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J Med Chem. 1999 Jan 14;42(1):109-17.

Calculation of the pKa values for the ligands and side chains of Escherichia coli D-alanine:D-alanine ligase.

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Departments of Chemistry and Biochemistry and of Pharmacology, University of California, San Diego, La Jolla, California 92093-0365, USA.


Poisson-Boltzmann electrostatics methods have been used to calculate the pKa shifts for the ligands and titratable side chains of D-alanine:D-alanine ligase of the ddlb gene of Escherichia coli (DdlB). The focus of this study is to determine the ionization state of the second D-alanine (D-Ala2) in the active site of DdlB. The pKa of the amine is shifted over 5 pKa units more alkaline in the protein, clearly implying that D-Ala2 is bound to DdlB in its zwitterionic state and not in the free-base form as had been previously suggested. Comparisons are made to the depsipeptide ligase from the vancomycin-resistance cascade, VanA. It is suggested that VanA has different enzymatic properties due to a change in binding specificity rather than altered catalytic behavior and that the specificity of binding D-lactate over D-Ala2 may arise from the difference in ionization characteristics of the ligands.

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