Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1)

Clare F. Megarity, Hoda Abdel-Aal Bettley, Mary Clare Caraher, Katherine A. Scott, Roger A. Whitehead, Thomas A. Jowitt, Aldo Gutierrez, Richard A. Bryce, Karen A. Nolan, Ian J. Stratford, David J Timson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.

Original languageEnglish
JournalChemBioChem
DOIs
Publication statusPublished - 5 Jun 2019

Fingerprint

NAD
Oxidoreductases
Dicumarol
Binding Sites
Proteins
Ligands
Enzymes
benzoquinone
Pharmaceutical Preparations

Bibliographical note

This is the peer reviewed version of the following article: Megarity, C. ., Abdel-Aal Bettley, H. , Caraher, M. ., Scott, K. ., Whitehead, R. ., Jowitt, T. ., Gutierrez, A. , Bryce, R. ., Nolan, K. ., Stratford, I. . and Timson, D. . (2019), Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem, which has been published in final form at doi:10.1002/cbic.201900313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Keywords

  • Quinone oxidoreductase
  • Protein flexibility
  • Elastic network model
  • Enzyme cooperativity
  • Cancer-associated protein

Cite this

Megarity, C. F., Abdel-Aal Bettley, H., Caraher, M. C., Scott, K. A., Whitehead, R. A., Jowitt, T. A., ... Timson, D. J. (2019). Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem. https://doi.org/10.1002/cbic.201900313
Megarity, Clare F. ; Abdel-Aal Bettley, Hoda ; Caraher, Mary Clare ; Scott, Katherine A. ; Whitehead, Roger A. ; Jowitt, Thomas A. ; Gutierrez, Aldo ; Bryce, Richard A. ; Nolan, Karen A. ; Stratford, Ian J. ; Timson, David J. / Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). In: ChemBioChem. 2019.
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abstract = "NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.",
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author = "Megarity, {Clare F.} and {Abdel-Aal Bettley}, Hoda and Caraher, {Mary Clare} and Scott, {Katherine A.} and Whitehead, {Roger A.} and Jowitt, {Thomas A.} and Aldo Gutierrez and Bryce, {Richard A.} and Nolan, {Karen A.} and Stratford, {Ian J.} and Timson, {David J}",
note = "This is the peer reviewed version of the following article: Megarity, C. ., Abdel-Aal Bettley, H. , Caraher, M. ., Scott, K. ., Whitehead, R. ., Jowitt, T. ., Gutierrez, A. , Bryce, R. ., Nolan, K. ., Stratford, I. . and Timson, D. . (2019), Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem, which has been published in final form at doi:10.1002/cbic.201900313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.",
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Megarity, CF, Abdel-Aal Bettley, H, Caraher, MC, Scott, KA, Whitehead, RA, Jowitt, TA, Gutierrez, A, Bryce, RA, Nolan, KA, Stratford, IJ & Timson, DJ 2019, 'Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1)', ChemBioChem. https://doi.org/10.1002/cbic.201900313

Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). / Megarity, Clare F.; Abdel-Aal Bettley, Hoda; Caraher, Mary Clare; Scott, Katherine A.; Whitehead, Roger A.; Jowitt, Thomas A.; Gutierrez, Aldo; Bryce, Richard A.; Nolan, Karen A.; Stratford, Ian J.; Timson, David J.

In: ChemBioChem, 05.06.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Megarity, Clare F.

AU - Abdel-Aal Bettley, Hoda

AU - Caraher, Mary Clare

AU - Scott, Katherine A.

AU - Whitehead, Roger A.

AU - Jowitt, Thomas A.

AU - Gutierrez, Aldo

AU - Bryce, Richard A.

AU - Nolan, Karen A.

AU - Stratford, Ian J.

AU - Timson, David J

N1 - This is the peer reviewed version of the following article: Megarity, C. ., Abdel-Aal Bettley, H. , Caraher, M. ., Scott, K. ., Whitehead, R. ., Jowitt, T. ., Gutierrez, A. , Bryce, R. ., Nolan, K. ., Stratford, I. . and Timson, D. . (2019), Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem, which has been published in final form at doi:10.1002/cbic.201900313. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

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Y1 - 2019/6/5

N2 - NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.

AB - NAD(P)H quinone oxidoreductase-1 (NQO1) is a homodimeric protein that acts as a detoxifying enzyme or as a chaperone protein. Dicourmarol interacts with NQO1 at the NAD(P)H binding site and can both inhibit enzyme activity and modulate the interaction of NQO1 with other proteins. We show that the binding of dicoumarol and related compounds to NQO1 generates negative cooperativity between the monomers. This does not occur in the presence of the reducing cofactor, NAD(P)H, alone. Alteration of Gly150 (but not Gly149 or Gly174) abolished the dicoumarol-induced negative cooperativity. Analysis of the dynamics of NQO1 with the Gaussian network model indicates a high degree of collective motion by monomers and domains within NQO1. Ligand binding is predicted to alter NQO1 dynamics both proximal to the ligand binding site and remotely, close to the second binding site. Thus, drug-induced modulation of protein motion might contribute to the biological effects of putative inhibitors of NQO1.

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KW - Protein flexibility

KW - Elastic network model

KW - Enzyme cooperativity

KW - Cancer-associated protein

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JF - ChemBioChem

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Megarity CF, Abdel-Aal Bettley H, Caraher MC, Scott KA, Whitehead RA, Jowitt TA et al. Negative cooperativity in NAD(P)H quinone oxidoreductase 1 (NQO1). ChemBioChem. 2019 Jun 5. https://doi.org/10.1002/cbic.201900313