ReviewTMAO: A small molecule of great expectations
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.
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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.