Steady-state and pre-steady-state kinetic evaluation of severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro cysteine protease: development of an ion-pair model for catalysis.
Identifieur interne : 001B68 ( Ncbi/Merge ); précédent : 001B67; suivant : 001B69Steady-state and pre-steady-state kinetic evaluation of severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro cysteine protease: development of an ion-pair model for catalysis.
Auteurs : James Solowiej [États-Unis] ; James A. Thomson ; Kevin Ryan ; Chun Luo ; Mingying He ; Jihong Lou ; Brion W. MurraySource :
- Biochemistry [ 0006-2960 ] ; 2008.
Descripteurs français
- KwdFr :
- 2-Iodo-acétamide (pharmacologie), Acrylates (pharmacocinétique), Activation enzymatique (), Alkylation, Antienzymes (pharmacocinétique), Catalyse, Cinétique, Concentration en ions d'hydrogène, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Cystéine (), Dipeptides (pharmacocinétique), Histidine (), Ions (métabolisme), Modèles biologiques, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Solvants (pharmacologie), Stabilité enzymatique (), Transferases (métabolisme), Virus du SRAS (enzymologie), Électricité statique.
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Ions, Protéines virales, Transferases.
- pharmacocinétique : Acrylates, Antienzymes, Dipeptides.
- pharmacologie : 2-Iodo-acétamide, Solvants.
- Activation enzymatique, Alkylation, Catalyse, Cinétique, Concentration en ions d'hydrogène, Cysteine endopeptidases, Cystéine, Histidine, Modèles biologiques, Protéines virales, Stabilité enzymatique, Électricité statique.
English descriptors
- KwdEn :
- Acrylates (pharmacokinetics), Alkylation, Catalysis, Cysteine (chemistry), Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Dipeptides (pharmacokinetics), Enzyme Activation (drug effects), Enzyme Inhibitors (pharmacokinetics), Enzyme Stability (drug effects), Histidine (chemistry), Hydrogen-Ion Concentration, Iodoacetamide (pharmacology), Ions (metabolism), Kinetics, Models, Biological, SARS Virus (enzymology), Solvents (pharmacology), Static Electricity, Transferases (metabolism), Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Cysteine, Cysteine Endopeptidases, Histidine, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Ions, Transferases, Viral Proteins.
- chemical , pharmacokinetics : Acrylates, Dipeptides, Enzyme Inhibitors.
- drug effects : Enzyme Activation, Enzyme Stability.
- enzymology : SARS Virus.
- chemical , pharmacology : Iodoacetamide, Solvents.
- Alkylation, Catalysis, Hydrogen-Ion Concentration, Kinetics, Models, Biological, Static Electricity.
Abstract
Severe acute respiratory syndrome (SARS) was a worldwide epidemic caused by a coronavirus that has a cysteine protease (3CLpro) essential to its life cycle. Steady-state and pre-steady-state kinetic methods were used with highly active 3CLpro to characterize the reaction mechanism. We show that 3CLpro has mechanistic features common and disparate to the archetypical proteases papain and chymotrypsin. The kinetic mechanism for 3CLpro-mediated ester hydrolysis, including the individual rate constants, is consistent with a simple double displacement mechanism. The pre-steady-state burst rate was independent of ester substrate concentration indicating a high commitment to catalysis. When homologous peptidic amide and ester substrates were compared, a series of interesting observations emerged. Despite a 2000-fold difference in nonenzymatic reactivity, highly related amide and ester substrates were found to have similar kinetic parameters in both the steady-state and pre-steady-state. Steady-state solvent isotope effect (SIE) studies showed an inverse SIE for the amide but not ester substrates. Evaluation of the SIE in the pre-steady-state revealed normal SIEs for both amide and ester burst rates. Proton inventory (PI) studies on amide peptide hydrolysis were consistent with two proton-transfer reactions in the transition state while the ester data was consistent with a single proton-transfer reaction. Finally, the pH-inactivation profile of 3CLpro with iodoacetamide is indicative of an ion-pair mechanism. Taken together, the data are consistent with a 3CLpro mechanism that utilizes an "electrostatic" trigger to initiate the acylation reaction, a cysteine-histidine catalytic dyad ion pair, an enzyme-facilitated release of P1, and a general base-catalyzed deacylation reaction.
DOI: 10.1021/bi702107v
PubMed: 18237196
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 001C23
- to stream PubMed, to step Curation: 001C23
- to stream PubMed, to step Checkpoint: 001A13
Links to Exploration step
pubmed:18237196Le document en format XML
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<term>Catalysis</term>
<term>Cysteine (chemistry)</term>
<term>Cysteine Endopeptidases (chemistry)</term>
<term>Cysteine Endopeptidases (metabolism)</term>
<term>Dipeptides (pharmacokinetics)</term>
<term>Enzyme Activation (drug effects)</term>
<term>Enzyme Inhibitors (pharmacokinetics)</term>
<term>Enzyme Stability (drug effects)</term>
<term>Histidine (chemistry)</term>
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<term>Kinetics</term>
<term>Models, Biological</term>
<term>SARS Virus (enzymology)</term>
<term>Solvents (pharmacology)</term>
<term>Static Electricity</term>
<term>Transferases (metabolism)</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
<term>Viral Proteins (metabolism)</term>
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<term>Acrylates (pharmacocinétique)</term>
<term>Activation enzymatique ()</term>
<term>Alkylation</term>
<term>Antienzymes (pharmacocinétique)</term>
<term>Catalyse</term>
<term>Cinétique</term>
<term>Concentration en ions d'hydrogène</term>
<term>Cysteine endopeptidases ()</term>
<term>Cysteine endopeptidases (métabolisme)</term>
<term>Cystéine ()</term>
<term>Dipeptides (pharmacocinétique)</term>
<term>Histidine ()</term>
<term>Ions (métabolisme)</term>
<term>Modèles biologiques</term>
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<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Protéines virales (métabolisme)</term>
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<term>Viral Proteins</term>
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<term>Transferases</term>
<term>Viral Proteins</term>
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<term>Hydrogen-Ion Concentration</term>
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<term>Static Electricity</term>
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<term>Cinétique</term>
<term>Concentration en ions d'hydrogène</term>
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<term>Cystéine</term>
<term>Histidine</term>
<term>Modèles biologiques</term>
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<front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) was a worldwide epidemic caused by a coronavirus that has a cysteine protease (3CLpro) essential to its life cycle. Steady-state and pre-steady-state kinetic methods were used with highly active 3CLpro to characterize the reaction mechanism. We show that 3CLpro has mechanistic features common and disparate to the archetypical proteases papain and chymotrypsin. The kinetic mechanism for 3CLpro-mediated ester hydrolysis, including the individual rate constants, is consistent with a simple double displacement mechanism. The pre-steady-state burst rate was independent of ester substrate concentration indicating a high commitment to catalysis. When homologous peptidic amide and ester substrates were compared, a series of interesting observations emerged. Despite a 2000-fold difference in nonenzymatic reactivity, highly related amide and ester substrates were found to have similar kinetic parameters in both the steady-state and pre-steady-state. Steady-state solvent isotope effect (SIE) studies showed an inverse SIE for the amide but not ester substrates. Evaluation of the SIE in the pre-steady-state revealed normal SIEs for both amide and ester burst rates. Proton inventory (PI) studies on amide peptide hydrolysis were consistent with two proton-transfer reactions in the transition state while the ester data was consistent with a single proton-transfer reaction. Finally, the pH-inactivation profile of 3CLpro with iodoacetamide is indicative of an ion-pair mechanism. Taken together, the data are consistent with a 3CLpro mechanism that utilizes an "electrostatic" trigger to initiate the acylation reaction, a cysteine-histidine catalytic dyad ion pair, an enzyme-facilitated release of P1, and a general base-catalyzed deacylation reaction.</div>
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<Abstract><AbstractText>Severe acute respiratory syndrome (SARS) was a worldwide epidemic caused by a coronavirus that has a cysteine protease (3CLpro) essential to its life cycle. Steady-state and pre-steady-state kinetic methods were used with highly active 3CLpro to characterize the reaction mechanism. We show that 3CLpro has mechanistic features common and disparate to the archetypical proteases papain and chymotrypsin. The kinetic mechanism for 3CLpro-mediated ester hydrolysis, including the individual rate constants, is consistent with a simple double displacement mechanism. The pre-steady-state burst rate was independent of ester substrate concentration indicating a high commitment to catalysis. When homologous peptidic amide and ester substrates were compared, a series of interesting observations emerged. Despite a 2000-fold difference in nonenzymatic reactivity, highly related amide and ester substrates were found to have similar kinetic parameters in both the steady-state and pre-steady-state. Steady-state solvent isotope effect (SIE) studies showed an inverse SIE for the amide but not ester substrates. Evaluation of the SIE in the pre-steady-state revealed normal SIEs for both amide and ester burst rates. Proton inventory (PI) studies on amide peptide hydrolysis were consistent with two proton-transfer reactions in the transition state while the ester data was consistent with a single proton-transfer reaction. Finally, the pH-inactivation profile of 3CLpro with iodoacetamide is indicative of an ion-pair mechanism. Taken together, the data are consistent with a 3CLpro mechanism that utilizes an "electrostatic" trigger to initiate the acylation reaction, a cysteine-histidine catalytic dyad ion pair, an enzyme-facilitated release of P1, and a general base-catalyzed deacylation reaction.</AbstractText>
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<PubMedPubDate PubStatus="entrez"><Year>2008</Year>
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<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">18237196</ArticleId>
<ArticleId IdType="doi">10.1021/bi702107v</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>États-Unis</li>
</country>
</list>
<tree><noCountry><name sortKey="He, Mingying" sort="He, Mingying" uniqKey="He M" first="Mingying" last="He">Mingying He</name>
<name sortKey="Lou, Jihong" sort="Lou, Jihong" uniqKey="Lou J" first="Jihong" last="Lou">Jihong Lou</name>
<name sortKey="Luo, Chun" sort="Luo, Chun" uniqKey="Luo C" first="Chun" last="Luo">Chun Luo</name>
<name sortKey="Murray, Brion W" sort="Murray, Brion W" uniqKey="Murray B" first="Brion W" last="Murray">Brion W. Murray</name>
<name sortKey="Ryan, Kevin" sort="Ryan, Kevin" uniqKey="Ryan K" first="Kevin" last="Ryan">Kevin Ryan</name>
<name sortKey="Thomson, James A" sort="Thomson, James A" uniqKey="Thomson J" first="James A" last="Thomson">James A. Thomson</name>
</noCountry>
<country name="États-Unis"><noRegion><name sortKey="Solowiej, James" sort="Solowiej, James" uniqKey="Solowiej J" first="James" last="Solowiej">James Solowiej</name>
</noRegion>
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</affiliations>
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