RESUMO
Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.(P73L; E158K; E308G) FMO3 in trans configuration with the second new one p.(F140S) FMO3. Recombinant FMO3 proteins of the wild-type and the novel two variants underwent kinetic analyses of their trimethylamine N-oxygenation activities. P73L; E158K; E308G and F140S FMO3 proteins exhibited moderately and severely decreased trimethylamine N-oxygenation capacities (~50% and ~10% of wild-type FMO3, respectively). Amino acids P73 and F140 were located on the outer surface region in a crystallographic structure recently reported of a FMO3 analog. Changes in these positions would indirectly impact on key FAD-binding residues. This is the first report and characterization of a patient of fish odor syndrome caused by genetic aberrations leading to impaired FMO3-dependent N-oxygenation of trimethylamine found in the Argentinian population. We found novel structural determinants of FAD-binding domains, expanding the list of known disease-causing mutations of FMO3. Our results suggest that individuals homozygous for any of these new variants would develop a severe form of this disorder.
Assuntos
Membrana Celular/enzimologia , Metilaminas/metabolismo , Oxigênio/metabolismo , Oxigenases/genética , Polimorfismo de Nucleotídeo Único/genética , Argentina , Criança , Feminino , Humanos , Erros Inatos do Metabolismo/enzimologia , Metilaminas/urina , Oxigenases/metabolismoRESUMO
BACKGROUND: Trimethylamine (TMA) is a volatile substance produced in the gut, absorbed into the blood and further metabolized by healthy individuals into trimethylamine-N-oxide (TMAO) by TMA-oxidase and then excreted in urine. Patients suffering from trimethylaminuria (TMAU) show an impaired enzymatic oxidation of TMA, excreting this amine in breath, urine and other body secretions which confers an unpleasant body odor. METHODS: We diagnosed a Brazilian adult male patient suspected of trimethylaminuria with a burden of choline bitartarate by monitoring the urinary excretion of TMA and TMAO by proton nuclear magnetic resonance spectroscopy ((1)H-NMR). RESULTS: The patient's urinalyses showed an augmented TMA (12.64+/-0.95 mg/l) and TMAO (88.42+/-0.82 mg/l) excretion 6 h after the overload test representing an oxidation capacity of 84.6%, consistent with a heterozygosis condition. Diets containing tuna fish or eggs resulted in an excretion of TMA and TMAO similar to that of the control diet. Only the diet based on dogfish, rich in TMAO, enhanced the excretion of TMA and TMAO reaching 24.65 and 1055.55 mg/l, respectively, in the 0-24 h urine sample. CONCLUSIONS: It was concluded first, that the patient was not able to metabolize the dietary overload of TMA and second, that more studies are needed to substantiate foods that should be avoided, especially regarding fish, due to their high TMA precursor contents.
Assuntos
Erros Inatos do Metabolismo/urina , Metilaminas/urina , Adulto , Aminas/metabolismo , Aminas/urina , Animais , Colina/farmacocinética , Dieta , Cação (Peixe) , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Odorantes , Oxirredução , Padrões de Referência , SoluçõesRESUMO
A number of non-oral causes for oral malodor have been discussed. Several well documented etiologies for non-oral malodor include renal failure, cirrhosis of the liver, and diabetes mellitus. Each of these conditions has been examined using analytical instrumentation. In addition there appear to be several other metabolic conditions involving enzymatic and transport anomalies (such as trimethylaminuria) which lead to the systemic production of volatile malodors that manifest themselves as halitosis and/or altered chemoreception. Our studies include patients who have been referred to us after being examined by numerous clinical specialists with no identification or relief from their problem. This is due in part to the intermittent nature of many of these problems as well as an apparent lack of knowledge concerning many of these metabolic problems and their relation to oral symptoms.