Urease is a Ni(II)-containing enzyme able to catalyse the conversion of urea to ammonia and carbamate. Urea, the most used soil nitrogen fertiliser worldwide, is thus rapidly hydrolysed into species of nitrogen that can be taken up by plants, a function that, while essential, might also significantly decrease the efficiency of this process due to the release of gaseous species of nitrogen into the atmosphere, contributing to the green-house effect and to air pollution. Moreover, urease is also a virulence factor for ureolytic bacterial human pathogens that affect the health and livelihood of millions of people, especially, but not only, in developing nations of Africa, Asia and Latin America. For these reasons, strategies for the efficient inhibition of urease activity by molecules that interact with the enzyme and counterbalance its negative effects must be pursued. Here, the inhibition of urease from Sporosarcina pasteurii (SPU) and Canavalia ensiformis (jack bean, JBU) by a class of six aromatic poly-hydroxylated molecules, namely mono- and dimethyl-substituted catechols, was investigated on the basis of the inhibitory efficiency of the catechol scaffold. The aim was to probe the key step of a mechanism proposed for the inhibition of SPU by catechol, namely the sulfanyl radical attack on the aromatic ring, as well as to obtain critical information on the effect of substituents of the catechol aromatic ring on the inhibition efficacy of its derivatives. The crystal structures of all six SPU-inhibitors complexes, determined at high resolution, as well as kinetic data obtained on JBU and theoretical studies of the reaction mechanism using quantum mechanical calculations, revealed the occurrence of an irreversible inactivation of urease by means of a radical-based autocatalytic multistep mechanism, and indicate that, among all tested catechols, the mono-substituted 3-methyl-catechol is the most efficient inhibitor for urease.

Inhibition of Urease, a Ni-Enzyme: The Reactivity of a Key Thiol With Mono- and Di-Substituted Catechols Elucidated by Kinetic, Structural, and Theoretical Studies

Cianci, Michele;
2021

Abstract

Urease is a Ni(II)-containing enzyme able to catalyse the conversion of urea to ammonia and carbamate. Urea, the most used soil nitrogen fertiliser worldwide, is thus rapidly hydrolysed into species of nitrogen that can be taken up by plants, a function that, while essential, might also significantly decrease the efficiency of this process due to the release of gaseous species of nitrogen into the atmosphere, contributing to the green-house effect and to air pollution. Moreover, urease is also a virulence factor for ureolytic bacterial human pathogens that affect the health and livelihood of millions of people, especially, but not only, in developing nations of Africa, Asia and Latin America. For these reasons, strategies for the efficient inhibition of urease activity by molecules that interact with the enzyme and counterbalance its negative effects must be pursued. Here, the inhibition of urease from Sporosarcina pasteurii (SPU) and Canavalia ensiformis (jack bean, JBU) by a class of six aromatic poly-hydroxylated molecules, namely mono- and dimethyl-substituted catechols, was investigated on the basis of the inhibitory efficiency of the catechol scaffold. The aim was to probe the key step of a mechanism proposed for the inhibition of SPU by catechol, namely the sulfanyl radical attack on the aromatic ring, as well as to obtain critical information on the effect of substituents of the catechol aromatic ring on the inhibition efficacy of its derivatives. The crystal structures of all six SPU-inhibitors complexes, determined at high resolution, as well as kinetic data obtained on JBU and theoretical studies of the reaction mechanism using quantum mechanical calculations, revealed the occurrence of an irreversible inactivation of urease by means of a radical-based autocatalytic multistep mechanism, and indicate that, among all tested catechols, the mono-substituted 3-methyl-catechol is the most efficient inhibitor for urease.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11566/287125
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