Insights on the mechanism of thioredoxin reductase inhibition by Gold N-heterocyclic carbene compounds using the synthetic linear Selenocysteine containing C-terminal peptide hTrxR(488-499): An ESI-MS investigation

Pratesi, Alessandro; Gabbiani, Chiara; Michelucci, Elena; Ginanneschi, Mauro; Papini, Anna Maria; Rubbiani, Riccardo; Ott, Ingo; Messori, Luigi

doi:10.1016/j.jinorgbio.2014.01.009

Cited by 88 publications

(85 citation statements)

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“…Electrospray ionization mass spectrometry (ESI MS) measurements suggest that gold carbene compounds preferentially bind to free cysteine (or seleno-cysteine) side chains [39][40] , with AuNHC + fragments or Au + ions coordinating the thiol (selenol) group upon release of the carbene ligand(s) [39][40] . Although the interaction of gold carbene compounds with many proteins (for example TrxR, phosphatases, glutathione reductases, serum albumin, Atox-1) has now been studied 19,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] , structural data on the adducts formed upon reaction still lack. Here, we report the first X-ray structure of the complex formed in the reaction between a protein, i.e.…”

Section: Reaction Between the Gold N-heterocyclic Carbene Compound Aumentioning

confidence: 99%

First Crystal Structure for a Gold Carbene–Protein Adduct

2016

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The X-ray structure of the adduct formed in the reaction between the gold N-heterocyclic carbene compound Au(NHC)Cl (with NHC = 1-butyl-3-methyl-imidazole-2-ylidene) and the model protein thaumatin is reported here. The structure reveals binding of Au(NHC)(+) fragments to distinct protein sites. Notably, binding of the gold compound occurs at lysine side chains and at the N-terminal tail; the metal binds the protein after releasing Cl(-) ligand, but retaining NHC fragment.

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Section: Reaction Between the Gold N-heterocyclic Carbene Compound Aumentioning

confidence: 99%

First Crystal Structure for a Gold Carbene–Protein Adduct

2016

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“…Thus, we report herein the synthesis and chemical and biological features of this fluorescent complex characterized by the ability to inhibit TrxR apparently through direct binding to the active site redox motif. Remarkably, this latter process has been conveniently investigated by high‐resolution ESI‐MS using the C‐terminal dodecapeptide of thioredoxin reductase hTrxR(488–499) bearing the active site redox motif, with a method already established in our laboratory …”

Section: Introductionmentioning

confidence: 99%

A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies

et al. 2018

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The silver(I) N‐heterocyclic carbene (NHC) complex bis(1‐(anthracen‐9‐ylmethyl)‐3‐ethylimidazol‐2‐ylidene) silver chloride ([Ag(EIA)2]Cl), bearing two anthracenyl fluorescent probes, has been synthesized and characterized. [Ag(EIA)2]Cl is stable in organic solvents and under physiological conditions, and shows potent cytotoxic effects in vitro toward human SH‐SY5Y neuroblastoma cells. The interactions of [Ag(EIA)2]Cl with a few model biological targets have been studied as well as its ability to be internalized in cells. The in vitro anticancer activity is apparently related to the level of drug internalization. Notably, [Ag(EIA)2]Cl does not react with a few model proteins, but is capable of binding the C‐terminal dodecapeptide of thioredoxin reductase hTrxR(488–499) and to strongly inhibit the activity of this enzyme. Binding occurs through an unconventional process leading to covalent binding of one or two carbene ligands to the C‐terminal dodecapeptide with concomitant release of the silver cation. To the best of our knowledge, this mode of interaction is reported here for the first time for Ag(NHC)2 complexes.

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“…The inhibition of TrxR is achieved by the formation of a covalent bond between the gold atom and a selenocysteine group present at the C terminus of the enzyme active site 46. 52, 53 Glutathione reductase (GR) is another enzyme that belongs to the antioxidant network, and shares a high degree of sequence homology (>75 % similarity) with TrxR. Instead of selenocysteine, GR has a cysteine at the C terminus of its active site 5.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Profile of a Series of Gold(III) (2‐phenyl)pyridine Complexes

et al. 2014

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Six phosphorescent (2-phenyl)pyridine (ppy) gold(III) 2,4,6-tris(trifluoromethyl)phenyl (FMes) complexes were synthesized and investigated for their anticancer potential. The compounds demonstrated strong antiproliferative activity, with EC50 values in the low micromolar range, along with significant accumulation in HeLa cancer cells after treatment for only 6 h (up to 119 ng gold per milligram of protein as measured by high-resolution continuum source atomic spectroscopy). Enzyme inhibition studies showed interaction of the gold(III) complexes with thioredoxin reductase (TrxR), a key homeostasis-regulation flavoprotein. TrxR was inhibited with IC50 values in the micromolar range. Furthermore, five of the complexes displayed selectivity toward TrxR against glutathione reductase (GR, a disulfide reductase structurally related to TrxR) by up to >49-fold. Because no major differences in bioactivity were observed across the series, [(ppy)Au(FMes)(PPh3 )OTf] (complex 4) was chosen for further in-depth biological characterization. Complex 4 was also found to interact with guanosine monophosphate in (1) H NMR studies under long incubation times. Interestingly, 4 induced a significant increase in intracellular levels of reactive oxygen species, which led to late apoptotic events and cytocidal effects.

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Insights on the mechanism of thioredoxin reductase inhibition by Gold N-heterocyclic carbene compounds using the synthetic linear Selenocysteine containing C-terminal peptide hTrxR(488-499): An ESI-MS investigation

Cited by 88 publications

References 22 publications

First Crystal Structure for a Gold Carbene–Protein Adduct

First Crystal Structure for a Gold Carbene–Protein Adduct

A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies

Anticancer Profile of a Series of Gold(III) (2‐phenyl)pyridine Complexes

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