NFE2L2 inducers bind to KEAP1:CUL3:RBX1:NFE2L2

Stable Identifier
Reaction [binding]
Homo sapiens
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NFE2L2 inducers (e.g. sulforaphane, fumarates, and their derivatives) block ubiquitination of NFE2L2 by binding more or less irreversibly to L-cysteine 315 and other cysteine residues of KEAP1. This strongly enhances induction of expression of all genes with antioxidant response elements (ARE), the most prominent being HMOX1 and NQO1 (Hong et al, 2005).

Sulforaphane has proved to be an effective chemoprotective agent in cell culture, carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer (Clarke et al, 2008). These preclinical studies demonstrate chemopreventive mode of actions of isothiocyanates, mainly related to a.) detoxification (induction of phase II enzymes), b.) anti-inflammatory properties by down-regulation of NFkappaB activity, c.) cyclin-mediated cell cycle arrest and d.) epigenetic modulation by inhibition of histone deacetylase activity. First prospective clinical trials were promising in patients with risk of prostate cancer recurrence (GrĂ¼ndemann and Huber, 2018; Kamal et al, 2020)

In cancer treatment, sulforaphane exhibited promising inhibitory effects on breast cancer, lung cancer, liver cancer, and other malignant tumors (Wu et al, 2020)

Five clinical trials showed a significant positive correlation between sulforaphane use and autism spectrum disorder (ASD) behavior and cognitive function. The current evidence shows with minimal side effects observed, sulforaphane appears to be a safe and effective treatment option for treating ASD (McGuinness and Kim, 2020).

Dimethyl fumarate (DMF) was effective in reducing the proportion of patients with MS relapse at 2 years (primary endpoint of DEFINE) and the annualized relapse rate (primary endpoint of CONFIRM) compared with placebo, with reduced disability progression also observed with the drug versus placebo in DEFINE. Dimethyl fumarate also reduced disease activity measures relative to placebo in these trials (Buress and Deeks, 2014; Xu et al, 2015). DMF is completely metabolized to monomethyl fumarate (MMF), and by giving it directly the usually mild side effects are alleviated further (Wynn et al, 2020).

Literature References
PubMed ID Title Journal Year
32672401 Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1

Unni, S, Deshmukh, P, Krishnappa, G, Kommu, P, Padmanabhan, B

FEBS J 2020
21391649 Modification of keap1 cysteine residues by sulforaphane

Hu, C, Eggler, AL, Mesecar, AD, van Breemen, RB

Chem Res Toxicol 2011
16359182 Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane

Hong, F, Freeman, ML, Liebler, DC

Chem Res Toxicol 2005
25793262 Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro

Brennan, MS, Matos, MF, Li, B, Hronowski, X, Gao, B, Juhasz, P, Rhodes, KJ, Scannevin, RH

PLoS One 2015
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