Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays
Identifieur interne : 002123 ( Ncbi/Curation ); précédent : 002122; suivant : 002124Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays
Auteurs : Alexander Paasche ; Markus Schiller ; Tanja Schirmeister ; Bernd EngelsSource :
- Chemmedchem [ 1860-7179 ] ; 2010.
Abstract
Url:
DOI: 10.1002/cmdc.201000020
PubMed: 20401893
PubMed Central: 7162195
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays</title><author><name sortKey="Paasche, Alexander" sort="Paasche, Alexander" uniqKey="Paasche A" first="Alexander" last="Paasche">Alexander Paasche</name><affiliation><nlm:aff id="aa"></nlm:aff></affiliation></author><author><name sortKey="Schiller, Markus" sort="Schiller, Markus" uniqKey="Schiller M" first="Markus" last="Schiller">Markus Schiller</name><affiliation><nlm:aff id="ab"></nlm:aff></affiliation></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name><affiliation><nlm:aff id="ab"></nlm:aff></affiliation></author><author><name sortKey="Engels, Bernd" sort="Engels, Bernd" uniqKey="Engels B" first="Bernd" last="Engels">Bernd Engels</name><affiliation><nlm:aff id="aa"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20401893</idno><idno type="pmc">7162195</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162195</idno><idno type="RBID">PMC:7162195</idno><idno type="doi">10.1002/cmdc.201000020</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000E77</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E77</idno><idno type="wicri:Area/Pmc/Curation">000E77</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000E77</idno><idno type="wicri:Area/Pmc/Checkpoint">000C13</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000C13</idno><idno type="wicri:Area/Ncbi/Merge">002123</idno><idno type="wicri:Area/Ncbi/Curation">002123</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays</title><author><name sortKey="Paasche, Alexander" sort="Paasche, Alexander" uniqKey="Paasche A" first="Alexander" last="Paasche">Alexander Paasche</name><affiliation><nlm:aff id="aa"></nlm:aff></affiliation></author><author><name sortKey="Schiller, Markus" sort="Schiller, Markus" uniqKey="Schiller M" first="Markus" last="Schiller">Markus Schiller</name><affiliation><nlm:aff id="ab"></nlm:aff></affiliation></author><author><name sortKey="Schirmeister, Tanja" sort="Schirmeister, Tanja" uniqKey="Schirmeister T" first="Tanja" last="Schirmeister">Tanja Schirmeister</name><affiliation><nlm:aff id="ab"></nlm:aff></affiliation></author><author><name sortKey="Engels, Bernd" sort="Engels, Bernd" uniqKey="Engels B" first="Bernd" last="Engels">Bernd Engels</name><affiliation><nlm:aff id="aa"></nlm:aff></affiliation></author></analytic><series><title level="j">Chemmedchem</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p><italic>We investigated the reactions between substituted α,β‐unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS‐CoV M<sup>pro</sup>) by etacrynic acid derivatives as well as for the excess toxicity of substituted α,β‐unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4‐addition followed by a ketonization step, and underscores the importance of a base‐catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron‐pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the</italic> s<italic>‐</italic>cis <italic>conformation leads to higher reactivity than the</italic> s<italic>‐</italic>trans <italic>conformation. The computed data explain the trends in measured inhibition potencies of substituted α,β‐unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.</italic></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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