Binuclear metallohydrolases: Complex mechanistic strategies for a simple chemical reaction

Schenk, Gerhard, Mitić, Nataša, Gahan, Lawrence R., Ollis, David L., McGeary, Ross P. and Guddat, Luke W. (2012) Binuclear metallohydrolases: Complex mechanistic strategies for a simple chemical reaction. Accounts of Chemical Research, 45 9: 1593-1603. doi:10.1021/ar300067g

Author Schenk, Gerhard
Mitić, Nataša
Gahan, Lawrence R.
Ollis, David L.
McGeary, Ross P.
Guddat, Luke W.
Title Binuclear metallohydrolases: Complex mechanistic strategies for a simple chemical reaction
Journal name Accounts of Chemical Research   Check publisher's open access policy
ISSN 0001-4842
Publication date 2012-09
Sub-type Article (original research)
DOI 10.1021/ar300067g
Volume 45
Issue 9
Start page 1593
End page 1603
Total pages 11
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted abstract
Binuclear metallohydrolases are a large family of enzymes that require two closely spaced transition metal ions to carry out a plethora of hydrolytic reactions. Representatives include purple acid phosphatases (PAPs), enzymes that play a role in bone metabolism and are the only member of this family with a heterovalent binuclear center in the active form (Fe3+–M2+, M = Fe, Zn, Mn). Other members of this family are urease, which contains a di-Ni2+ center and catalyzes the breakdown of urea, arginase, which contains a di-Mn2+ center and catalyzes the final step in the urea cycle, and the metallo-β-lactamases, which contain a di-Zn2+ center and are virulence factors contributing to the spread of antibiotic-resistant pathogens.

Binuclear metallohydrolases catalyze numerous vital reactions and are potential targets of drugs against a wide variety of human disorders including osteoporosis, various cancers, antibiotic resistance, and erectile dysfunctions. These enzymes also tend to catalyze more than one reaction. An example is an organophosphate (OP)-degrading enzyme from Enterobacter aerogenes (GpdQ). Although GpdQ is part of a pathway that is used by bacteria to degrade glycerolphosphoesters, it hydrolyzes a variety of other phosphodiesters and displays low levels of activity against phosphomono- and triesters. Such a promiscuous nature may have assisted the apparent recent evolution of some binuclear metallohydrolases to deal with situations created by human intervention such as OP pesticides in the environment. OP pesticides were first used approximately 70 years ago, and therefore the enzymes that bacteria use to degrade them must have evolved very quickly on the evolutionary time scale. The promiscuous nature of enzymes such as GpdQ makes them ideal candidates for the application of directed evolution to produce new enzymes that can be used in bioremediation and against chemical warfare.

In this Account, we review the mechanisms employed by binuclear metallohydrolases and use PAP, the OP-degrading enzyme from Agrobacterium radiobacter (OPDA), and GpdQ as representative systems because they illustrate both the diversity and similarity of the reactions catalyzed by this family of enzymes. The majority of binuclear metallohydrolases utilize metal ion-activated water molecules as nucleophiles to initiate hydrolysis, while some, such as alkaline phosphatase, employ an intrinsic polar amino acid. Here we only focus on catalytic strategies applied by the former group.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Publication Date (Web): June 14, 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 35 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 18 Jun 2012, 11:45:05 EST by Lucy O'Brien on behalf of School of Chemistry & Molecular Biosciences