ExplorEnz: EC 3.4.13.22

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3.4.13.22

Accepted name:

D-Ala-D-Ala dipeptidase

Reaction:

D-Ala-D-Ala + H₂O = 2 D-Ala

Other name(s):

D-alanyl-D-alanine dipeptidase; vanX D-Ala-D-Ala dipeptidase; VanX

Comments:

A Zn²⁺-dependent enzyme [4]. The enzyme protects Enterococcus faecium from the antibiotic vancomycin, which can bind to the -D-Ala-D-Ala sequence at the C-terminus of the peptidoglycan pentapeptide (see diagram). This enzyme reduces the availability of the free dipeptide D-Ala-D-Ala, which is the precursor for this pentapeptide sequence, allowing D-Ala-(R)-lactate (for which vancomycin has much less affinity) to be added to the cell wall instead [2,3]. The enzyme is stereospecific, as L-Ala-L-Ala, D-Ala-L-Ala and L-Ala-D-Ala are not substrates [2]. Belongs in peptidase family M15.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB

References:

1.	Reynolds, P.E., Depardieu, F., Dutka-Malen, S., Arthur, M. and Courvalin, P. Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. Mol. Microbiol. 13 (1994) 1065–1070. [DOI] [PMID: 7854121]
2.	Wu, Z., Wright, G.D. and Walsh, C.T. Overexpression, purification, and characterization of VanX, a D-, D-dipeptidase which is essential for vancomycin resistance in Enterococcus faecium BM4147. Biochemistry 34 (1995) 2455–2463. [PMID: 7873524]
3.	McCafferty, D.G., Lessard, I.A. and Walsh, C.T. Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX. Biochemistry 36 (1997) 10498–10505. [DOI] [PMID: 9265630]
4.	Bussiere, D.E., Pratt, S.D., Katz, L., Severin, J.M., Holzman, T. and Park, C.H. The structure of VanX reveals a novel amino-dipeptidase involved in mediating transposon-based vancomycin resistance. Mol. Cell. 2 (1998) 75–84. [DOI] [PMID: 9702193]
5.	Tan, A.L., Loke, P. and Sim, T.S. Molecular cloning and functional characterisation of VanX, a D-alanyl-D-alanine dipeptidase from Streptomyces coelicolor A3(2). Res. Microbiol. 153 (2002) 27–32. [DOI] [PMID: 11881895]
6.	Matthews, M.L., Periyannan, G., Hajdin, C., Sidgel, T.K., Bennett, B. and Crowder, M.W. Probing the reaction mechanism of the D-ala-D-ala dipeptidase, VanX, by using stopped-flow kinetic and rapid-freeze quench EPR studies on the Co(II)-substituted enzyme. J. Am. Chem. Soc. 128 (2006) 13050–13051. [DOI] [PMID: 17017774]

[EC 3.4.13.22 created 2006]