KEAP1


Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.

Structure

Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat and C-terminal region domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.

Interactions

Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.
Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2. Keap1 is not only a tumor suppressor gene, but also a metastasis suppressor gene.

As a drug target

Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.
A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators, are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes. The lead compound in this series, bardoxolone methyl, was in late-stage clinical trials for the treatment of chronic kidney disease in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients. However, the Phase 3 trial was halted due to safety concerns.