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Generation and Utilization of NADPH in the Endoplasmic Reticulum: Impact on Metabolic and Hormonal Regulation
Third-party funded project |
Project title |
Generation and Utilization of NADPH in the Endoplasmic Reticulum: Impact on Metabolic and Hormonal Regulation |
Principal Investigator(s) |
Odermatt, Alex
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Organisation / Research unit |
Departement Pharmazeutische Wissenschaften / Molecular and Systems Toxicology (Odermatt) |
Project start |
01.05.2012 |
Probable end |
30.04.2015 |
Status |
Completed |
Abstract |
The reduced pyridine nucleotide NADPH acts as cofactor for a multitude of reduction reactions and is essential for major physiological processes. NADPH cannot freely move across cellular membranes, and distinct pools exist in the cytoplasm, the mitochondria and the endoplasmic reticulum (ER). In contrast to the cytoplasm, much less is known on NADPH generation and utilization in the ER.
To date, only one enzyme has been identified in the ER that generates NADPH. It uses glucose-6-phosphate as substrate and its activity is dependent on the cellular energy state. The reactions within the ER that utilize NADPH are not well studied. To date only one enzyme within the ER is known to utilize NADPH. It interconverts inactive and active glucocorticoids and therefore represents a hormonal response mechanism to alterations in energy status of cells that express this enzyme.
There are, however, several important questions that need to be addressed: 1) what is the role of the NADPH generating enzyme in cells that do not express the glucocorticoid activating enzyme? 2) which other enzymes require NADPH in the ER for their function? 3) how can NADPH be generated in the absence of the glucose-6-phosphate dependent enzyme, are there other mechanisms to generate NADPH in the ER? 4) How do pyridine nucleotides reach the ER and how is the pool in the ER initially formed? 5) does the product of the NADPH generating enzyme in the ER react further, i.e. is there a pentose-phosphate cycle in the ER? 6) what are the consequences of impaired redox control and NADPH homeostasis in the ER for metabolic functions?
By employing biochemical and cell biological methods we attempt to identify additional enzymes within the ER that are dependent on NADPH. Upon identification, expression plasmids will be constructed, followed by expression of proteins in cells, functional characterization and investigation of their physiological roles. Moreover, we will characterize the role of the luminal glucocorticoid activating enzyme in the metabolism of other substrates, including bile acids, oxysterols and xenobiotics, with respect to NADPH dependence.
The proposed research should significantly enhance the current knowledge on NADPH generation and utilization in the ER. The expected findings are relevant regarding the understanding of the coupling between cellular energy state, hormonal regulation, ER redox regulation, and oxidative stress-induced damage. Disturbed functions of the enzymes investigated are likely to be associated with metabolic diseases. |
Financed by |
Swiss National Science Foundation (SNSF)
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Published results () |
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ID |
Autor(en) |
Titel |
ISSN / ISBN |
Erschienen in |
Art der Publikation |
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1519859 |
Chantong, Boonrat; Kratschmar, Denise V; Nashev, Lyubomir G; Balazs, Zoltan; Odermatt, Alex |
Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells |
1742-2094 |
Journal of neuroinflammation |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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1519860 |
Legeza, Balázs; Balázs, Zoltán; Nashev, Lyubomir G; Odermatt, Alex |
The microsomal enzyme 17β-hydroxysteroid dehydrogenase 3 faces the cytoplasm and uses NADPH generated by glucose-6-phosphate dehydrogenase. |
0013-7227 |
Endocrinology |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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1558186 |
Odermatt, Alex; Kratschmar, Denise V |
Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases : an overview |
0303-7207 |
Molecular and cellular endocrinology |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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2237792 |
Hofer, Sandra; Kratschmar, Denise V.; Schernthanner, Brigitte; Vuorinen, Anna; Schuster, Daniela; Odermatt, Alex; Easmon, Johnny |
Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors |
0960-894X ; 1464-3405 |
Bioorganic and Medicinal Chemistry Letters |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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2237807 |
Pandya, Keyur; Dietrich, David; Seibert, Julia; Vederas, John C; Odermatt, Alex |
Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists |
0960-894X |
Bioorganic & medicinal chemistry letters |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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2237808 |
Penno, Carlos A.; Morgan, Stuart A.; Vuorinen, Anna; Schuster, Daniela; Lavery, Gareth G.; Odermatt, Alex |
Impaired oxidoreduction by 11β-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid |
0022-2275 ; 1539-7262 |
Journal of Lipid Research |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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2291938 |
Nashev, Lyubomir G; Atanasov, Atanas G; Baker, Michael E; Odermatt, Alex |
Cysteine-10 on 17 β-Hydroxysteroid dehydrogenase 1 has stabilizing interactions in the cofactor binding region and renders sensitivity to sulfhydryl modifying chemicals |
1687-8876 |
International journal of cell biology |
Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) |
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