Hepatic trimethylamine N-oxygenation and metaorganismal TMAO synthesis

Conserved mammalian hepatic monooxygenase module in which endoplasmic reticulum membrane-anchored flavin-containing monooxygenase 3 (FMO3) catalyzes the NADPH- and O2-dependent N-oxygenation of gut microbiota-derived trimethylamine (TMA) to odorless trimethylamine N-oxide (TMAO), as well as the N- and S-oxygenation of diverse nucleophilic xenobiotics and drugs. In both humans and mice, dietary quaternary amines (phosphatidylcholine, choline, carnitine) are cleaved by gut microbial lyases (CutC/CutD, CntA/CntB) to release volatile TMA, which enters the portal circulation and is oxidized in hepatocytes by FMO3 via a stable C4a-hydroperoxyflavin intermediate. Loss of human FMO3 causes autosomal recessive trimethylaminuria (fish-odor syndrome), and loss of mouse Fmo3 abolishes hepatic TMA-to-TMAO conversion.

MODULE:hepatic_trimethylamine_n_oxygenationDRAFTCONCRETEMetabolic Pathwaymodules/hepatic_trimethylamine_n_oxygenation.yaml
trimethylamine monooxygenase activityGO:0034899 N,N-dimethylaniline monooxygenase activityGO:0004499 amine catabolic processGO:0009310 xenobiotic metabolic processGO:0006805
PMID:9536088
Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.
Human FMO3 catalyzes the hepatic N-oxygenation of dietary-derived trimethylamine and xenobiotics; loss-of-function mutations cause trimethylaminuria.
We show here that mutations in the human flavin-containing monooxygenase isoform 3 gene ( FMO3 ) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype.
PMID:9776311
Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3.
At physiological pH, human FMO3 is the specific and efficient hepatic TMA N-oxygenase responsible for metabolic clearance of TMA to TMAO in vivo.
Therefore, at physiological pH, human FMO3 is a very specific and efficient TMA N-oxygenase, and is likely responsible for the metabolic clearance of TMA in vivo in humans.
PMID:9344459
Molecular cloning, sequencing, and expression in Escherichia coli of mouse flavin-containing monooxygenase 3 (FMO3): comparison with the human isoform.
Recombinant mouse and human FMO3 share conserved catalytic activity toward trimethylamine and nucleophilic S-/N-containing substrates.
Catalytic activities of mouse and human FMO3 were high toward the substrate methimazole; however, in the presence of trimethylamine and thioacetamide, FMO-dependent methimazole oxidation by both enzymes was reduced by greater than 85%.
PMID:29981269
Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk.
Defines the two-step metaorganismal pathway in which gut microbial TMA lyases produce TMA from dietary precursors and host hepatic FMO3 converts portal-vein TMA into TMAO in mice and humans.
Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs).
file:genes/human/FMO3/FMO3-ai-review.yaml
Human FMO3 gene review
Grounds human FMO3 (UniProtKB:P31513) as the adult hepatic ER-anchored flavin-containing monooxygenase responsible for TMA N-oxygenation and xenobiotic N-/S-oxygenation.
file:genes/mouse/Fmo3/Fmo3-ai-review.yaml
Mouse Fmo3 gene review
Grounds mouse Fmo3 (UniProtKB:P97501) as the orthologous hepatic flavin-containing monooxygenase required for TMA-to-TMAO conversion.

Boundary: Gut microbial cleavage of dietary choline and carnitine to TMA by microbial CutC/CutD and CntA/CntB is upstream metaorganismal context supplying portal-vein TMA to hepatocytes. Within the hepatocyte endoplasmic reticulum membrane, NADPH--cytochrome P450 reductase (POR) is NOT required for FMO3 catalysis because FMO3 directly binds NADPH and O2 to generate its own C4a-hydroperoxyflavin intermediate. Ontology note: While GO includes the specific molecular function term GO:0034899 (trimethylamine monooxygenase activity), the PAINT deuterostome node PTN000545689 carries an IBD annotation for the broader EC 1.14.13.8 class term GO:0004499 (N,N-dimethylaniline monooxygenase activity), and GO currently lacks a dedicated trimethylamine N-oxide biosynthetic process term, so process participation is captured with GO:0009310 (amine catabolic process) and GO:0006805 (xenobiotic metabolic process). Member genes with reviews in this repository: human/FMO3 (UniProtKB:P31513), mouse/Fmo3 (UniProtKB:P97501).

1Nodes
0Parts
0Variant Sets
0Variants
1Annotons
0Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:hepatic_trimethylamine_n_oxygenation deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

2 gene-function check(s) reflected in core functions · 0 conflict(s) · 0 evidence or coverage gap(s) (3 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
fmo3_tma_n_oxygenase FMO3 (human)
UniProtKB:P31513
Family Representative 		trimethylamine monooxygenase activity
GO:0034899 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fmo3_tma_n_oxygenase Fmo3 (mouse)
UniProtKB:P97501
Family Representative 		trimethylamine monooxygenase activity
GO:0034899 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fmo3_tma_n_oxygenase Flavin-containing monooxygenase 3 (FMO3)
PANTHER:PTHR23023:SF44
Family 		trimethylamine monooxygenase activity
GO:0034899 		Family Supported
Family review supports GO:0034899 for PANTHER:PTHR23023:SF44. Physiological NADPH- and FAD-dependent trimethylamine N-oxygenation (GO:0034899) is the signature core activity of the mammalian FMO3 subfamily (PANTHER:PTHR23023:SF44), where loss-of-function causes trimethylaminuria, whereas Brassicaceae FMOGS-OX enzymes catalyze glucosinolate S-oxygenation and fungal FMO homologs catalyze thiol oxidation.

Gene-review completeness (2/2 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
FMO3 P31513 ✓ ✓ ✗
Fmo3 P97501 ✓ ✓ ✗

Details

Context
MammaliaNCBITaxon:40674 Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090
hepatocyteCL:0000182
liverUBERON:0002107
endoplasmic reticulum membraneGO:0005789
Hepatic trimethylamine N-oxygenationMetabolic Pathwayhepatic_trimethylamine_n_oxygenation

Endoplasmic reticulum membrane-anchored FMO3 reduces bound FAD with NADPH and reacts with O2 to form a stable C4a-hydroperoxyflavin intermediate that oxygenates gut microbiota-derived trimethylamine (TMA) to trimethylamine N-oxide (TMAO) and detoxifies nucleophilic N- and S-containing xenobiotics.

trimethylamine monooxygenase activityGO:0034899 N,N-dimethylaniline monooxygenase activityGO:0004499 amine catabolic processGO:0009310 xenobiotic metabolic processGO:0006805
Context
MammaliaNCBITaxon:40674 Homo sapiensNCBITaxon:9606 Mus musculusNCBITaxon:10090
hepatocyteCL:0000182
liverUBERON:0002107
endoplasmic reticulum membraneGO:0005789

Annotons

FMO3 hepatic trimethylamine and xenobiotic N-/S-monooxygenase
fmo3_tma_n_oxygenase
Participant: Family: Flavin-containing monooxygenase 3 (FMO3)
Family:
Flavin-containing monooxygenase 3 (FMO3)PANTHER:PTHR23023:SF44
Representative Members: FMO3 (human)UniProtKB:P31513 Fmo3 (mouse)UniProtKB:P97501

Function

trimethylamine monooxygenase activityGO:0034899 Catalyzes NADPH- and O2-dependent N-oxygenation of trimethylamine to trimethylamine N-oxide (TMAO) and N-/S-oxygenation of xenobiotics and drugs via a C4a-hydroperoxyflavin intermediate.

Processes

amine catabolic processGO:0009310 xenobiotic metabolic processGO:0006805

Locations

endoplasmic reticulum membraneGO:0005789 endoplasmic reticulumGO:0005783

Sole catalytic enzyme of the hepatic TMA-to-TMAO oxidation step; binds FAD and NADPH directly on the cytosolic face of the ER membrane to oxygenate portal-vein TMA and nucleophilic xenobiotics.

PMID:9536088
Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.
Human FMO3 catalyzes TMA and xenobiotic N-oxygenation in liver; loss of activity causes trimethylaminuria.
We show here that mutations in the human flavin-containing monooxygenase isoform 3 gene ( FMO3 ) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype.
PMID:9776311
Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3.
FMO3 is the specific and efficient hepatic TMA N-oxygenase at physiological pH in humans.
Therefore, at physiological pH, human FMO3 is a very specific and efficient TMA N-oxygenase, and is likely responsible for the metabolic clearance of TMA in vivo in humans.
PMID:29981269
Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk.
Host hepatic FMO3 converts portal-vein TMA produced by gut microbial lyases into TMAO in mouse and human.
Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs).