The diverse functionality of NQO1 and its roles in redox control

Abstract

In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD⁺ generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

Keywords: DT-Diaphorase; NQO1; Nrf2; Oxidative stress; Quinone; Redox switch.

Fig. 1

Induction of NQO1 and the role of NQO1 in quinone metabolism and defense against oxidative stress.

Fig. 2

Schematic representation of the redox-dependent immunoreactivity of NQO1. When NAD(P)H is readily available NQO1 adopts the reduced conformation (blue) preventing antibodies from binding to redox-dependent epitopes within helix 7 (A180) and to the C-terminal tails. When NAD(P)H levels drop the enzyme cannot maintain the reduced conformation and the redox-dependent epitopes are exposed allowing for immunoprecipitation. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Redox-dependent binding of NQO1 to microtubules. NAD(P)H levels direct the conformation of NQO1 and binding to microtubules. Inactivation of NQO1 by the inhibitor MI2321 alters the conformation of NQO1 preventing it from binding to microtubules disrupting the balance of acetylation/deacetylation (α-tubulin, K40) in the lumen of the microtubule leading to increased α-tubulin acetylation. Figure has been modified from Ref. [186].

Fig. 4

The effects of NQO1 on markers of nutritional excess caused by feeding a high fat diet. For detailed discussion of histological, physiological, omic and biochemical changes associated with NQO1 overexpression in mice fed a high fat diet, see reference 223.