Mitic, Natasa and Smith, Sarah J. and Neves, Ademir and Guddat, Luke W. and Gahan, Lawrence R. and Schenk, Gerhard
The Catalytic Mechanisms of Binuclear Metallohydrolases.
Chemical Reviews, 106 (8).
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
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.
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