Studies on the Nature and Regulation of the Cellular Thiol:Disulphide Potential

Ziegler, Daniel M.; Duffel, Michael W.; Poulsen, Lawrence L.

doi:10.1002/9780470720554.ch12

Cited by 10 publications

(6 citation statements)

References 23 publications

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“…FMOs are also notably similar to the Group A enzymes dihydrolipoamide dehydrogenase (DLD), glutathione reductase (GR), and low-molecular-weight thioredoxin reductase (TRXR) (2,4). These groups are distinguished from other flavin-dependent monooxygenases (Groups C-H) by their combined use of FAD and NAD(P)H. Any functional interplay between FMOs and Group A enzymes, perhaps as an NAD(P)H-thiol redox buffering system, is largely unexplored (5).…”

Section: Evolution and Classificationmentioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Section: Evolution and Classificationmentioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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“…Although the physiological role of FMO3 cysteamine S-oxygenation is not clear, Zieglar and Poulsen proposed in the 1970s that FMO might be involved in protein disulfide bond formation through oxidation of cysteamine. It was also proposed that oxygenation of cysteamine may be a significant source of disulfide, maintaining the cellular thiol:disulfide potential in a cell (Ziegler et al, 1979). Further, Suh and Robertus (2002) showed that yeast FMO serve as a modulator of cellular thiols and maintains optimum redox potential within the endoplasmic reticulum, allowing for proper folding of disulfide bondcontaining proteins (Suh and Robertus, 2002).…”

Section: Fig 11mentioning

confidence: 99%

“…FMO is involved in the oxygenation of sulfur-containing endogenous substrates, e.g., catalyzing the conversion of cysteamine (reduced form) to cystamine (disulfide form) (Poulsen, 1981). Although the physiological role of cysteamine S-oxygenation by Fmo3 is not clear, in the 1970s, Zieglar and Poulsen proposed that oxygenation of cysteamine may be a significant source of disulfide, maintaining the cellular thiol:disulfide potential in a cell (Ziegler et al, 1979). Upregulation of Fmo3 during APAP-induced hepatotoxicity and oxygenation of cysteamine by Fmo3 may serve to help control the overall thiol:disulfide redox state of the cell, which in turn may modulate cellular metabolism and/or activate signal transduction pathways leading to altered susceptibility to APAP (or protection).…”

mentioning

confidence: 99%

Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes

Rudraiah

Rohrer

Gurevich

et al. 2014

Toxicological Sciences

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Acetaminophen (APAP) pretreatment with a hepatotoxic dose (400 mg/kg) in mice results in resistance to a second, higher dose (600 mg/kg) of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in our mouse model of APAP autoprotection. The role of liver Fmo3, which detoxifies xenobiotics, in APAP autoprotection is unknown. The purpose of this study was to characterize the gene regulation and protein expression of liver Fmo3 during APAP hepatotoxicity. The functional consequences of Fmo3 induction were also investigated. Plasma and livers were collected from male C57BL/6J mice over a period of 72 h following a single dose of APAP (400 mg/kg) to measure Fmo3 mRNA and protein expression. Although Fmo3 mRNA levels increased significantly following APAP treatment, protein expression changed marginally. In contrast, both Fmo3 mRNA and protein expression were significantly higher in APAP autoprotected livers. Unlike male C57BL/6J mice, female mice have ∼80-times higher constitutive Fmo3 mRNA levels and are highly resistant to APAP hepatotoxicity. Coadministration of APAP with the FMO inhibitor methimazole rendered female mice susceptible to APAP hepatotoxicity, with no changes in susceptibility detected in male mice. Furthermore, a human hepatocyte cell line (HC-04) clone over-expressing human FMO3 showed enhanced resistance to APAP cytotoxicity. Taken together, these findings establish for the first time induction of Fmo3 protein expression and function by xenobiotic treatment. Our results also indicate that Fmo3 expression and function plays a role in protecting the liver from APAP-induced toxicity. Although the mechanism(s) of this protection remains to be elucidated, this work describes a novel protective function for this enzyme.

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“…The physiological role of the uncoupled reaction products of hFMO3 is still unknown. It has been suggested that the generation of hydrogen peroxide by FMO could play a role in control of the overall redox state of the cell [27] or in the synthesis of protein disulfide bonds through cysteamine oxidation [32,33]. On the other hand, toxicological effects such as hepatic injury through radical production and lipid peroxidation have also been reported in rat FMO catalyzing the oxidation of thioacetamide [34].…”

Section: Discussionmentioning

confidence: 99%

Uncoupled human flavin-containing monooxygenase 3 releases superoxide radical in addition to hydrogen peroxide

Catucci

Gao

Rampolla

et al. 2019

Free Radical Biology and Medicine

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Studies on the Nature and Regulation of the Cellular Thiol:Disulphide Potential

Cited by 10 publications

References 23 publications

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes

Uncoupled human flavin-containing monooxygenase 3 releases superoxide radical in addition to hydrogen peroxide

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