A place for thioether chemistry in cellular copper ion recognition and trafficking

Davis, Anna V.; O’Halloran, Thomas V.

doi:10.1038/nchembio0308-148

Cited by 208 publications

(173 citation statements)

References 30 publications

(1 reference statement)

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“…opper is an essential element for life, and maintaining its proper homeostasis is critical for the growth, development, and fitness of living organisms (1)(2)(3)(4)(5)(6)(7). Indeed, loss of copper homeostasis in the body has severe consequences owing to its potent redox activity, which, if uncontrolled, can lead to aberrant oxidative and nitrosative stress events that accompany diseases ranging from cancer (8) to cardiovascular disorders (9-11) to Alzheimer's and related neurodegenerative diseases (4,(12)(13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Hirayama¹,

Bittner²,

Gray

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

194

138

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Copper is an essential metal nutrient that is tightly regulated in the body because loss of its homeostasis is connected to severe diseases such as Menkes and Wilson diseases, Alzheimer’s disease, prion disorders, and amyotrophic lateral sclerosis. The complex relationships between copper status and various stages of health and disease remain challenging to elucidate, in part due to a lack of methods for monitoring dynamic changes in copper pools in whole living organisms. Here we present the synthesis, spectroscopy, and in vivo imaging applications of Coppersensor 790, a first-generation fluorescent sensor for visualizing labile copper pools in living animals. Coppersensor 790 combines a near-infrared emitting cyanine dye with a sulfur-rich receptor to provide a selective and sensitive turn-on response to copper. This probe is capable of monitoring fluctuations in exchangeable copper stores in living cells and mice under basal conditions, as well as in situations of copper overload or deficiency. Moreover, we demonstrate the utility of this unique chemical tool to detect aberrant increases in labile copper levels in a murine model of Wilson disease, a genetic disorder that is characterized by accumulation of excess copper. The ability to monitor real-time copper fluxes in living animals offers potentially rich opportunities to examine copper physiology in health and disease.

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mentioning

confidence: 99%

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Hirayama¹,

Bittner²,

Gray

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

194

138

View full text Add to dashboard Cite

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“…The results from this study support this model. Cu(I) binding is favored by sulfur donor ligands such as the cysteine thiolate and Cu coordination to cysteinyl thiols has been well documented among Cu-sensing and Cu-trafficking proteins (36,37). Thus, cytosolic Cu is trafficked and maintained as Cu(I) complexed to proteins with cysteine-rich motifs such as CXXC.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, cytosolic Cu is trafficked and maintained as Cu(I) complexed to proteins with cysteine-rich motifs such as CXXC. Because of high levels of small thiol-containing molecules such as GSH, overall, the eukaryotic cytosol is a reducing environment in which the cysteine residues of Cutrafficking proteins are thought to be reduced and available to bind Cu(I) (36). However, the susceptibility of thiol groups to oxidative modifications makes them prime candidates for posttranslational modifications such as glutathionylation, either for redox regulation and signaling or for protection during conditions of oxidative stress (19,38).…”

Section: Discussionmentioning

confidence: 99%

Role of Glutaredoxin1 and Glutathione in Regulating the Activity of the Copper-transporting P-type ATPases, ATP7A and ATP7B

Singleton

McInnes

Cater

et al. 2010

Journal of Biological Chemistry

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The copper-transporting P-type ATPases (Cu-ATPases), ATP7A and ATP7B, are essential for the regulation of intracellular copper homeostasis. In this report we describe new roles for glutathione (GSH) and glutaredoxin1 (GRX1) in Cu homeostasis through their regulation of Cu-ATPase activity. GRX1 is a thiol oxidoreductase that catalyzes the reversible reduction of GSH-mixed disulfides to their respective sulfhydryls (deglutathionylation). Here, we demonstrated that glutathionylation of the Cu-ATPases and their interaction with GRX1 were affected by alterations in Cu levels. The data support our hypothesis that the Cu-ATPases serve as substrates for Cu-dependent GRX1-mediated deglutathionylation. This in turn liberates the CuATPase cysteinyl thiol groups for Cu binding and transport. GSH depletion experiments led to reversible inhibition of the Cu-ATPases that correlated with effects on intracellular Cu levels and GRX1 activity. Finally, knockdown of GRX1 expression resulted in an increase in intracellular Cu accumulation. Together, these data directly implicate GSH and GRX1 with important new roles in redox regulation of the Cu-ATPases, through modulation of Cu binding by the Cu-ATPase cysteine motifs.

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“…[1][2][3][4] It mainly binds to metallothionein in cytoplasm and involves in cellular respiration, antioxidant defence and neurotransmitter. 5,6 And the abnormal levels of copper were proposed to be related to certain diseases such as cardiovascular, diabetes, cancer and neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

A Coumarin-based Fluorescent Sensor for Selective Detection of Copper (II)

Wang¹,

Guo²,

Hou³

et al. 2014

Bulletin of the Korean Chemical Society

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Cu (II) detection is of great importance owing to its significant function in various biological processes. In this report, we developed a novel coumarin-based chemosensor bearing the salicylaldimine unit (2) for Cu 2+ selective detection. The results from fluorescence spectra demonstrated that the sensor could selectively recognize Cu 2+ over other metal cations and the detection limit is as low as 0.2 µM. Moreover, the confocal fluorescence imaging in HepG2 cells illustrated its potential for biological applications.

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A place for thioether chemistry in cellular copper ion recognition and trafficking

Cited by 208 publications

References 30 publications

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Role of Glutaredoxin1 and Glutathione in Regulating the Activity of the Copper-transporting P-type ATPases, ATP7A and ATP7B

A Coumarin-based Fluorescent Sensor for Selective Detection of Copper (II)

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