TMAO: A small molecule of great expectations

doi:10.1016/j.nut.2015.05.006

Nutrition

Volume 31, Issues 11–12, November–December 2015, Pages 1317-1323

https://doi.org/10.1016/j.nut.2015.05.006 Get rights and content

Highlights

•
Trimethylamine N-oxide (TMAO) is a small organic compound whose concentration in blood increases after ingesting dietary l-carnitine and phosphatidylcholine.
•
Recent clinical studies show a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events.
•
We reviewed well-established chemical and biologic properties of TMAO and dietary sources of TMAO.
•
We looked at studies suggesting possible involvement of TMAO in the etiology of cardiovascular and other diseases, such as kidney failure, diabetes, and cancer.

Abstract

Trimethylamine N-oxide (TMAO) is a small organic compound whose concentration in blood increases after ingesting dietary l-carnitine and phosphatidylcholine. Recent clinical studies show a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events defined as death, myocardial infarction, or stroke. Several experimental studies suggest a possible contribution of TMAO to the etiology of cardiovascular diseases by affecting lipid and hormonal homeostasis. On the other hand, TMAO-rich seafood, which is an important source of protein and vitamins in the Mediterranean diet, has been considered beneficial for the circulatory system. Although in humans TMAO is known mainly as a waste product of choline metabolism, a number of studies suggest an involvement of TMAO in important biological functions in numerous organisms, ranging from bacteria to mammals. For example, cells use TMAO to maintain cell volume under conditions of osmotic and hydrostatic pressure stresses. In this article, we reviewed well-established chemical and biological properties of TMAO and dietary sources of TMAO, as well as looked at the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and other diseases, such as kidney failure, diabetes, and cancer.

Introduction

In Charles Dickens' novel Great Expectations, Pip, a poor orphan, faces the turning point in his life when he receives an unexpected fortune. This raises great expectations in Pip that go beyond the said fortune. Unfortunately, as Pip lives a new life, his great expectations are ruined. Likewise, in a world in which more people die annually from cardiovascular diseases (CVD) than from any other cause, a newly discovered marker raises great expectations in both patients and doctors. Recently, an association between an elevated fasting plasma trimethylamine N-oxide (TMAO) and an increased risk for major adverse cardiovascular events has been identified. New research suggests that TMAO affects lipid and hormonal homeostasis and thereby possibly contributes to the development of CVD. TMAO is a metabolite of phosphatidylcholine and l-carnitine, both abundant in red meat. For this reason, TMAO has been proposed to constitute a link between diet and CVD. On the other hand, it is well established that TMAO plays a protective role in cell homeostasis in numerous animal species. For example, cells use TMAO to maintain cell volume under conditions of osmotic and hydrostatic pressure stresses.

Is TMAO the long sought-after link between “unhealthy diet” and CVD, or do we, like Pip, rely too much on what we do not have yet? In what follows here, we review studies on chemical and biological properties of TMAO and its possible role in the development of CVD and other diseases.

Section snippets

Chemical and physical properties of TMAO, interactions with proteins

TMAO is an organic compound belonging to the class of amine oxides with the formula (CH₃)₃ NO (Fig. 1). It occurs in the form of a colorless solid and is usually encountered as a dihydrate. Chemically, it is obtained in a straightforward procedure starting from trimethylamine (TMA), (Fig. 2).

TMAO is capable of affecting the structure and activity of many biologically important compounds. For example, it has been well established that TMAO is an important stabilizer of the protein-folded state

TMAO: A waste product?

TMAO is a common compound found in animals, but is also present in plants and fungi [18], [19], [20]. The origin of TMAO may be exogenous and endogenous. In humans, most TMAO seems to come from the oxygenation of TMA, a TMAO precursor produced by gut flora [21]. In contrast, in marine animals TMAO may be synthetized endogenously [22]; however, the mechanisms involved are not clear [23]. The concentration of TMAO in marine animals significantly exceeds its concentration in other organisms [24].

Metabolism of TMAO

It seems that, in contrast to some marine animals that may synthetize it endogenously, TMAO in terrestrial mammals comes from exogenous sources [18], [21], [22], [35]. TMAO concentration in blood increases after ingestion of dietary choline and l-carnitine [30], [36]. Choline is acquired from the diet and endogenous synthesis; however, the latter source is not sufficient to meet human requirements. The average human diet contains about 500 mg of free choline. Dietary sources rich in choline

TMAO at the bench and bedside

So far, clinicians have focused mainly on the role of TMAO in fish odor syndrome. However, recently TMAO has attracted large attention after the publication of several papers suggesting that it may be an important diagnostic marker in CVD [21], [43], [49].

Perspectives

Elevated plasma TMAO is associated with an increased risk for major adverse cardiovascular events in humans and several experimental studies suggest a possible involvement of TMAO in the etiology of CVD. On the other hand, it is well established that TMAO performs important, protective functions in numerous organisms, ranging from bacteria to fish. For instance, it maintains cell volume, protecting cells from osmotic and hydrostatic damage. It is possible that, although TMAO plays an important

Acknowledgments

The authors acknowledge Dr. T. Zera for his critical comments on the manuscript.

References (93)

M.V. Athawale et al.
Osmolyte trimethylamine-N-oxide does not affect the strength of hydrophobic interactions: origin of osmolyte compatibility
Biophys J
(2005)
D. Bolen et al.
The osmophobic effect: natural selection of a thermodynamic force in protein folding
J Mol Biol
(2001)
L. Goldstein et al.
Biosynthesis of trimethylamine oxide in the nurse shark, Ginglymostoma cirratum
Comp Biochem Physiol A Comp Physiol
(1972)
M.B. Burg et al.
Intracellular organic osmolytes: Function and regulation
J Biol Chem
(2008)
S.H. Zeisel et al.
Conversion of dietary choline to trimethylamine and dimethylamine in rats: dose-response relationship
J Nutr
(1989)
C.A. Miller et al.
Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study
Am J Clin Nutr
(2014)
A.A. West et al.
Egg n-3 fatty acid composition modulates biomarkers of choline metabolism in free-living lacto-ovo-vegetarian women of reproductive age
J Acad Nutr Diet
(2014)
F.J. Kuczler et al.
Choline influx across the brush border of guinea pig jejunum
Acta Biochim Biophys
(1977)
J.R. Ussher et al.
Gut microbiota metabolism of L-carnitine and cardiovascular risk
Atherosclerosis
(2013)
C. Rigault et al.
Genomic structure, alternative maturation and tissue expression of the human BBOX1 gene
Acta Biochim Biophys
(2006)

J. Demarquoy et al.

Radioisotopic determination of L-carnitine content in foods commonly eaten in Western countries

Food Chem

(2004)

C. Rigault et al.

Changes in L-carnitine content of fish and meat during domestic cooking

Meat Sci

(2008)

J.D. Bell et al.

Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide

Acta Biochim Biophys

(1991)

E.M. Lenz et al.

Metabonomics, dietary influences and cultural differences: a 1 H NMR-based study of urine samples obtained from healthy British and Swedish subjects

J Pharm Biomed Anal

(2004)

M. Ufnal et al.

Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats

Can J Cardiol

(2014)

R.L. Woltjer et al.

Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment

Neurobiol Dis

(2007)

R. D'Angelo et al.

FMO3 allelic variants in Sicilian and Sardinian populations: trimethylaminuria and absence of fish-like body odor

Gene

(2013)

C. Doucet et al.

Influence of colloid, preservation medium and trimetazidine on renal medulla injury

Acta Biochim Biophys

(2004)

X. Gao et al.

Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet

J Biosci Bioeng

(2014)

T. Huo et al.

Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride

J Pharm Biomed Anal

(2009)

F. Georgescauld et al.

Rescue of the neuroblastoma mutant of the human nucleoside diphosphate kinase A/nm23-H1 by the natural osmolyte trimethylamine-N-oxide

FEBS Lett

(2009)

H.C. Tseng et al.

Natural methylamine osmolytes, trimethylamine N-oxide and betaine, increase tau-induced polymerization of microtubules

Biochem Biophys Res Commun

(1998)

J.C. Chamcheu et al.

Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation: involvement of heat shock proteins and MAP kinases

J Invest Dermatol

(2011)

H. Yoshida et al.

Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch

Neurobiol Dis

(2002)

J. Baker et al.

The biosynthesis of trimethylamine-N-oxide

J Biol Chem

(1962)

T.C. Gluick et al.

Trimethylamine N-oxide stabilizes RNA tertiary structure and attenuates the denaturating effects of urea

J Am Chem Soc

(2003)

J. Ma et al.

Microscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO)

Proc Natl Acad Sci U S A

(2014)

C. Krywka et al.

Effect of osmolytes on pressure-induced unfolding of proteins: a high-pressure SAXS study

Chemphyschem

(2008)

J. Mondal et al.

When does trimethylamine N-oxide fold a polymer chain and urea unfold it?

J Phys Chem B

(2013)

R. Sarma et al.

Exploring the molecular mechanism of trimethylamine-N-oxide's ability to counteract the protein denaturing effects of urea

J Phys Chem B

(2013)

B.J. Bennion et al.

Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: a chemical chaperone at atomic resolution

Proc Natl Acad Sci U S A

(2004)

K.A. Sharp et al.

Water structure changes induced by hydrophobic and polar solutes revealed by simulations and infrared spectroscopy

J Chem Phys

(2001)

S.S. Cho et al.

Entropic stabilization of proteins by TMAO

J Phys Chem B

(2011)

S. Paul et al.

Structure and interaction in aqueous urea-trimethylamine-N-oxide solutions

J Am Chem Soc

(2007)

H. Kokubo et al.

Peptide conformational preferences in osmolyte solutions: transfer free energies of decaalanine

J Am Chem Soc

(2011)

L. Yang et al.

Effects of cosolvents on the hydration of carbon nanotubes

J Am Chem Soc

(2010)

L.M.F. Holthauzen et al.

Mixed osmolytes: the degree to which one osmolyte affects the protein stabilizing ability of another

Protein Sci

(2007)

T.O. Street et al.

A molecular mechanism for osmolyte-induced protein stability

Proc Natl Acad Sci U S A

(2006)

C.Y. Hu et al.

Trimethylamine N-oxide influence on the backbone of proteins: an oligoglycine model

Proteins

(2010)

D.R. Canchi et al.

Molecular mechanism for the preferential exclusion of TMAO from protein surfaces

J Phys Chem B

(2012)

P.H. Yancey

Water stress, osmolytes and proteins

Am Zool

(2001)

K. Preugschat et al.

Effects of feeding diets containing increasing proportions of bunt-infected wheat (Tilletia caries) on performance and health of pigs

Arch Anim Nutr

(2014)

I.R. Phillips et al.

Trimethylaminuria

R.A. Koeth et al.

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

Nat Med

(2013)

B.A. Seibel et al.

Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage

J Exp Biol

(2002)

P.H. Yancey

Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

J Exp Biol

(2005)

Cited by (242)

Effects of dietary rumen-protected choline supplementation to periparturient dairy cattle on inflammation and metabolism in mammary and liver tissue during an intramammary lipopolysaccharide challenge
2024, Journal of Dairy Science
The objective of this experiment was to examine the effects of supplementation and dose of rumen-protected choline (RPC) on markers of inflammation and metabolism in liver and mammary tissue during an intramammary lipopolysaccharide (LPS) challenge. Parous Holstein cows were blocked by calving month and randomly assigned within block to receive 45 g/d of RPC (20.4 g/d of choline ions; CHOL45), 30 g/d of RPC (13.6 g/d of choline ions; CHOL30), or no RPC (CON) as a top-dress starting 24 d before expected calving until 21 d postpartum. Cows were alternately assigned within treatment group to either receive an intramammary LPS challenge (200 μg in each rear quarter; Escherichia coli O111:B4) or not at 17 DIM (CHOL45, n = 9; CHOL45-LPS, n = 9; CHOL30, n = 11; CHOL30-LPS, n = 10; CON, n = 10; CON-LPS, n = 9). Hepatic and mammary tissues were collected from all cows on d 17 postpartum. Hepatic and mammary tissues were collected at ∼7.5 and 8 h, respectively, after the LPS challenge. An additional mammary biopsy was conducted on LPS-challenged cows (CHOL45-LPS, CHOL30-LPS, and CON-LPS) at 48 h postchallenge. Hepatic and mammary RNA copy numbers were quantified for genes involved in apoptosis, methylation, inflammation, oxidative stress, and mitochondrial function using NanoString technology. Targeted metabolomics was conducted only on mammary tissue samples (both 8 and 48 h biopsies) to quantify 143 metabolites including choline metabolites, amino acids, biogenic amines and derivatives, organic acids, carnitines, and glucose. Hepatic IFNG was greater in CHOL45 as compared with CON in unchallenged cows, suggesting an improvement in type 1 immune responses. Hepatic CASP3 was greater in CHOL45-LPS as compared with CON-LPS, suggesting greater apoptosis. Mammary IL6 was reduced in CHOL30-LPS cows as compared with CHOL45-LPS and CON-LPS (8 and 48 h). Mammary GPX4 and COX5A were reduced in CHOL30-LPS as compared with CON-LPS (8 h), and SDHA was reduced in CHOL30-LPS as compared with CON-LPS (8 and 48 h). Both CHOL30-LPS and CHOL45-LPS cows had lesser mammary ATP5J than CON-LPS, suggesting that dietary RPC supplementation altered mitochondrial function following LPS challenge. Treatment did not affect mammary concentrations of any metabolite in unchallenged cows, and only 4 metabolites were affected by dietary RPC supplementation in LPS-challenged cows. Mammary concentrations of isobutyric acid and 2 acyl-carnitines (C4:1 and C10:2) were reduced in CHOL45-LPS as compared with CHOL30-LPS and CON-LPS. Taken together, reductions in medium- and short-chain carnitines along with an increase in long-chain carnitines in mammary tissue from CHOL45-LPS cows suggests less fatty acid entry into the β oxidation pathway. Although the intramammary LPS challenge profoundly affected markers for inflammation and metabolism in liver and mammary tissue, dietary RPC supplementation had minimal effects on inflammatory markers and the mammary metabolome.
A systematic review of metabolomic findings in adult and pediatric renal disease
2024, Clinical Biochemistry
Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.
Effects of dietary rumen-protected choline supplementation to periparturient dairy cattle on inflammation, metabolism, and performance during an intramammary lipopolysaccharide challenge
2023, Journal of Dairy Science
Recent studies have suggested that dietary rumen-protected choline (RPC) supplementation can modulate immune function, attenuate inflammation, and improve performance in periparturient dairy cattle; however, this has yet to be evaluated during a mastitis challenge. Therefore, the objective of this study was to examine the effects of supplementation and dose of RPC on metabolism, inflammation, and performance during an intramammary lipopolysaccharide (LPS) challenge. Parous Holstein cows (parity, mean ± SD, 1.9 ± 1.1 at enrollment) were blocked by calving month and randomly assigned within block to receive either 45 g/d of RPC (20.4 g/d of choline ions; CHOL45, n = 18), 30 g/d of RPC (13.6 g/d of choline ions; CHOL30, n = 21), or no RPC (CON, n = 19) as a top-dress starting 24 d before expected calving until 21 d postpartum. Cows were alternately assigned within treatment group to either receive an intramammary LPS challenge (200 μg in each rear quarter; Escherichia coli O111:B4) or not at 17 DIM. Before the challenge, CHOL45 and CHOL30 cows produced 3.4 and 3.8 (±1.2 SED) kg/d more milk than CON, respectively. Dietary RPC supplementation did not mitigate the milk loss associated with the intramammary LPS challenge; however, CHOL45 and CHOL30 cows produced 3.1 and 3.5 (±1.4 SED) kg/d more milk than CON, respectively in the carryover period (22 to 84 DIM). Dietary RPC supplementation enhanced plasma β-hydroxybutyrate (BHB) concentrations before the LPS challenge, and increased plasma nonesterified fatty acids (NEFA) and acetylcarnitine concentrations during the LPS challenge, potentially reflecting greater adipose tissue mobilization, fatty acid transport and oxidation. Aside from trimethylamine N-oxide and sarcosine, which were increased in CHOL45-LPS as compared with CON-LPS, most other choline metabolite concentrations in plasma were unaffected by treatment, likely because more choline was being secreted in milk. Plasma lactic acid concentrations were decreased in CHOL45-LPS and CHOL30-LPS as compared with CON-LPS, suggesting a reduction in glycolysis or an enhancement in the flux through the lactic acid cycle to support gluconeogenesis. Plasma concentrations of fumaric acid, a byproduct of AA catabolism and the urea cycle, were increased in both choline groups as compared with CON-LPS during the LPS challenge. Cows in the CHOL45 group had greater plasma antioxidant potential before the LPS challenge and reduced plasma methionine sulfoxide concentrations during the LPS challenge compared with CON-LPS, suggesting an improvement in oxidant status. Nevertheless, concentrations of inflammatory markers such as haptoglobin and tumor necrosis factor α (TNFα) were not affected by treatment. Taken together, our data suggest that the effects of dietary RPC supplementation on milk yield could be mediated through metabolic pathways and are unlikely to be related to the resolution of inflammation in periparturient dairy cattle. Lastly, dose responses to dietary RPC supplementation were not found for various economically important outcomes including milk yield, limiting the justification for feeding a greater dietary RPC dose in industry.
Dynamics of a methane hydrophobe in aqueous choline chloride solution: Insights from molecular dynamics simulations
2023, Chemical Physics Impact
Motion of hydrophobic moieties in solvent plays a crucial role in biomolecular functioning and is strongly influenced by the properties of the surrounding environment. To have a molecular-level picture of the dynamics of tiny hydrophobes, we simulate a methane molecule in different concentrations of aqueous choline chloride (ChCl) solution. Our analyses reveal slower translational dynamics of methane and the emergence of spatiotemporal heterogeneity at the timescales across which methane shows cage and jump motion. This results non-Gaussianity in the dynamics and it becomes increasingly pronounced with higher ChCl concentration. This illustrates more confined motion of methane inside the smaller and closely spaced cages. Hence, the jump percentage increases, and the jump length decreases. However, the maximum contribution to total diffusion comes from residual diffusion, which accounts for caging and small step displacements.
Environmental biotransformation mechanisms by flavin-dependent monooxygenase: A computational study
2023, Chemosphere
The enzyme-catalyzed metabolic biotransformation of xenobiotics plays a significant role in toxicology evolution and subsequently environmental health risk assessment. Recent studies noted that the phase I human flavin-dependent monooxygenase (e.g., FMO3) can catalyze xenobiotics into more toxic metabolites. However, details of the metabolic mechanisms are insufficient. To fill the mechanism in the gaps, the systemic density functional theory calculations were performed to elucidate diverse FMO-catalyzed oxidation reactions toward environmental pollutants, including denitrification (e.g., nitrophenol), N-oxidation (e.g., nicotine), desulfurization (e.g., fonofos), and dehalogenation (e.g., pentachlorophenol). Similar to the active center compound 0 of cytochrome P450, FMO mainly catalyzed reactions with the structure of the tricyclic isoalloxazine C-4a-hydroperoxide (FADHOOH). As will be shown, FMO-catalyzed pathways are more favorable with a concerted than stepwise mechanism; Deprotonation is necessary to initiate the oxidation reactions for phenolic substrates; The regioselectivity of nicotine by FMO prefers the N-oxidation other than N-demethylation pathway; Formation of the P–S–O triangle ring is the key step for desulfurization of fonofos by FMO. We envision that these fundamental mechanisms catalyzed by FMO with a computational method can be extended to other xenobiotics of similar structures, which may aid the high-throughput screening and provide theoretical predictions in the future.
Osmolytes: Wonder molecules to combat protein misfolding against stress conditions
2023, International Journal of Biological Macromolecules
The proper functioning of any protein depends on its three dimensional conformation which is achieved by the accurate folding mechanism. Keeping away from the exposed stress conditions leads to cooperative unfolding and sometimes partial folding, forming the structures like protofibrils, fibrils, aggregates, oligomers, etc. leading to several neurodegenerative diseases like Parkinson's disease, Alzheimer's, Cystic fibrosis, Huntington, Marfan syndrome, and also cancers in some cases, too. Hydration of proteins is necessary, which may be achieved by the presence of organic solutes called osmolytes within the cell. Osmolytes belong to different classes in different organisms and play their role by preferential exclusion of osmolytes and preferential hydration of water molecules and achieves the osmotic balance in the cell otherwise it may cause problems like cellular infection, cell shrinkage leading to apoptosis and cell swelling which is also the major injury to the cell. Osmolyte interacts with protein, nucleic acids, intrinsically disordered proteins by non-covalent forces. Stabilizing osmolytes increases the Gibbs free energy of the unfolded protein and decreases that of folded protein and vice versa with denaturants (urea and guanidinium hydrochloride). The efficacy of each osmolyte with the protein is determined by the calculation of m value which reflects its efficiency with protein. Hence osmolytes can be therapeutically considered and used in drugs.

View all citing articles on Scopus

: A.Z. and R.O. wrote the paragraph “Chemical and physical properties of TMAO …” and prepared illustrations 1 to 4. M.U. wrote the remaining paragraphs and prepared illustration 5. All the authors have approved the final version of the manuscript.

View full text

ReviewTMAO: A small molecule of great expectations

Highlights

Abstract

Introduction

Section snippets

Chemical and physical properties of TMAO, interactions with proteins

TMAO: A waste product?

Metabolism of TMAO

TMAO at the bench and bedside

Perspectives

Acknowledgments

Biophys J

J Mol Biol

Comp Biochem Physiol A Comp Physiol

J Biol Chem

J Nutr

Am J Clin Nutr

J Acad Nutr Diet

Acta Biochim Biophys

Atherosclerosis

Acta Biochim Biophys

Food Chem

Meat Sci

Acta Biochim Biophys

J Pharm Biomed Anal

Can J Cardiol

Neurobiol Dis

Gene

Acta Biochim Biophys

J Biosci Bioeng

J Pharm Biomed Anal

FEBS Lett

Biochem Biophys Res Commun

J Invest Dermatol

Neurobiol Dis

J Biol Chem

Trimethylamine N-oxide stabilizes RNA tertiary structure and attenuates the denaturating effects of urea

J Am Chem Soc

Microscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO)

Proc Natl Acad Sci U S A

Effect of osmolytes on pressure-induced unfolding of proteins: a high-pressure SAXS study

Chemphyschem

When does trimethylamine N-oxide fold a polymer chain and urea unfold it?

J Phys Chem B

Exploring the molecular mechanism of trimethylamine-N-oxide's ability to counteract the protein denaturing effects of urea

J Phys Chem B

Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: a chemical chaperone at atomic resolution

Proc Natl Acad Sci U S A

Water structure changes induced by hydrophobic and polar solutes revealed by simulations and infrared spectroscopy

J Chem Phys

Entropic stabilization of proteins by TMAO

J Phys Chem B

Structure and interaction in aqueous urea-trimethylamine-N-oxide solutions

J Am Chem Soc

Peptide conformational preferences in osmolyte solutions: transfer free energies of decaalanine

J Am Chem Soc

Effects of cosolvents on the hydration of carbon nanotubes

J Am Chem Soc

Mixed osmolytes: the degree to which one osmolyte affects the protein stabilizing ability of another

Protein Sci

A molecular mechanism for osmolyte-induced protein stability

Proc Natl Acad Sci U S A

Trimethylamine N-oxide influence on the backbone of proteins: an oligoglycine model

Proteins

Molecular mechanism for the preferential exclusion of TMAO from protein surfaces

J Phys Chem B

Water stress, osmolytes and proteins

Am Zool

Effects of feeding diets containing increasing proportions of bunt-infected wheat (Tilletia caries) on performance and health of pigs

Arch Anim Nutr

Trimethylaminuria

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

Nat Med

Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage

J Exp Biol

Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

J Exp Biol

Review
TMAO: A small molecule of great expectations