The ion channel of F-ATP synthase is the target of toxic organotin compounds

Ballmoos, Christoph von; Brunner, Josef; Dimroth, Peter

doi:10.1073/pnas.0402869101

Cited by 87 publications

(53 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…von Ballmoos et al showed that subunit a of F 1 F 0 ATP synthase is the target site of TBT for inhibition, by using a synthetic photoaffinity-labeled probe. 13) However, these data were obtained at concentrations of a few µM, and F 1 F 0 ATP synthase may be scarcely inhibited by nM order concentrations of organotin.…”

Section: Atp Synthase Inhibitionmentioning

confidence: 96%

Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

Kotake

2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Organotins such as tributyltin are suspected of having multiple toxic effects in mammals, in addition to their endocrine-disrupting function. Endogenous organotin concentrations in human blood range from a few to a few hundred nM. In this review, we summarize recent findings on the mechanisms of toxicity of environmental organotins such as tributyltin (TBT) and triphenyltin (TPT) in mammals. TBT and TPT are potent inhibitors of mitochondrial ATP synthase, and a recent study suggests that TBT binds directly to ATP synthase. Organotins disturb steroid biosynthesis and degradation. TBT and TPT are dual agonists of retinoid X receptor (RXR) and peroxisome proliferator-activated receptor γ (PPARγ); they also induce the differentiation of adipocytes in vitro and in vivo, probably through PPARγ activation, suggesting that they may work as obesogens. Environmental organotins are also neurotoxic; they induce behavioral abnormality and are toxic to the developing central nervous system. In vitro studies have shown that organotins induce intracellular Ca 2 elevation and glutamate excitotoxicity. Recently, it was reported that endogenous levels of TBT decrease expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor subunit GluR2, leading to neuronal vulnerability. Most of the experimental studies have employed organotins at concentrations of µM order, and it remains important to clarify the molecular mechanisms of events induced by endogenous levels of environmental organotins.

show abstract

Section: Atp Synthase Inhibitionmentioning

confidence: 96%

Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

Kotake

2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…The sites of action of organotin compounds are located in the ion channel within subunit a. Here, they are believed to inhibit ATP synthase by competing with Na ϩ or H ϩ for the same binding site (418). Diorganotin-3-hydroxyflavone complexes such as dibutyltin 3-hydroxyflavone bromide and diphenyltin 3-hydroxyflavone chloride show a marked fluorescence enhancement on binding to mitochondrial ATP synthase (405).…”

Section: Organotin Compounds and Structural Relativesmentioning

confidence: 99%

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Hong

Pedersen

2008

Microbiol Mol Biol Rev

275

302

View full text Add to dashboard Cite

SUMMARY ATP synthase, a double-motor enzyme, plays various roles in the cell, participating not only in ATP synthesis but in ATP hydrolysis-dependent processes and in the regulation of a proton gradient across some membrane-dependent systems. Recent studies of ATP synthase as a potential molecular target for the treatment of some human diseases have displayed promising results, and this enzyme is now emerging as an attractive molecular target for the development of new therapies for a variety of diseases. Significantly, ATP synthase, because of its complex structure, is inhibited by a number of different inhibitors and provides diverse possibilities in the development of new ATP synthase-directed agents. In this review, we classify over 250 natural and synthetic inhibitors of ATP synthase reported to date and present their inhibitory sites and their known or proposed modes of action. The rich source of ATP synthase inhibitors and their known or purported sites of action presented in this review should provide valuable insights into their applications as potential scaffolds for new therapeutics for human and animal diseases as well as for the discovery of new pesticides and herbicides to help protect the world's food supply. Finally, as ATP synthase is now known to consist of two unique nanomotors involved in making ATP from ADP and Pi, the information provided in this review may greatly assist those investigators entering the emerging field of nanotechnology.

show abstract

“…This indicated that there may be a very tight association of the compounds with a protein(s) involved in ATP synthesis such as ATP synthase. Others have shown that TBT binds to ATP synthase in bacteria (von Ballmoos et al, 2004). It is quite possible that the OTs tested in this study may also bind quite tightly to some component(s) such as ATP synthase.…”

Section: Discussionmentioning

confidence: 83%

“…These findings are consistent with the results seen with butyltins, DBT and TBT (Dudimah et al, 2006a, b). TBT has been shown to inhibit the function of the mitrochondrial ATP synthase (von Ballmoos et al, 2004;Matsuno-Yagi and Hatefi., 1993). Thus, sustained decreases in ATP levels seen with TBT exposures may be partially due to the ability to inhibit ATP synthase.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of a series of triorganotins on ATP levels in human natural killer cells

Holloway

Pannell

Whalen

2008

Environmental Toxicology and Pharmacology

View full text Add to dashboard Cite

Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. A series of triorganotins, (trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT)) have been shown to decrease the lytic function of human NK cells. TPT and MDPT were much more effective than DMPT or TMT at reducing lytic function. This study investigates the role that decreased ATP levels may play in decreases in the lytic function of NK cells induced by these OTs. A 24 h exposure to as high as 10 μM TMT caused no decrease in ATP levels even though this level of TMT caused a greater than 75% loss of lytic function. TPT at 200 nM caused a decrease in ATP levels of about 20% while decreasing lytic function by greater than 85%. There was no association between ATP levels and lytic function for any of the compounds when NK cells were exposed for 1h or 24 h. However, after a 48 h exposure to both DMPT and TPT decreased lytic function was associated with decreased ATP levels. There was an association between decreased lytic function and decreased ATP levels after a 6 day exposure to each of the four compounds. These studies indicate that the loss of lytic function seen after 1 h and 24 h exposures to this series of organotins cannot be accounted for by decreases in ATP. However, after longer exposures loss of lytic function may be in part be attributable to inadequate ATP levels.

show abstract

The ion channel of F-ATP synthase is the target of toxic organotin compounds

Cited by 87 publications

References 38 publications

Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

Effects of a series of triorganotins on ATP levels in human natural killer cells

Contact Info

Product

Resources

About