Abstract
In order to elucidate the elementary mechanism of the promiscuous esterase activity of human carbonic anhydrase (h-CA), we present an accurate theoretical investigation on the hydrolysis of fully-acetylated d-glucose functionalized as sulfamate. This h-CA’s inhibitor is of potential relevance in cancer therapy. The study has been performed within the framework of three-layer ONIOM (QM-high:QM’-medium:MM-low) hybrid approach. The computations revealed that the hydrolysis process is not energetically favored, in agreement with the observed weak carbonic anhydrase’s esterase activity.
Highlights
Different enzymes, in particular metallo-enzymes, are able to modulate their reactivity, as well as the substrate-selectivity of the system [1]
The calculated root mean square deviation (RMSD) referred to the protein backbone of the optimized geometry is 1.51 Å with respect to the initial conformation
The pocket of carbonic anhydrase is 15 Å deep and accommodates this substrate, which is much larger than CO2, with the participation of residues that usually are not involved in the formation of the molecular complex (Figure 1)
Summary
In particular metallo-enzymes, are able to modulate their reactivity, as well as the substrate-selectivity of the system [1]. Promiscuous catalysis, proposed in 1921 for explaining the C-C bond formation by pyruvate decarboxylase [4], was considered a dark side of enzyme specificity and, only in 1999, DID this aspect become more popular [5]. ” is considered an important tool in biotechnology [4,6,7,8]. H-CAs are zinc-containing metallo-enzymes that efficiently catalyze the reversible hydration of carbon dioxide, thereby playing a crucial role in pH regulation [9,10,11,12,13,14,15,16]. Starting from the early 1960s, when the esterase activity of carbonic anhydrase was observed for the first time [18], several structural, functional and mutational studies showed that the hydratase and esterase activities of CA shared similar mechanisms in the same catalytic pocket [9,19,20,21,22,23,24]
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