NFE2L2
Encyclopedia
Nuclear factor-like 2, also known as NFE2L2 or Nrf2, is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

 that in humans is encoded by the NFE2L2 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...

. NFE2L2 induces the expression of various genes including those that encode for several antioxidant
Antioxidant
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...

 enzymes, and it may play a physiological role in the regulation 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...

. Investigational drugs that target NFE2L2 are of interest as potential therapeutic interventions for oxidative-stress related pathologies.

Function

NFE2
NFE2
Transcription factor NF-E2 45 kDa subunit is a protein that in humans is encoded by the NFE2 gene.-Interactions:NFE2 has been shown to interact with CREB-binding protein.- External links :...

, NFE2L1
NFE2L1
Nuclear factor erythroid 2-related factor 1 is a protein that in humans is encoded by the NFE2L1 gene....

, and NFE2L2 (this protein) comprise a family of human genes encoding basic leucine zipper (bZIP
BZIP domain
The Basic Leucine Zipper Domain is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required for the dimerization of two DNA binding regions. The DNA binding region...

) transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s. They share highly conserved regions that are distinct from other bZIP families, such as JUN
C-jun
c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...

 and FOS
C-Fos
In the field of molecular biology and Genetics, c-Fos is a protein encoded by the FOS gene.-Structure and function:c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors. c-Fos has a leucine-zipper DNA binding domain, and a transactivation domain at...

, although remaining regions have diverged considerably from each other.

Under normal or unstressed conditions, Nrf2 is tethered in the cytoplasm by another protein called Kelch like-ECH-associated protein 1 (Keap1). Keap1 acts as a substrate adaptor protein for Cullin 3-based ubiquitination, which results in the proteasomal degradation of Nrf2, and under normal conditions Nrf2 has a half-life of only 20 minutes. 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...

 or electrophilic stress disrupts critical cysteine residues in Keap1, resulting in a disruption of the Keap1-Cul3 ubiquitination system and a build-up of Nrf2 in the cytoplasm. Unbound Nrf2 is then able to translocate into the nucleus, where it will heterodimerize with a small Maf protein and bind to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, where it will initiate their transcription.

Target Genes

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:
  • NAD(P)H quinone oxidoreductase 1 (Nqo1
    NAD(P)H dehydrogenase (quinone 1)
    NADH dehydrogenase [quinone] 1 is an enzyme that in humans is encoded by the NQO1 gene.-Interactions:NADH dehydrogenase has been shown to interact with HSPA4.-Further reading:...

    ) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and 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...

    .
  • Glutamate-cysteine ligase
    Glutamate-cysteine ligase
    In enzymology, a glutamate-cysteine ligase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are ATP, L-glutamate, and L-cysteine, whereas its 3 products are ADP, phosphate, and gamma-L-glutamyl-L-cysteine....

    , catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM
    GCLM
    Glutamate--cysteine ligase regulatory subunit is an enzyme that in humans is encoded by the GCLM gene.-Further reading:...

    ) subunits form a heterodimer, which is the rate-limiting step in the synthesis of glutathione
    Glutathione
    Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

     (GSH), a very powerful endogenous antioxidant
    Antioxidant
    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...

    . Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.
  • Heme oxygenase-1 (HMOX1
    HMOX1
    HMOX1 is a human gene that encodes for the enzyme heme oxygenase 1 . Heme oxygenase is an essential enzyme in heme catabolism, it cleaves heme to form biliverdin....

    , HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin
    Biliverdin
    Biliverdin is a green tetrapyrrolic bile pigment, and is a product of heme catabolism. It is the pigment responsible for a greenish color sometimes seen in bruises.- Metabolism :...

    , the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis
    Sepsis
    Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

    , hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

    , atherosclerosis
    Atherosclerosis
    Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

    , acute lung injury, kidney injury, and pain.
  • The glutathione S-transferase
    Glutathione S-transferase
    Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...

     (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic
    Xenobiotic
    A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...

     electrophile
    Electrophile
    In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...

    s. After detoxification by GSH conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.
  • The UDP-glucuronosyltransferase
    Glucuronosyltransferase
    Uridine 5'-diphospho-glucuronosyltransferase is a glycosyltransferase that catalyzes addition of the glycosyl group from a UTP-sugar to a small hydrophobic molecule.This is glucuronidation reaction.Alternative names:...

     (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water soluble and readily excreted. Important substrates for glucuronidation include bilirubin
    Bilirubin
    Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

     and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.
  • Multidrug resistance-associated protein
    ABCC2
    Multidrug resistance-associated protein 2 also called canalicular multispecific organic anion transporter 1 or ATP-binding cassette sub-family C member 2 is a protein that in humans is encoded by the ABCC2 gene....

    s (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharamacokinetics and toxicity of compounds.

Structure

Nrf2 is a basic leucine zipper (bZip
BZIP domain
The Basic Leucine Zipper Domain is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required for the dimerization of two DNA binding regions. The DNA binding region...

) transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

 with a Cap “n” Collar (CNC) structure.

Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins. The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.
The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.
The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CBP), which possesses intrinsic histone acetyltransferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....

 activity.
The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.

Nrf2 as a drug target

Investigational drugs that target NFE2L2 have been evaluated in animal models as therapeutic interventions for oxidative-stress related pathologies. One such compound, bardoxolone methyl, is undergoing testing in human clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s.

The dithiolethiones are a class of organosulfur compounds, of which, oltipraz
Oltipraz
Oltipraz is a schistosomicide.It is also used in tumor prevention....

 is the most well-studied. Oltipraz has been shown to inhibit cancer formation in a variety of rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials involving oltipraz have demonstrated significant side-effects with no or questionable chemopreventive efficacy. In one clinical study, side-effects after 8 weeks of treatment included numbness, tingling, and pain in the extremities. In another study, side-effects after 4 weeks included gastrointestinal toxicity. Oltipraz has also been shown to generate superoxide radical, which can be quite toxic.

A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as antioxidant inflammation modulators (AIMs), are in clinical development at Reata Pharmaceuticals
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...

. 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), has completed Phase 2 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...

. Data indicate that bardoxolone methyl
Bardoxolone methyl
Bardoxolone methyl is an orally-available first-in-class synthetic triterpenoid belonging to the antioxidant inflammation modulator class...

 improves markers of kidney function, including producing a significant increase in estimated glomerular filtration rate that correlates with changes in blood urea nitrogen, serum phosphorus, uric acid, and magnesium. Improvements were sustained over 6 months of therapy and remained significant compared to placebo.) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid 2011.) Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases.)

Interactions

NFE2L2 has been shown to interact
Protein-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 CREB-binding protein, KEAP1
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 Broad complex, Tramtrack and Bric-à-Brac domain contains the Cys151 residue, which is important in stress sensing...

, C-jun
C-jun
c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...

, EIF2AK3
EIF2AK3
Eukaryotic translation initiation factor 2-alpha kinase 3 is an enzyme that in humans is encoded by the EIF2AK3 gene. Patients with mutations in this gene develop Wolcott-Rallison syndrome.-Interactions:...

 and Ubiquitin C
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...

.

External links

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