Structural highlights
Function
[NQO2_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.[1]
Publication Abstract from PubMed
A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease.
Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition.,Dufour M, Yan C, Siegel D, Colucci MA, Jenner M, Oldham NJ, Gomez J, Reigan P, Li Y, De Matteis CI, Ross D, Moody CJ Chembiochem. 2011 Apr 19. doi: 10.1002/cbic.201100085. PMID:21506232[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Calamini B, Santarsiero BD, Boutin JA, Mesecar AD. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. Biochem J. 2008 Jul 1;413(1):81-91. PMID:18254726 doi:10.1042/BJ20071373
- ↑ Dufour M, Yan C, Siegel D, Colucci MA, Jenner M, Oldham NJ, Gomez J, Reigan P, Li Y, De Matteis CI, Ross D, Moody CJ. Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition. Chembiochem. 2011 Apr 19. doi: 10.1002/cbic.201100085. PMID:21506232 doi:10.1002/cbic.201100085
