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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]].
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]].


== As a Drug Target==
== 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.<ref name="pmid26579458">{{cite journal |vauthors=Abed DA, Goldstein M, Albanyan H, Jin H, Hu L |title=Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents |journal=Acta Pharm Sin B |volume=5 |issue=4 |pages=285–99 |year=2015 |pmid=26579458 |pmc=4629420 |doi=10.1016/j.apsb.2015.05.008 |url=}}</ref><ref name="pmid27192495">{{cite journal |vauthors=Lu MC, Ji JA, Jiang ZY, You QD |title=The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update |journal=Med Res Rev |volume=36 |issue=5 |pages=924–63 |year=2016 |pmid=27192495 |doi=10.1002/med.21396 |url=}}</ref><ref name="pmid28510041">{{cite journal |vauthors=Deshmukh P, Unni S, Krishnappa G, Padmanabhan B |title=The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases |journal=Biophys Rev |volume=9 |issue=1 |pages=41–56 |year=2017 |pmid=28510041 |pmc=5425799 |doi=10.1007/s12551-016-0244-4 |url=}}</ref><ref name="pmid28253260">{{cite journal |vauthors=Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cochemé HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L |title=Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease |journal=PLoS Genet. |volume=13 |issue=3 |pages=e1006593 |year=2017 |pmid=28253260 |pmc=5333801 |doi=10.1371/journal.pgen.1006593 |url=}}</ref>
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.<ref name="pmid26579458">{{cite journal |vauthors=Abed DA, Goldstein M, Albanyan H, Jin H, Hu L |title=Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents |journal=Acta Pharm Sin B |volume=5 |issue=4 |pages=285–99 |year=2015 |pmid=26579458 |pmc=4629420 |doi=10.1016/j.apsb.2015.05.008 |url=}}</ref><ref name="pmid27192495">{{cite journal |vauthors=Lu MC, Ji JA, Jiang ZY, You QD |title=The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update |journal=Med Res Rev |volume=36 |issue=5 |pages=924–63 |year=2016 |pmid=27192495 |doi=10.1002/med.21396 |url=}}</ref><ref name="pmid28510041">{{cite journal |vauthors=Deshmukh P, Unni S, Krishnappa G, Padmanabhan B |title=The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases |journal=Biophys Rev |volume=9 |issue=1 |pages=41–56 |year=2017 |pmid=28510041 |pmc=5425799 |doi=10.1007/s12551-016-0244-4 |url=}}</ref><ref name="pmid28253260">{{cite journal |vauthors=Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cochemé HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L |title=Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease |journal=PLoS Genet. |volume=13 |issue=3 |pages=e1006593 |year=2017 |pmid=28253260 |pmc=5333801 |doi=10.1371/journal.pgen.1006593 |url=}}</ref>


A series of synthetic oleane [[triterpenoid]] compounds, known as antioxidant inflammation modulators (AIMs), are being developed by [[Reata Pharmaceuticals|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.{{Citation needed|date=August 2011}})  The lead compound in this series, [[bardoxolone methyl]] (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of [[chronic kidney disease]] (CKD) in patients with type 2 [[diabetes mellitus]] and showed an ability to improve markers of renal function in these patients.{{Citation needed|date=August 2011}}) However, the Phase 3 trial was halted due to safety concerns.
A series of synthetic oleane [[triterpenoid]] compounds, known as antioxidant inflammation modulators (AIMs), are being developed by [[Reata Pharmaceuticals|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.{{Citation needed|date=August 2011}} The lead compound in this series, [[bardoxolone methyl]] (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of [[chronic kidney disease]] (CKD) in patients with type 2 [[diabetes mellitus]] and showed an ability to improve markers of renal function in these patients.{{Citation needed|date=August 2011}} However, the Phase 3 trial was halted due to safety concerns.


==References==
==References==
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*{{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Res. | volume = 14 | issue = 7 | pages = 1324–32 | year = 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
*{{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Res. | volume = 14 | issue = 7 | pages = 1324–32 | year = 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
*{{cite journal | vauthors = Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M | title = Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 | journal = Mol. Cell. Biol. | volume = 24 | issue = 16 | pages = 7130–9 | year = 2004 | pmid = 15282312 | pmc = 479737 | doi = 10.1128/MCB.24.16.7130-7139.2004 }}
*{{cite journal | vauthors = Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M | title = Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 | journal = Mol. Cell. Biol. | volume = 24 | issue = 16 | pages = 7130–9 | year = 2004 | pmid = 15282312 | pmc = 479737 | doi = 10.1128/MCB.24.16.7130-7139.2004 }}
*{{cite journal | vauthors = Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R, Jordan-Sciutto KL | title = Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein | journal = Biochemistry | volume = 43 | issue = 38 | pages = 12113–22 | year = 2004 | pmid = 15379550 | doi = 10.1021/bi0494166 }}
*{{cite journal | vauthors = Strachan GD, Morgan KL, Otis LL, Caltagarone J, Gittis A, Bowser R, Jordan-Sciutto KL | title = Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein | journal = Biochemistry | volume = 43 | issue = 38 | pages = 12113–22 | year = 2004 | pmid = 15379550 | doi = 10.1021/bi0494166 | pmc = 3670950 }}
*{{cite journal | vauthors = Li X, Zhang D, Hannink M, Beamer LJ | title = Crystal structure of the Kelch domain of human Keap1 | journal = J. Biol. Chem. | volume = 279 | issue = 52 | pages = 54750–8 | year = 2005 | pmid = 15475350 | doi = 10.1074/jbc.M410073200 }}
*{{cite journal | vauthors = Li X, Zhang D, Hannink M, Beamer LJ | title = Crystal structure of the Kelch domain of human Keap1 | journal = J. Biol. Chem. | volume = 279 | issue = 52 | pages = 54750–8 | year = 2005 | pmid = 15475350 | doi = 10.1074/jbc.M410073200 }}
*{{cite journal | vauthors = Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M | title = Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex | journal = Mol. Cell. Biol. | volume = 24 | issue = 24 | pages = 10941–53 | year = 2004 | pmid = 15572695 | pmc = 533977 | doi = 10.1128/MCB.24.24.10941-10953.2004 }}
*{{cite journal | vauthors = Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M | title = Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex | journal = Mol. Cell. Biol. | volume = 24 | issue = 24 | pages = 10941–53 | year = 2004 | pmid = 15572695 | pmc = 533977 | doi = 10.1128/MCB.24.24.10941-10953.2004 }}
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{{PDB Gallery|geneid=9817}}
{{PDB Gallery|geneid=9817}}
{{gene-19-stub}}


[[Category:Kelch proteins]]
[[Category:Kelch proteins]]

Latest revision as of 12:56, 11 June 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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

Structure

Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. 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 interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[2][3][4]

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.

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.[5][6][7][8]

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.[citation needed] The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients.[citation needed] However, the Phase 3 trial was halted due to safety concerns.

References

  1. ↑ "Entrez Gene: KEAP1 kelch-like ECH-associated protein 1".
  2. ↑ Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (Oct 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. 23 (20): 7198–209. doi:10.1128/mcb.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
  3. ↑ Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (Sep 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proc. Natl. Acad. Sci. U.S.A. 105 (36): 13568–73. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
  4. ↑ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (Aug 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180.
  5. ↑ Abed DA, Goldstein M, Albanyan H, Jin H, Hu L (2015). "Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents". Acta Pharm Sin B. 5 (4): 285–99. doi:10.1016/j.apsb.2015.05.008. PMC 4629420. PMID 26579458.
  6. ↑ Lu MC, Ji JA, Jiang ZY, You QD (2016). "The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update". Med Res Rev. 36 (5): 924–63. doi:10.1002/med.21396. PMID 27192495.
  7. ↑ Deshmukh P, Unni S, Krishnappa G, Padmanabhan B (2017). "The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases". Biophys Rev. 9 (1): 41–56. doi:10.1007/s12551-016-0244-4. PMC 5425799. PMID 28510041.
  8. ↑ Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cochemé HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L (2017). "Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease". PLoS Genet. 13 (3): e1006593. doi:10.1371/journal.pgen.1006593. PMC 5333801. PMID 28253260.

Further reading

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