Counteraction ability of TMAO toward different denaturing agents

Vigorita, Marilisa; Cozzolino, Serena; Oliva, Rosario; Graziano, Giuseppe; Vecchio, Pompea Del

doi:10.1002/bip.23104

Cited by 20 publications

(18 citation statements)

References 61 publications

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“…With regard to a potentially protective role of TMAO, there are numerous other studies showing that TMAO protects the structural and functional proteins of cells from denaturants such as high osmotic pressure, hydrostatic pressure, NaCl, urea or a high temperature [15,33,34,35].…”

Section: Discussionmentioning

confidence: 99%

TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

Jaworska

Hering

Mosieniak

et al. 2019

Toxins

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Trimethylamine-N-oxide (TMAO) has been suggested as a marker and mediator of cardiovascular diseases. However, data are contradictory, and the mechanisms are obscure. Strikingly, the role of the TMAO precursor trimethylamine (TMA) has not drawn attention in cardiovascular studies even though toxic effects of TMA were proposed several decades ago. We assessed plasma TMA and TMAO levels in healthy humans (HH) and cardiovascular patients qualified for aortic valve replacement (CP). The cytotoxicity of TMA and TMAO in rat cardiomyocytes was evaluated using an MTT test. The effects of TMA and TMAO on albumin and lactate dehydrogenase (LDH) were assessed using fluorescence correlation spectroscopy. In comparison to HH, CP had a two-fold higher plasma TMA (p < 0.001) and a trend towards higher plasma TMAO (p = 0.07). In CP plasma, TMA was inversely correlated with an estimated glomerular filtration rate (eGFR, p = 0.002). TMA but not TMAO reduced cardiomyocytes viability. Incubation with TMA but not TMAO resulted in the degradation of the protein structure of LDH and albumin. In conclusion, CP show increased plasma TMA, which is inversely correlated with eGFR. TMA but not TMAO exerts negative effects on cardiomyocytes, likely due to its disturbing effect on proteins. Therefore, TMA but not TMAO may be a toxin and a marker of cardiovascular risk.

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Section: Discussionmentioning

confidence: 99%

TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

Jaworska

Hering

Mosieniak

et al. 2019

Toxins

View full text Add to dashboard Cite

show abstract

“…The pKa of TMAO is 4.7 ± 0.1 [113] and at acidic pH it is in the protonated form. This form is not able to stabilize the native protein state [113]. In the deprotonated form, TMAO possesses a large dipole moment and can interact very well with water, forming three strong hydrogen bonds leading to an increase in the magnitude of the solvent-excluded volume effect [113].…”

Section: Tmao As a Small Chaperonementioning

confidence: 98%

“…The mechanism of action of TMAO still needs to be clarified and future work should shed light on how TMAO actually interacts with the protein structure. Nevertheless, the pH dependent nature of TMAO is often neglected when theoretical or experimental studies are carried out [113]. The pKa of TMAO is 4.7 ± 0.1 [113] and at acidic pH it is in the protonated form.…”

Section: Tmao As a Small Chaperonementioning

confidence: 99%

“…Nevertheless, the pH dependent nature of TMAO is often neglected when theoretical or experimental studies are carried out [113]. The pKa of TMAO is 4.7 ± 0.1 [113] and at acidic pH it is in the protonated form. This form is not able to stabilize the native protein state [113].…”

Section: Tmao As a Small Chaperonementioning

confidence: 99%

“…This form is not able to stabilize the native protein state [113]. In the deprotonated form, TMAO possesses a large dipole moment and can interact very well with water, forming three strong hydrogen bonds leading to an increase in the magnitude of the solvent-excluded volume effect [113]. Indeed, Vigorita et al have argued that when protonated, TMAO could not possibly form three bonds with water and lose its stabilizing effect caused by water attraction [113].…”

Section: Tmao As a Small Chaperonementioning

confidence: 99%

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Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

et al. 2019

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Trimethylamine N-Oxide (TMAO) is the product of the monooxygenation reaction catalyzed by a drug-metabolizing enzyme, human flavin-containing monooxygenase 3 (hFMO3), and its animal orthologues. For several years, researchers have looked at TMAO and hFMO3 as two distinct molecules playing specific but separate roles, the former to defend saltwater animals from osmotic or hydrostatic stress and the latter to process xenobiotics in men. The presence of high levels of plasmatic TMAO in elasmobranchs and other animals was demonstrated a long time ago, whereas the actual physiological role of hFMO3 is still unknown because the enzyme has been mainly characterized for its ability to oxidize drugs. Recently TMAO was found to be related to several human health conditions such as atherosclerosis, cardiovascular, and renal diseases. This correlation poses a striking question of how other vertebrates (and invertebrates) can survive in the presence of very high TMAO concentrations (micromolar in humans, millimolar in marine mammals and several hundred millimolar in elasmobranchs). Therefore, it is important to address how TMAO, its precursors, and FMO catalytic activity are interconnected.

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Cosolvent and Crowding Effects on the Temperature‐ and Pressure‐Dependent Dissociation Process of the α/β‐Tubulin Heterodimer

et al. 2019

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Tubulin is one of the main components of the cytoskeleton of eukaryotic cells. The formation of microtubules depends strongly on environmental and solution conditions, and has been found to be among the most pressure sensitive processes in vivo. We explored the effects of different types of cosolvents, such as trimethylamine‐N‐oxide (TMAO), sucrose and urea, and crowding agents to mimic cell‐like conditions, on the temperature and pressure stability of the building block of microtubules, i. e. the α/β‐tubulin heterodimer. To this end, fluorescence and FTIR spectroscopy, differential scanning and pressure perturbation calorimetry as well as fluorescence anisotropy and correlation spectroscopies were applied. The pressure and temperature of dissociation of α/β‐tubulin as well as the underlying thermodynamic parameters upon dissociation, such as volume and enthalpy changes, have been determined for the different solution conditions. The temperature and pressure of dissociation of the α/β‐tubulin heterodimer and hence its stability increases dramatically in the presence of TMAO and the nanocrowder sucrose. We show that by adjusting the levels of compatible cosolutes and crowders, cells are able to withstand deteriorating effects of pressure even up to the kbar‐range.

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Counteraction ability of TMAO toward different denaturing agents

Cited by 20 publications

References 61 publications

TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology

Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

Cosolvent and Crowding Effects on the Temperature‐ and Pressure‐Dependent Dissociation Process of the α/β‐Tubulin Heterodimer

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