Sites of alkylation of human Keap1 by natural chemoprevention agents.

Sites of alkylation of human Keap1 by natural chemoprevention agents. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Sites of alkylation of human Keap1 by natural chemoprevention agents. Abstract Text:

Yan Luo,Aimee L Eggler,Dongting Liu,Guowen Liu,Andrew D Mesecar,Richard B van Breemen,Yan Luo,Aimee L Eggler,Dongting Liu,Guowen Liu,Andrew D Mesecar,Richard B van Breemen,Yan Luo,Aimee L Eggler,Dongting Liu,Guowen Liu,Andrew D Mesecar,Richard B van Breemen,

Under basal conditions, the interaction of the cytosolic protein Keap1 (Kelch-like ECH-associated protein 1) with the transcription factor nuclear factor-E(2)-related factor 2 (Nrf2) results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). Alkylation of one or more of the 27 cysteine sulfhydryl groups of human Keap1 is proposed to lead to Nrf2 nuclear accumulation, to upregulation of cytoprotective gene expression by the ARE, and to prevention of degenerative diseases, such as cancer. Therefore, identification of the most reactive of these cysteine residues toward specific electrophiles should help clarify this mechanism of cancer prevention, also known as chemoprevention. To address this issue, preliminary analyses of tryptic digests of Keap1 alkylated by the model electrophile 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido) butane were carried out using liquid chromatographic-tandem mass spectrometry (LC-MS/MS) with a cylindrical ion trap mass spectrometer and also using LC-MS/MS with a hybrid linear ion trap FT ICR mass spectrometer. Because the FT ICR instrument provided more complete peptide sequencing coverage and enabled the identification of more alkylated cysteine residues, only this instrument was used in subsequent studies of Keap1 alkylation by three electrophilic natural products that can upregulate the ARE, xanthohumol, isoliquiritigenin, and 10-shogaol. Among the various cysteine residues of Keap1, C151 was most reactive toward these three electrophiles. These in vitro results agree with evidence from in vivo experiments, and indicate that C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the ARE through Nrf2.

Sites of alkylation of human Keap1 by natural chemoprevention agents. Publishing Authors By Initials

Y Luo,AL Eggler,D Liu,G Liu,AD Mesecar,RB van Breemen,Y Luo,AL Eggler,D Liu,G Liu,AD Mesecar,RB van Breemen,Y Luo,AL Eggler,D Liu,G Liu,AD Mesecar,RB van Breemen,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Sites of alkylation of human Keap1 by natural chemoprevention agents. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Society for Mass Spectrome

VOLUME: 18

Page Numbers: 2226-32

Journal Abbreviation: J. Am. Soc. Mass Spectrom.

ISSN: 1044-0305

DAY: 2

MONTH: 10

YEAR: 2007

Sites of alkylation of human Keap1 by natural chemoprevention agents. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9010412

Sites of alkylation of human Keap1 by natural chemoprevention agents. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Sites of alkylation of human Keap1 by natural chemoprevention agents. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Sites of alkylation of human Keap1 by natural chemoprevention agents.

AFFILIATION: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois, USA.

Country: United States

AGENCY: United States NCCAM

GRANT: P50 AT-00155

ACRONYM: AT

MEDLINETA: J Am Soc Mass Spectrom

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Sites of alkylation of human Keap1 by natural chemoprevention agents Related Publications

• Absorption and subcellular localization of lycopene in human prostate cancer cells.
• An improved LC-MS/MS method for the quantification of prostaglandins E(2) and D(2) production in biological fluids.
• Binding of the hop (Humulus lupulus L.) chalcone xanthohumol to cytosolic proteins in Caco-2 intestinal epithelial cells.
• Biotransformation of the chemopreventive agent 2',4',4-trihydroxychalcone (isoliquiritigenin) by UDP-glucuronosyltransferases.
• Ca2+ signaling in smooth muscle: TRPC6, NCX and LNats in nanodomains.
• Development of a Screening Assay for Ligands to the Estrogen Receptor Based on Magnetic Microparticles and LC-MS.
• Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome.
• Estrogen effects on the vascular wall.
• Imbalanced synthesis of cyclooxygenase-derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome.
• In vitro metabolism of isoliquiritigenin by human liver microsomes.
• Increased matrix metalloproteinase 2 activity in the human internal mammary artery is associated with ageing, hypertension, diabetes and kidney dysfunction.
• Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9.
• Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome.
• Quantitative analyses of beta-carotene and retinol in serum and feces in support of clinical bioavailability studies.
• Sites of alkylation of human Keap1 by natural chemoprevention agents.
• Transient receptor potential channel 6-mediated, localized cytosolic [Na+] transients drive Na+/Ca2+ exchanger-mediated Ca2+ entry in purinergically stimulated aorta smooth muscle cells.
• [In Process Citation]