Please use this identifier to cite or link to this item: http://repositorio.inesctec.pt/handle/123456789/6130
Title: Computational study of the covalent bonding of microcystins to cysteine residues - a reaction involved in the inhibition of the PPP family of protein phosphatases
Authors: Susana Rodrigues Pereira
Vasconcelos,VM
Antunes,A
Issue Date: 2013
Abstract: Microcystins (MCs) are cyclic peptides, produced by cyanobacteria, that are hepatotoxic to mammals. The toxicity mechanism involves the potent inhibition of protein phosphatases, as the toxins bind the catalytic subunits of five enzymes of the phosphoprotein phosphatase (PPP) family of serine/threonine-specific phosphatases: Ppp1 (aka PP1), Ppp2 (aka PP2A), Ppp4, Ppp5 and Ppp6. The interaction with the proteins includes the formation of a covalent bond with a cysteine residue. Although this reaction seems to be accessory for the inhibition of PPP enzymes, it has been suggested to play an important part in the biological role of MCs and furthermore is involved in their nonenzymatic conjugation to glutathione. In this study, the molecular interaction of microcystins with their targeted PPP catalytic subunits is reviewed, including the relevance of the covalent bond for overall inhibition. The chemical reaction that leads to the formation of the covalent bond was evaluated in silico, both thermodynamically and kinetically, using quantum mechanical-based methods. As a result, it was confirmed to be a Michael-type addition, with simultaneous abstraction of the thiol hydrogen by a water molecule, transfer of hydrogen from the water to the alpha,beta-unsaturated carbonyl group of the microcystin and addition of the sulfur to the beta-carbon of the microcystin moiety. The calculated kinetics are in agreement with previous experimental results that had indicated the reaction to occur in a second step after a fast noncovalent interaction that inhibited the enzymes per se.
URI: http://repositorio.inesctec.pt/handle/123456789/6130
http://dx.doi.org/10.1111/j.1742-4658.2011.08454.x
metadata.dc.type: article
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