Detoxification of Trimethylamine N-Oxide by the Mitochondrial Amidoxime Reducing Component mARC

Although known for years, the toxic effects of trimethylamine N-oxide (TMAO), a physiological metabolite, were just recently discovered and are currently under investigation. It is known that elevated TMAO plasma levels correlate with an elevated risk for cardiovascular disease (CVD). Even though there is a general consensus about the existence of a causal relationship between TMAO and CVD, the underlying mechanisms are not fully understood. TMAO is an oxidation product of the hepatic flavin-containing monooxygenases (FMO), mainly of isoform 3, and it is conceivable that humans also have an enzyme reversing this toxification by reducing TMAO to its precursor trimethylamine (TMA). All prokaryotic enzymes that use TMAO as a substrate have molybdenum-containing cofactors in common. Such molybdenum-containing enzymes also exist in mammals, with the so-called mitochondrial amidoxime reducing component (mARC) representing the most recently discovered mammalian molybdenum enzyme. The enzyme has been found to exist in two isoforms, mARC1 and mARC2, both being capable of reducing a variety of N-oxygenated compounds, including nonphysiological N-oxides. To investigate whether the two isoforms of this enzyme are able to reduce and detoxify TMAO, we developed a suitable analytical method and tested TMAO reduction with a recombinant enzyme system. We found that one of the two recombinant human mARC proteins, namely, hmARC1, reduces TMAO to TMA. The N-reductive activity is relatively low and identified via the kinetic parameters with K