Effect of Zn⋯Zn separation on the hydrolytic activity of model dizinc phosphodiesterases

Bernhard Bauer-Siebenlist, Franc Meyer, E. Farkas, Denis Vidovic, Sebastian Dechert

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

From the study of highly preorganized model systems, experimental support has been obtained for a possible functional role of the Zn-(H)O⋯HO(H)-Zn motif in oligozinc hydrolases. The mechanistic relevance of such an array, which may be described as a hydrated form of a pseudo-terminal Zn-bound hydroxide, has recently been supported by DFT calculations on various metallohydrolase active sites. In the present targeted approach, the Zn⋯Zn distance in two related dizinc complexes has been controlled through the use of multifunctional pyrazolate-based ligand scaffolds, giving either a tightly bridged Zn-O(H)-Zn or a more loosely bridged Zn-(H)O⋯HO(H)-Zn species in the solid state. Zn-bound water has been found to exhibit comparable acidity irrespective of whether the resulting hydroxide is supported by strong hydrogen-bonding in the O2H3 moiety or is in a bridging position between two zinc ions, indicating that water does not necessarily have to adopt a bridging position in order for its pKa to be sufficiently lowered so as to provide a Zn-bound hydroxide at physiological pH. Comparative reactivity studies on the cleavage of bis(4-nitrophenyl)phosphate (BNPP) mediated by the two dizinc complexes have revealed that the system with the larger Zn⋯Zn separation is hydrolytically more potent, both in the hydrolysis and the transesterification of BNPP. The extent of active site inhibition by the reaction products has also been found to be governed by the Zn⋯Zn distance, since phosphate diester coordination in a bridging mode within the clamp of two zinc ions is only favored for Zn⋯Zn distances well above 4 Å. Different binding affinities are rationalized in terms of the structural characteristics of the product-inhibited complexes for the two different ligand scaffolds, with dimethyl phosphate found as a bridging ligand within the bimetallic pocket.

Original languageEnglish
Pages (from-to)4349-4360
Number of pages12
JournalChemistry - A European Journal
Volume11
Issue number15
DOIs
Publication statusPublished - Jul 18 2005

Fingerprint

Phosphoric Diester Hydrolases
Phosphates
Ligands
Scaffolds
Zinc
Ions
Water
Transesterification
Clamping devices
Hydrolases
Reaction products
Acidity
Discrete Fourier transforms
Hydrolysis
Hydrogen bonds
hydroxide ion
bis(4-nitrophenyl)phosphate

Keywords

  • Bioinorganic chemistry
  • Dinuclear complexes
  • Phosphatase models
  • Pyrazolate ligands
  • Zinc complexes

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Effect of Zn⋯Zn separation on the hydrolytic activity of model dizinc phosphodiesterases. / Bauer-Siebenlist, Bernhard; Meyer, Franc; Farkas, E.; Vidovic, Denis; Dechert, Sebastian.

In: Chemistry - A European Journal, Vol. 11, No. 15, 18.07.2005, p. 4349-4360.

Research output: Contribution to journalArticle

Bauer-Siebenlist, Bernhard ; Meyer, Franc ; Farkas, E. ; Vidovic, Denis ; Dechert, Sebastian. / Effect of Zn⋯Zn separation on the hydrolytic activity of model dizinc phosphodiesterases. In: Chemistry - A European Journal. 2005 ; Vol. 11, No. 15. pp. 4349-4360.
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