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The Catalytic Mechanisms of Binuclear Metallohydrolases

Mitic, Natasa and Smith, Sarah J. and Neves, Ademir and Guddat, Luke W. and Gahan, Lawrence R. and Schenk, Gerhard (2006) The Catalytic Mechanisms of Binuclear Metallohydrolases. Chemical Reviews, 106 (8). pp. 3338-3363. ISSN 0009-2665

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Abstract

Binuclear metallohydrolases are a structurally diverse group of enzymes that use binuclear metal ion centers to catalyze the hydrolysis of amides and esters of carboxylic and phosphoric acids. Representatives are listed in Table 1, together with their metal ion composition and, if known, their metabolic role(s). Several of these enzymes are either targets for drug design against a wide variety of human disorders, including osteoporosis, cancer, cystic fibrosis, and depression, or are of significance in bioremediation since they can be modified to degrade pesticides or organophosphorus nerve gases. In 1996, Wilcox summarized the then current knowledge about the structure, function, and mechanism of all known binuclear metallohydrolases.1 In subsequent years more specialized articles followed,2 focusing on the binuclear manganese-containing arginases, catalases, and enolases,3 the Ser/Thr protein phosphatases (in particular calcineurin),4-6 Despite their structural versatility and variations in metal ion specificity (Table 1), binuclear metallohydrolases employ variants of a similar basic mechanism. Similarities in the first coordination sphere are found across the entire family of enzymes (Figure 1), but in the proposed models for catalysis, the identity of the attacking nucleophile, the stabilization of reaction intermediates, and the relative contribution of the metal ions vary substantially. Here, an updated review of the current understanding of metallohydrolase-catalyzed reactions is presented. The motivation is to present, compare, and critically assess current models for metal ion assisted hydrolytic reaction mechanisms. The focus here is on four systems, purple acid phosphatases (PAPs), Ser/Thr protein phosphatases (PPs), 3¢-5¢ exonucleases, and 5¢-nucleotidases (5¢-NTs), which have contributed to major advancement of our current understanding of the catalytic mechanisms that operate in such enzymes. Although three of the four enzymes (PAPs, PPs, and 5¢-NTs) are evolutionarily related,11 the enzymes selected for this review are diverse with respect to their structure, metal ion composition, and function. The authors have concentrated mainly on references covering the past decade; however, relevant earlier literature is included where appropriate. We extend our apologies to researchers whose contributions may not have been covered by this review. In terms of the catalytic mechanism, the identity of the reaction-initiating nucleophile and the roles of the metal ions in catalysis are addressed. Where possible, predicted structures of transition states and their stabilization are discussed. Each description of an enzyme family concludes with an illustration of the currently accepted model for its catalytic mechanism. The various models proposed for the hydrolytic reaction mechanism are compared in context with observed variations in physicochemical and functional properties. Similar to Wilcox’s review, this article reflects the recent achievements of bioinorganic chemists. However, since many binuclear metallohydrolases are targets for the development of drugs, pesticides and anti-warfare agents, structural biologists and those involved in drug discovery and development will find this review useful and timely.

Item Type: Article
Additional Information: The definitive version of this article is published in Chemical Reviews, (2006) Vol.106 No.8, pp.3338-3363, DOI: 10.1021/cr050318f. © 2006 American Chemical Society
Keywords: Catalytic Mechanisms; Binuclear Metallohydrolases; enzymes; binuclear; metal ion centers;
Subjects: Science & Engineering > Chemistry
Item ID: 3703
Depositing User: Gary Schenk
Date Deposited: 29 May 2012 15:28
Journal or Publication Title: Chemical Reviews
Publisher: American Chemical Soriety
Refereed: Yes
URI:

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