Binuclear metallohydrolases

Foremost, metal ions that catalyze hydrolysis reactions must be strong Lewis acids (electron acceptors). This property enables metal ions to facilitate hydrolytic reactions by enhancing the electrophilicity of the organic substrate and/or nucleophilicity of the water molecule, and allows hydrolysis reactions to proceed at, or around, neutral pH. Lewis acidity can be observed as a lowering of the pA/ values of bound ligands, such as a bound water molecule in hydrolysis reactions. The pA), of a water molecule decreases substantially upon coordination by a metal ion (Table 1), allowing the water molecule to become deprotonated near neutral pH. Coordination of more than one metal ion to a protic ligand, such as the case with binuclear metallohydrolases. 

Enzymes that contain binuclear metal centers are also well suited to catalyze hydrolysis reactions, including a number of the reactions described above for the mononuclear metallohydrolases. Additionally, several of the examples that are discussed here belong to the enzyme superfamilies described above, specifically the amidohydrolase, zinc a,/3-hydrolase, and metallo-/31 superfamilies. The substrates for the binuclear metallohydrolases are also biologically diverse, including proteins, peptides, nucleotides, polyamines, and xenobiotics. The binuclear nature of these metal centers produces an active site with altered properties compared to the mononuclear counterparts, and therefore catalysis by these enzymes occurs with alternative reaction mechanisms. Readers are referred to the preceding sections for background information pertaining to enzymes that have already been discussed. 

Figure 12 Proposed catalytic mechanisms for the binuclear metallohydrolases using a (a) single bifunctional GABC...

For PAPs and related binuclear metallohydrolases, a point of contention has been the number of water/hydroxide molecules coordinating to the resting active... 

Straeter N, Lipscomb WN, Klabunde T, Krebs B. Two-metal ion catalysis in enzymic acyl- and phosphoryl-transfer reactions. Angew Chem Int Ed Engl. 1996 35 2375-2433. Wilcox DE. Binuclear metallohydrolases. Chem Rev. 1996 96 2435-2458. 

Parts of this chapter have appeared in [L.J. Daumann et al., Spectroscopic and mechanistic studies of dinuclear metallohydrolases and their biomimetic complexes Dalton Trans. 2014, 43, 910-928. and L.J. Daumann et al., "The Role of Zn-OR and Zn-OH Nucleophiles and the Influence of p-Substituents in the Reactions of Binuclear Phosphatase Mimetics Dalton Trans. 2012, 41, 1695-1708.]—Reproduced by permission of The Royal Society of Chemistry. 

Metallohydrolases form a large group of predominantly binuclear enzymes that are involved in a wide array of biological functions. We have previously reviewed recent advances in their structure and function relationships [527]. Here, we focus on two members that have established iron centers, and which have been studied with EPR-related techniques. 

---