Pseudoenzymatic dealkylation of alkyltins by biological dithiols

Porcelli, Fernando; Triggiani, Doriana; Buck‐Koehntop, Bethany A.; Masterson, Larry R.; Veglia, Gianluigi

doi:10.1007/s00775-009-0565-x

Cited by 6 publications

(2 citation statements)

References 65 publications

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“…snn was originally identified as a cDNA specifically expressed in TMT-sensitive tissues such as hematopoietic organs and immune system lineages [ 57 ]. Subsequent studies showed binding of TMT to Stannin [ 58 – 60 ] and of Stannin to 14-3-3ζ [ 44 ]. Although the molecular and cellular consequences of such binding and the roles of Stannin in TMT toxicity and under normal physiology have not been fully elucidated, several results might suggest a relationship with PI metabolism.…”

Section: Discussionmentioning

confidence: 99%

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

et al. 2016

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Translation of hundreds of small ORFs (smORFs) of less than 100 amino acids has recently been revealed in vertebrates and Drosophila. Some of these peptides have essential and conserved cellular functions. In Drosophila, we have predicted a particular smORF class encoding ~80 aa hydrophobic peptides, which may function in membranes and cell organelles. Here, we characterise hemotin, a gene encoding an 88aa transmembrane smORF peptide localised to early endosomes in Drosophila macrophages. hemotin regulates endosomal maturation during phagocytosis by repressing the cooperation of 14-3-3ζ with specific phosphatidylinositol (PI) enzymes. hemotin mutants accumulate undigested phagocytic material inside enlarged endo-lysosomes and as a result, hemotin mutants have reduced ability to fight bacteria, and hence, have severely reduced life span and resistance to infections. We identify Stannin, a peptide involved in organometallic toxicity, as the Hemotin functional homologue in vertebrates, showing that this novel regulator of phagocytic processing is widely conserved, emphasizing the significance of smORF peptides in cell biology and disease.

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Section: Discussionmentioning

confidence: 99%

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

et al. 2016

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“…TBT was reported to preferentially bind to dithiols and to establish a stable tetrahedral structural arrangement with the protein structure after debutylation through the formation of covalent bonds between tin and two sulfur atoms. [21,[39][40][41] On this basis, the possible presence of dithiol targets on F 1 F O -ATPase was checked by using both hydrophilic and hydrophobic MTR so as to covalently block isolated -SH groups and to prevent possible bifunctional TBT binding by creating sulfur-tin-sulfur bridges. Either hydrophilic (mersalyl acid and DTNB) or hydrophobic (NEM) MTR was used.…”

Section: Tbt Interacts With Individual Thiolsmentioning

confidence: 99%

Tri‐n‐butyltin binding to a low‐affinity site decreases the F₁F_O‐ATPase sensitivity to oligomycin in mussel mitochondria

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Ventrella

Trombetti

et al. 2012

Applied Organom Chemis

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In mussel digestive gland mitochondria the environmental pollutant tri‐n‐butyltin (TBT), other than strongly inhibiting ATPase activity at <1.0 μ m, at ≥1.0 μ m concentration was previously found to desensitize F1FO‐ATPase to the antibiotic oligomycin. While F1FO‐ATPase inhibition is widely known as one of the main mitochondrial damages caused by TBT, the enzyme's desensitization to oligomycin was quite unexpected. The possible mechanisms involved are here stepwise approached, aiming at enlightening the molecular mechanism(s) of TBT toxicity and the still poorly investigated oligomycin interaction with FO. The findings strongly suggest that the oligomycin desensitization directly stems from the covalent binding of TBT to monothiols of the F1FO‐ATPase. This binding implies sulfur oxidation, irrespective of the possible formation of radical species in mitochondria, a mechanism which does not seem to be involved here. It is hypothesized that TBT interacts with the enzyme complex in at least two sites distinguished by different affinities: TBT binding to the high‐affinity site would lead to ATPase inhibition, while TBT binding to monothiols in the low‐affinity site could mirror the decrease in F1FO‐ATPase oligomycin sensitivity at ≥1.0 μ m TBT. Experiments carried out on inside‐out submitochondrial particles hint that TBT binding destabilizes the oligomycin‐blocked FO conformation, allowing proton flux recovery within FO, without uncoupling the catalytic function from proton channeling. Copyright © 2012 John Wiley & Sons, Ltd.

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Templating α-amylase peptide inhibitors with organotin compounds

et al. 2011

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Metal centers have been widely used to nucleate secondary structures in linear peptides. However, very few examples have been reported for peptide/organometal complexes. Here, we illustrate the use of organotin compounds as nucleation centers for secondary structures of linear peptide inhibitors of α-amylase. Specifically, we utilized methyl-substituted tin compounds to template short type I β-turns similar to the binding loop of tendamistat, the natural inhibitor of the enzyme, which are able to bind and inhibit α-amylase. We show that enzyme activity is inhibited by neither the unstructured peptide nor the organotin compounds, but rather the peptide/organotin complex, which inhibits the enzyme with K (i) ~ 0.5 μM. The results delineate a strategy to use organometallic compounds to drive the active conformation in small linear peptides.

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Pseudoenzymatic dealkylation of alkyltins by biological dithiols

Cited by 6 publications

References 65 publications

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

Tri‐n‐butyltin binding to a low‐affinity site decreases the F₁F_O‐ATPase sensitivity to oligomycin in mussel mitochondria

Templating α-amylase peptide inhibitors with organotin compounds

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Pseudoenzymatic dealkylation of alkyltins by biological dithiols

Cited by 6 publications

References 65 publications

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans

Tri‐n‐butyltin binding to a low‐affinity site decreases the F1FO‐ATPase sensitivity to oligomycin in mussel mitochondria

Templating α-amylase peptide inhibitors with organotin compounds

Contact Info

Product

Resources

About

Tri‐n‐butyltin binding to a low‐affinity site decreases the F₁F_O‐ATPase sensitivity to oligomycin in mussel mitochondria