Phenotypic Modulation of Cancer-Associated Antioxidant NQO1 Activity by Post-Translational Modifications and the Natural Diversity of the Human Genome

Abstract

Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is a multifunctional and antioxidant stress protein whose expression is controlled by the Nrf2 signaling pathway. hNQO1 dysregulation is associated with cancer and neurological disorders. Recent works have shown that its activity is also modulated by different post-translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, and these may synergize with naturally-occurring and inactivating polymorphisms and mutations. Herein, I describe recent advances in the study of the effect of PTMs and genetic variations on the structure and function of hNQO1 and their relationship with disease development in different genetic backgrounds, as well as the physiological roles of these modifications. I pay particular attention to the long-range allosteric effects exerted by PTMs and natural variation on the multiple functions of hNQO1.

Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future

“…In fact, closely-related NQO1, that uses NADH, a typical co-substrate for oxidoreduction reaction, is at least ten times more studied with regard to polymorphic variants than NQO2. Recent systemic reviews confirm that NQO1 PGx is much more advanced compared to NQO2 PGx and addresses specific topics [113][114][115]. We can expect that a better grasp of the regulatory mechanisms of NQO2 enzymatic activity would trigger a stronger interest and faster progress in our understanding of NQO2 genetics, biology and pharmacology in the future.…”

Impact of NQO1 dysregulation in CNS disorders

“…The frequency and distribution of different NQO1 polymorphisms vary among various ethnic and racial populations [ 71 , 79 , 80 ]. Considering genotype–phenotype correlations in the multifunctionality of the NQO1 protein, genetic diversity, and the influence of post-translational modifications, NQO1 emerges as an exemplary model of a disease-associated antioxidant protein [ 81 ]. Furthermore, various therapies designed to correct the stability and dynamics of NQO1 polymorphic proteins and to regulate intracellular factors leading to loss-of-function are proposed as promising approaches for achieving better outcomes [ 17 ].…”