherichia coli: identification of the murD gene encoding the D-glutamic-acid-adding enzyme." J Bacteriol 171(11);6126-34. PMID: 2681153

MenginLecreulx94: Mengin-Lecreulx D, Blanot D, van Heijenoort J (1994). "Replacement of diaminopimelic acid by cystathionine or lanthionine in the peptidoglycan of Escherichia coli." J Bacteriol 1994;176(14);4321-7. PMID: 8021219

MenginLecreulx98: Mengin-Lecreulx D, Ayala J, Bouhss A, van Heijenoort J, Parquet C, Hara H (1998). "Contribution of the Pmra promoter to expression of genes in the Escherichia coli mra cluster of cell envelope biosynthesis and cell division genes." J Bacteriol 180(17);4406-12. PMID: 9721276

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

Michaud90a: Michaud C, Parquet C, Flouret B, Blanot D, van Heijenoort J (1990). "Revised interpretation of the sequence containing the murE gene encoding the UDP-N-acetylmuramyl-tripeptide synthetase of Escherichia coli." Biochem J 269(1);277-8. PMID: 2198024

Na13: Na D, Yoo SM, Chung H, Park H, Park JH, Lee SY (2013). "Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs." Nat Biotechnol 31(2);170-4. PMID: 23334451

Sova09: Sova M, Kovac A, Turk S, Hrast M, Blanot D, Gobec S (2009). "Phosphorylated hydroxyethylamines as novel inhibitors of the bacterial cell wall biosynthesis enzymes MurC to MurF." Bioorg Chem 37(6);217-22. PMID: 19804894

Tao89: Tao JS, Ishiguro EE (1989). "Nucleotide sequence of the murE gene of Escherichia coli." Can J Microbiol 35(11);1051-4. PMID: 2692800

Typas12: Typas A, Banzhaf M, Gross CA, Vollmer W (2012). "From the regulation of peptidoglycan synthesis to bacterial growth and morphology." Nat Rev Microbiol 10(2);123-36. PMID: 22203377

UniProt09: UniProt Consortium (2009). "UniProt version 15.8 released on 2009-10-01 00:00:00." Database.

UniProt10: UniProt Consortium (2010). "UniProt version 2010-11 released on 2010-11-02 00:00:00." Database.

UniProt10a: UniProt Consortium (2010). "UniProt version 2010-07 released on 2010-06-15 00:00:00." Database.

UniProt11: UniProt Consortium (2011). "UniProt version 2011-06 released on 2011-06-30 00:00:00." Database.

UniProt11a: UniProt Consortium (2011). "UniProt version 2011-11 released on 2011-11-22 00:00:00." Database.

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on the manual assignment of UniProtKB Subcellular Location terms in UniProtKB/Swiss-Prot entries."

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

UniProtGOA12: UniProt-GOA (2012). "Gene Ontology annotation based on UniPathway vocabulary mapping."

Vicente98: Vicente M, Gomez MJ, Ayala JA (1998). "Regulation of transcription of cell division genes in the Escherichia coli dcw cluster." Cell Mol Life Sci 54(4);317-24. PMID: 9614967

Other References Related to Gene Regulation

Eraso14: Eraso JM, Markillie LM, Mitchell HD, Taylor RC, Orr G, Margolin W (2014). "The Highly Conserved MraZ Protein Is a Transcriptional Regulator in Escherichia coli." J Bacteriol 196(11);2053-66. PMID: 24659771

Gohler11: Gohler AK, Kokpinar O, Schmidt-Heck W, Geffers R, Guthke R, Rinas U, Schuster S, Jahreis K, Kaleta C (2011). "More than just a metabolic regulator - elucidation and validation of new targets of PdhR in Escherichia coli." BMC Syst Biol 5(1);197. PMID: 22168595

Ishino89: Ishino F, Jung HK, Ikeda M, Doi M, Wachi M, Matsuhashi M (1989). "New mutations fts-36, lts-33, and ftsW clustered in the mra region of the Escherichia coli chromosome induce thermosensitive cell growth and division." J Bacteriol 171(10);5523-30. PMID: 2676977


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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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