Is FMO3 the main liver enzyme that converts microbial TMA to circulating TMAO, and do common FMO3 variants raise TMAO by increasing conversion efficiency?

The gut microbiota metabolizes dietary precursors into trimethylamine (TMA), which is absorbed and transported to the liver for oxidation into circulating trimethylamine N-oxide (TMAO).

Primary hepatic pathway

• FMO3 dominance: Flavin-containing monooxygenase 3 (FMO3) is the primary hepatic enzyme responsible for this conversion. Recombinant human FMO3 demonstrates a high affinity for TMA, characterized by a Michaelis constant ($K_m$) of approximately 28 µM and a maximal velocity ($V_{max}$) of about 36.3 nmol/nmol FMO3/min.
• Negligible alternative pathways: Other FMO isoforms (FMO1, FMO2, FMO4, and FMO5) contribute negligibly to hepatic TMA oxidation due to low expression in adult liver tissue or poor TMA affinity.

Genetic variants and metabolic efficiency

• The rs2266780 paradox: Clinical cohort data, particularly in chronic kidney disease populations, link the minor G allele of the common FMO3 variant rs2266780 (E308G) to elevated plasma TMAO. However, this variant does not enhance conversion; instead, it acts as a partial loss-of-function modifier that reduces FMO3 protein abundance and catalytic capacity.
• The rs2266782 variant: Conversely, recombinant studies of another common variant, rs2266782 (E158K), report a 35% increase in catalytic efficiency compared to wild-type FMO3. This demonstrates that genetic impacts on conversion kinetics are highly variant-specific.

Bottom line

• Hepatic FMO3 is the primary, non-redundant enzyme converting microbial TMA to circulating TMAO. While some common FMO3 variants are associated with higher circulating TMAO, the claim that they achieve this by enhancing conversion efficiency is unsupported for key variants like rs2266780, which actually decrease enzyme abundance, even though other specific variants like rs2266782 can increase catalytic efficiency.