Control of Thiolate Nucleophilicity and Specificity in Zinc Metalloproteins by Hydrogen Bonding:  Lessons from Model Compound Studies

Abstract

A single hydrogen bond between an amide N-H and a thiolate sulfur in model complexes designed to mimic the binding site of zinc thiolate proteins, is shown to reduce the reactivity of the thiolate toward electrophiles by up to 2 orders of magnitude. In addition a single such bond is also sufficient to achieve nearly 100% regiospecificity of reaction between a strong, and hence inherently indiscriminate, alkylating agent like trimethyl oxonium tetrafluoroborate and a single sulfur in a dithiolate construct. The importance of these results in understanding how two systems such as the zinc fingers of the GATA family and the Escherichia coli DNA repair protein Ada which share the same pseudotetrahedral structure and tetrascysteinyl ligation around the zinc can fulfill such widely divergent (structural vs reactive) roles and how specificity of reaction in multithiolate-containing systems can be achieved is discussed.

Nucleophilicity of zinc-bound thiolates

“…We and others have shown in previous studies [21][22][23][24]30] that substituting the phenylthiolate by the o-NHC(O)H-phenylthiolate, inducing a H bond with the sulfur atom of the arylthiolate, reduces the reactivity of the corresponding zinc-bound arylthiolate. The same aryl-substitution on complexes 6 and 13 leads to two new complexes, noted 6' and 13', respectively, for which it is possible to evaluate the influence of the H bond toward the arylthiolate on the nucleophilicity of both the aryl-and the alkyl-thiolate.…”

“…[15] The influence of the nature of the metal cation on the nucleophilicity of p-toluenethiolate has been studied both experimentally and by DFT computation, revealing that nickel-and zinc-thiolate complexes are more reactive than ironand cobalt-thiolate complexes. [16] In the case of zinc complexes, both the composition of the ligand set, [17][18][19][20] in terms of donating capability and steric hindrance, and the presence of hydrogen bonding towards the reactive thiolate [21][22][23][24] have been shown to modulate the reactivity against electrophiles.…”

Biomimetic Applications of Metal Systems Supported by Scorpionates

“…14a) (Hammes & Carrano, 1999). With two nitrogen donors and an oxygen donor this ligand is well suited to mimic the active sites of thermolysin or carboxypeptidase A, although the zinc(II) in these models is bound by a phenolato donor instead of a carboxylato donor (Smith et al, 2003;Smith et al, 2005). Alkyl zinc complexes bearing various bis(pyrazol-1-yl)acetato ligands (HC(pz R,R' ) 2 (COO) -) offer an easy access to better structural model complexes for zinc peptidases with a 2-His-1-carboxylate motif.…”

“…Alkyl zinc complexes bearing various bis(pyrazol-1-yl)acetato ligands (HC(pz R,R' ) 2 (COO) -) offer an easy access to better structural model complexes for zinc peptidases with a 2-His-1-carboxylate motif. Starting from methyl complexes [(HC(pz R,R' ) 2 (COO)ZnCH 3 ] so far several complexes with carboxylato-, thiolato-and also hydroxamato-ligands have been obtained by methane releasing reactions with carboxylic acids, thiols and hydroxamic acids (Beck et al, 2001;Hegelmann et al, 2003;Smith et al, 2003;Smith et al, 2005). According to the NMR spectra these complexes often exhibit a κ 1 /κ 2 equilibrium (Fig.…”

“…Thiolates, carboxylates and hydroxamates are the most common zinc binding groups used in zinc peptidase inhibitors such as ACE inhibitors. Most of these models for carboxypeptidases have been characterised by X-ray structure determinations (Beck et al, 2001;Hegelmann et al, 2003;Smith et al, 2003;Smith et al, 2005), the model complexes helping to develop new zinc binding groups for potential peptidase inhibitors.…”