KEAP1
Encyclopedia
Kelch-like ECH-associated protein 1 is a protein
that in humans is encoded by the Keap1 gene
.
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.
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 (AIMs), 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
(also known as CDDO-Me or RTA 402), is currently in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus
and has been shown to improve markers of renal function in these patients.)
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the Keap1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Structure
Keap1 has four discrete protein domains. The Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is important in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys272 and Cys288, which are important for the repression of Nrf2 activity. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.Interactions
Keap1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
.
Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2.
Keap1 as a Drug Target
Because Nrf2 activation leads to a coordinated antioxidantAntioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.
A series of synthetic oleane triterpenoid
Triterpenoid
Triterpenoids are terpenoid derviatives of triterpene molecules.They may have useful anti-cancer properties.Notable examples*Betulinic acid, possible anti-cancer drug*Bardoxolone methyl, inflammation modulator*Triterpenoid saponins...
compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc
Reata Pharmaceuticals
Reata Pharmaceuticals, Inc. is a biopharmaceutical company based in Irving, Texas. Founded in 2002, Reata is currently developing oral anti-inflammatory drugs targeting Nrf2, a master regulator of the antioxidant response in humans...
. 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
Bardoxolone methyl
Bardoxolone methyl is an orally-available first-in-class synthetic triterpenoid belonging to the antioxidant inflammation modulator class...
(also known as CDDO-Me or RTA 402), is currently in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and has been shown to improve markers of renal function in these patients.)