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Chemical Compound Review

Dialanine     2-(2- aminopropanoylamino)propanoic acid

Synonyms: Alanylalanine, Ala-ala, Di-L-Alanine, DL-Ala-DL-Ala, CHEMBL52461, ...
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Disease relevance of DL-Alanyl-DL-alanine


High impact information on DL-Alanyl-DL-alanine

  • Vancomycin, a broad-spectrum antibiotic, inhibits the growth of cell walls by complex formation with peptides terminating in D-alanyl-D-alanine [6].
  • VanX is a zinc-dependent D-alanyl-D-alanine dipeptidase that is a critical component in a system that mediates transposon-based vancomycin resistance in enterococci [7].
  • Although the genome of Arabidopsis thaliana contains five genes that are essential for peptidoglycan synthesis, MurE, MurG, two genes for d-Ala-d-Ala ligase (Ddl), and the gene for translocase I (MraY), their functions have not been determined [8].
  • The combined action of DdpX and the permease would permit hydrolysis of D-Ala-D-Ala transported back into the cytoplasm from the periplasm as cell-wall crosslinks are refashioned [3].
  • The modes of substrate binding have been deduced by analogy to D-Ala-D-Ala ligase and to pyruvate kinase [9].

Chemical compound and disease context of DL-Alanyl-DL-alanine


Biological context of DL-Alanyl-DL-alanine

  • Furthermore, the chimera catalyzes hydrolysis exclusively at the carboxyl-terminal amide bond which is the site of cleavage by D-Ala-D-Ala carboxypeptidase [14].
  • LAS enzymes are a group of metallopeptidases that share an active site architecture and a core folding motif and have been named according to the group members lysostaphin, D-Ala-D-Ala carboxypeptidase and sonic hedgehog [15].
  • This phenotype correlates with substitution of D-Ala-D-lactate (D-Ala-D-Lac) termini for D-Ala-D-Ala termini in peptidoglycan intermediates in which the depsipeptide has much lower affinity than the dipeptide for vancomycin binding [16].
  • Amino acid sequence similarity was detected between VANA and D-Ala: D-Ala ligases from Enterobacteriaceae [11].
  • Increased transcription of the vanHAX operon was associated with increased incorporation of D-Ala-D-Lac into peptidoglycan precursors to the detriment of D-Ala-D-Ala, and with a gradual increase in the vancomycin-resistance levels [17].

Anatomical context of DL-Alanyl-DL-alanine


Associations of DL-Alanyl-DL-alanine with other chemical compounds

  • In pathogenic vancomycin-resistant enterococci, vanX is part of a five-gene cluster that is switched on to reprogram cell-wall biosynthesis to produce peptidoglycan chain precursors terminating in D-alanyl-D-lactate (D-Ala-D-lactate) rather than D-Ala-D-Ala [3].
  • The Tyr-->Phe substitution on the active site omega-loop in D-Ala-D-Ala ligases is thus a molecular indicator of both the ability to make D-Ala-D-Lac and intrinsic resistance to the vancomycin class of glycopeptide antibiotics [16].
  • An antibiotic, D-cycloserine (DCS), inhibits the catalytic activities of alanine racemase (ALR) and d-alanyl-d-alanine ligase (DDL), which are necessary for the biosynthesis of the bacterial cell wall [4].
  • Upon exposure to vancomycin, the VanRS two-component system switches on expression of all seven van genes, and the VanHAX enzymes reprogram the cell wall such that precursors terminate D-Ala-D-lactate (Lac) rather than D-Ala-D-Ala, thus conferring resistance to vancomycin, which only binds D-Ala-D-Ala-containing precursors [21].
  • Pentapeptide, UDP-MurNac-pentapeptide, as well as D-alanyl-D-alanine were in vitro substrates for the carboxypeptidase which was not inhibited by penicillin [22].

Gene context of DL-Alanyl-DL-alanine

  • The C terminus (360 amino acids) is, however, homologous to D-Ala, D-Ala ligase (24% identity; 38% similarity), an enzyme having the same protein fold as known GS proteins [23].
  • The N-terminal sequence of gamma-GCS-GS is similar to Escherichia coli gamma-GCS, but the C-terminal sequence is an ATP-grasp domain more similar to d-Ala, d-Ala ligase than to any known GS [24].
  • Mutating the LL to dialanine (AA) caused an increase in the levels of mature BACE [25].
  • Two highly conserved residues in region II were examined through site-directed mutagenesis of the murein D-alanyl-D-alanine-adding enzyme from Escherichia coli (murF; E158 and H188) [26].
  • Viability of the E. coliDeltaddlADeltaddlB mutant in the absence of exogenous D-Ala-D-Ala dipeptide became dependent on the expression of the chlamydial murC-ddl thus demonstrating functional ligase activity [27].

Analytical, diagnostic and therapeutic context of DL-Alanyl-DL-alanine

  • X-ray crystallography has been used to examine the binding of three members of the beta-lactam family of antibiotics to the D-alanyl-D-alanine peptidase from Streptomyces R61, a target of penicillins [28].
  • Binding constants between the glycopeptides teicoplanin (Teic) and ristocetin (Rist) and their derivatives to D-Ala-D-Ala terminus peptides were determined by on-column receptor synthesis coupled to partial-filling affinity capillary electrophoresis (PFACE) or affinity capillary electrophoresis (ACE) [29].
  • Antibodies to the D-Ala-D-Ala moiety of peptidoglycan were measured by a sensitive and specific ELISA [30].
  • Furthermore, sequence analysis of the ddl gene revealed the presence of an IS982-like element (ISEfm1) which interrupted the D-Ala-D-Ala ligase [31].
  • Analysis of JH2-2 peptidoglycan by HPLC and MS after growth in the presence of 3% NaCl showed a relative increase in unsubstituted monomers and a relative decrease in alanine- and dialanine-substituted monomers [32].


  1. Tertiary structural similarity between a class A beta-lactamase and a penicillin-sensitive D-alanyl carboxypeptidase-transpeptidase. Samraoui, B., Sutton, B.J., Todd, R.J., Artymiuk, P.J., Waley, S.G., Phillips, D.C. Nature (1986) [Pubmed]
  2. Phosphinate analogs of D-, D-dipeptides: slow-binding inhibition and proteolysis protection of VanX, a D-, D-dipeptidase required for vancomycin resistance in Enterococcus faecium. Wu, Z., Walsh, C.T. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  3. VanX, a bacterial D-alanyl-D-alanine dipeptidase: resistance, immunity, or survival function? Lessard, I.A., Walsh, C.T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  4. Self-protection mechanism in D-cycloserine-producing Streptomyces lavendulae. Gene cloning, characterization, and kinetics of its alanine racemase and D-alanyl-D-alanine ligase, which are target enzymes of D-cycloserine. Noda, M., Kawahara, Y., Ichikawa, A., Matoba, Y., Matsuo, H., Lee, D.G., Kumagai, T., Sugiyama, M. J. Biol. Chem. (2004) [Pubmed]
  5. Kinetic evidence for the formation of D-alanyl phosphate in the mechanism of D-alanyl-D-alanine ligase. Mullins, L.S., Zawadzke, L.E., Walsh, C.T., Raushel, F.M. J. Biol. Chem. (1990) [Pubmed]
  6. Structure of vancomycin and its complex with acetyl-D-alanyl-D-alanine. Sheldrick, G.M., Jones, P.G., Kennard, O., Williams, D.H., Smith, G.A. Nature (1978) [Pubmed]
  7. The structure of VanX reveals a novel amino-dipeptidase involved in mediating transposon-based vancomycin resistance. Bussiere, D.E., Pratt, S.D., Katz, L., Severin, J.M., Holzman, T., Park, C.H. Mol. Cell (1998) [Pubmed]
  8. Genes for the peptidoglycan synthesis pathway are essential for chloroplast division in moss. Machida, M., Takechi, K., Sato, H., Chung, S.J., Kuroiwa, H., Takio, S., Seki, M., Shinozaki, K., Fujita, T., Hasebe, M., Takano, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Swiveling-domain mechanism for enzymatic phosphotransfer between remote reaction sites. Herzberg, O., Chen, C.C., Kapadia, G., McGuire, M., Carroll, L.J., Noh, S.J., Dunaway-Mariano, D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  10. Role of Ser-238 and Lys-240 in the hydrolysis of third-generation cephalosporins by SHV-type beta-lactamases probed by site-directed mutagenesis and three-dimensional modeling. Huletsky, A., Knox, J.R., Levesque, R.C. J. Biol. Chem. (1993) [Pubmed]
  11. Mechanisms and implications of glycopeptide resistance in enterococci. Derlot, E., Courvalin, P. Am. J. Med. (1991) [Pubmed]
  12. Gain of D-alanyl-D-lactate or D-lactyl-D-alanine synthetase activities in three active-site mutants of the Escherichia coli D-alanyl-D-alanine ligase B. Park, I.S., Lin, C.H., Walsh, C.T. Biochemistry (1996) [Pubmed]
  13. Partial purification and specificity studies of the D-glutamate-adding and D-alanyl-D-alanine-adding enzymes from Escherichia coli K12. Michaud, C., Blanot, D., Flouret, B., Van Heijenoort, J. Eur. J. Biochem. (1987) [Pubmed]
  14. Altering enzymatic activity: recruitment of carboxypeptidase activity into an RTEM beta-lactamase/penicillin-binding protein 5 chimera. Chang, Y.H., Labgold, M.R., Richards, J.H. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  15. Peptidoglycan amidase MepA is a LAS metallopeptidase. Marcyjaniak, M., Odintsov, S.G., Sabala, I., Bochtler, M. J. Biol. Chem. (2004) [Pubmed]
  16. D-Alanyl-D-lactate and D-alanyl-D-alanine synthesis by D-alanyl-D-alanine ligase from vancomycin-resistant Leuconostoc mesenteroides. Effects of a phenylalanine 261 to tyrosine mutation. Park, I.S., Walsh, C.T. J. Biol. Chem. (1997) [Pubmed]
  17. Quantitative analysis of the metabolism of soluble cytoplasmic peptidoglycan precursors of glycopeptide-resistant enterococci. Arthur, M., Depardieu, F., Reynolds, P., Courvalin, P. Mol. Microbiol. (1996) [Pubmed]
  18. Active-site-serine D-alanyl-D-alanine-cleaving-peptidase-catalysed acyl-transfer reactions. Procedures for studying the penicillin-binding proteins of bacterial plasma membranes. Ghuysen, J.M., Frère, J.M., Leyh-Bouille, M., Nguyen-Distèche, M., Coyette, J. Biochem. J. (1986) [Pubmed]
  19. Alanine enhances jejunal sodium absorption in the presence of glucose: studies in piglet viral diarrhea. Rhoads, J.M., MacLeod, R.J., Hamilton, J.R. Pediatr. Res. (1986) [Pubmed]
  20. Comparative proteomic analysis of Staphylococcus aureus strains with differences in resistance to the cell wall-targeting antibiotic vancomycin. Pieper, R., Gatlin-Bunai, C.L., Mongodin, E.F., Parmar, P.P., Huang, S.T., Clark, D.J., Fleischmann, R.D., Gill, S.R., Peterson, S.N. Proteomics (2006) [Pubmed]
  21. The role of the novel Fem protein VanK in vancomycin resistance in Streptomyces coelicolor. Hong, H.J., Hutchings, M.I., Hill, L.M., Buttner, M.J. J. Biol. Chem. (2005) [Pubmed]
  22. Inducible carboxypeptidase activity in vancomycin-resistant enterococci. Gutmann, L., Billot-Klein, D., al-Obeid, S., Klare, I., Francoual, S., Collatz, E., van Heijenoort, J. Antimicrob. Agents Chemother. (1992) [Pubmed]
  23. Glutathione synthesis in Streptococcus agalactiae. One protein accounts for gamma-glutamylcysteine synthetase and glutathione synthetase activities. Janowiak, B.E., Griffith, O.W. J. Biol. Chem. (2005) [Pubmed]
  24. Gamma-glutamylcysteine synthetase-glutathione synthetase: domain structure and identification of residues important in substrate and glutathione binding. Janowiak, B.E., Hayward, M.A., Peterson, F.C., Volkman, B.F., Griffith, O.W. Biochemistry (2006) [Pubmed]
  25. The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta). Pastorino, L., Ikin, A.F., Nairn, A.C., Pursnani, A., Buxbaum, J.D. Mol. Cell. Neurosci. (2002) [Pubmed]
  26. 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. Eveland, S.S., Pompliano, D.L., Anderson, M.S. Biochemistry (1997) [Pubmed]
  27. Characterization of Chlamydia MurC-Ddl, a fusion protein exhibiting D-alanyl-D-alanine ligase activity involved in peptidoglycan synthesis and D-cycloserine sensitivity. McCoy, A.J., Maurelli, A.T. Mol. Microbiol. (2005) [Pubmed]
  28. Crystallographic mapping of beta-lactams bound to a D-alanyl-D-alanine peptidase target enzyme. Kelly, J.A., Knox, J.R., Zhao, H., Frère, J.M., Ghaysen, J.M. J. Mol. Biol. (1989) [Pubmed]
  29. On-column derivatization of the antibiotics teicoplanin and ristocetin coupled to affinity capillary electrophoresis. Silverio, C.F., Azad, M., Gomez, F.A. Electrophoresis (2003) [Pubmed]
  30. Antibodies to peptidoglycan in patients with spondylarthritis: a clue to disease aetiology? Park, H., Schumacher, H.R., Zeiger, A.R., Rosenbaum, J.T. Ann. Rheum. Dis. (1984) [Pubmed]
  31. Molecular characterization of the vanD gene cluster and a novel insertion element in a vancomycin-resistant enterococcus isolated in Canada. Boyd, D.A., Conly, J., Dedier, H., Peters, G., Robertson, L., Slater, E., Mulvey, M.R. J. Clin. Microbiol. (2000) [Pubmed]
  32. Resistance to cefotaxime and peptidoglycan composition in Enterococcus faecalis are influenced by exogenous sodium chloride. Mainardi, J.L., Billot-Klein, D., Coutrot, A., Legrand, R., Schoot, B., Gutmann, L. Microbiology (Reading, Engl.) (1998) [Pubmed]
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