Disease relevance of Alanyl-lactate

• VanD-type Enterococcus faecium BM4416 was constitutively resistant to vancomycin and to teicoplanin by synthesis of peptidoglycan precursors ending in D-alanyl-D-lactate [1].
• In vancomycin-resistant Gram-positive bacteria, structurally related enzymes synthesize D-alanyl-D-lactate or d-alanyl-d-serine [2].
• The glycopeptide antibiotic producer Streptomyces toyocaensis NRRL 15009 has both D-alanyl-D-alanine and D-alanyl-D-lactate ligases [3].

High impact information on Alanyl-lactate

• The molecular basis of vancomycin resistance in clinically relevant Enterococci: crystal structure of D-alanyl-D-lactate ligase (VanA) [4].
• This structure shows that the active site has unexpected interactions and is distinct from previous models for d-alanyl-d-lactate ligase mechanistic studies [4].
• Tn 1546 encodes a dehydrogenase (VanH) and a ligase (VanA) that synthesize D-alanyl-D-lactate (D-Ala-D-Lac), a D,D-dipeptidase (VanX) that hydrolyses D-Ala-D-Ala and a two-component regulatory system (VanR-VanS) that controls transcription of the vanHAX operon [5].
• The vanX gene was located downstream from genes encoding the VanA ligase and the VanH dehydrogenase which synthesize the depsipeptide D-alanyl-D-lactate (D-Ala-D-Lac) [6].
• Two differing theories, one positing the generation of high affinity, specific binding to D-alanyl-D-lactate via glycopeptide dimerization and/or membrane anchoring, and the other supporting direct targeting of the modified glycopeptide to the transglycosylation complex, seek to explain the mechanism of action on vancomycin resistant enterococci [7].

Chemical compound and disease context of Alanyl-lactate

• VanD type Enterococcus faecium 10/96A is constitutively resistant to vancomycin and to low levels of teicoplanin by nearly exclusive synthesis of peptidoglycan precursors terminating in D-alanyl-D-lactate (L. M. Dalla Costa, P. E. Reynolds, H. A. Souza, D. C. Souza, M. F. Palepou, and N. Woodford, Antimicrob. Agents Chemother. 44:3444-3446, 2000) [8].

Biological context of Alanyl-lactate

• BACKGROUND: The D-alanyl-D-lactate (D-Ala-D-Lac) ligase is required for synthesis of altered peptidoglycan (PG) termini in the VanA phenotype of vancomycin-resistant enterococci (VRE), and the D-alanyl-D-serine (D-Ala-D-Ser) ligase is required for the VanC phenotype of VRE [9].
• They were constitutively resistant by synthesis of peptidoglycan precursors ending with d-alanyl-d-lactate and harbored a chromosomal vanD gene cluster which was not transferable by conjugation to other enterococci [10].

Anatomical context of Alanyl-lactate

• These depsipeptides, terminating in D-alanyl-D-lactate, mimic the cell-wall precursors of resistant bacteria [11].

Associations of Alanyl-lactate with other chemical compounds

• Tn1546 encodes the VanH dehydrogenase which reduces pyruvate to D-lactate (D-Lac) and the VanA ligase which catalyses synthesis of the depsipeptide D-alanyl-D-lactate (D-Ala-D-Lac) [12].

References