An unusual case of trimethylaminuria

Ruocco, Vincenzo; Florio, Maria Teresa; Filioli, F. Grimaldi; Guerrera, V.; Prota, Giuseppe

doi:10.1111/j.1365-2133.1989.tb04175.x

Cited by 22 publications

(10 citation statements)

References 4 publications

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“…FMO3 is a major form of the enzyme present in adult human liver, where it plays an important role in the metabolism of trimethylamine (TMA). TMA is derived in vivo primarily from bacterial degradation of dietary choline, carnitine, and lecithin [2][3][4] which are found in foods such as egg yolk, liver, kidney, legumes, soybeans, peas, shellfish, and salt-water fish [4]. TMA is thought to be the primary endogenous substrate for FMO3, although it is possible that other biogenic amines such as tyramine [5] and phenylethylamine [6] may also be physiologically relevant substrates.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria

Yeung

Adman

Rettie

2007

Archives of Biochemistry and Biophysics

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Impaired conversion of trimethylamine to trimethylamine N-oxide by human flavin containing monooxygenase 3 (FMO3) is strongly associated with primary trimethylaminuria, also known as 'fish-odor' syndrome. Numerous non-synonymous mutations in FMO3 have been identified in patients suffering from this metabolic disorder (e.g. N61S, M66I, P153L, R492W), but the molecular mechanism(s) underlying the functional deficit attributed to these alleles has not been elucidated. The purpose of the present study was to determine the impact of these disease-associated genetic variants on FMO3 holoenzyme formation and on steady-state kinetic parameters for metabolism of several substrates, including trimethylamine. For comparative purposes, several common allelic variants not associated with primary trimethylaminuria (i.e. E158K, V257M, E308G and the E158K/ E308G haplotype) were also analyzed. When recombinantly expressed in insect cells, only the M66I and R492W mutants failed to incorporate/retain the FAD cofactor. Of the remaining mutant proteins P153L and N61S displayed substantially reduced (<10%) catalytic efficiencies for trimethylamine N-oxygenation relative to the wild-type enzyme. For N61S, reduced catalytic efficiency was solely a consequence of an increased K m , whereas for P153L, both K m and k cat were altered. Similar results were obtained when benzydamine N-oxygenation was monitored. A homology model for FMO3 was constructed based on the crystal structure for yeast FMO which places the N61 residue alone, of the mutants analyzed here, in close proximity to the FAD catalytic center. These data demonstrate that primary trimethylaminuria is multifactorial in origin in that enzyme dysfunction can result from kinetic incompetencies as well as impaired assembly of holoprotein.

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Section: Introductionmentioning

confidence: 99%

Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria

Yeung

Adman

Rettie

2007

Archives of Biochemistry and Biophysics

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“…In these cases, there was neither familial nor personal history of the disorder, although common to all cases was the presence of previous or current liver pathology, such as hepatitis. It was therefore suggested that the acquisition of the disorder in these cases may be linked to insertion of viral DNA into the genome, which adversely affects the normal expression of the FMO3 gene 8 9…”

Section: Discussionmentioning

confidence: 99%

Trimethylaminuria

Sabir¹,

Jones

Padmakumar

2016

BMJ Case Reports

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We report the case of a 9-year-old boy referred to secondary care with an unusual presentation of a fishy odour to his hands, feet, saliva and urine. Laboratory investigations including urine analysis and genetic testing confirmed the diagnosis of trimethylaminuria. The patient was referred to a geneticist and dietician, and consequently treated with dietary modification. He now has an arguably much improved quality of life.

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“…Whether the immunologic events associated with some forms of liver disease adversely affect FMO activity remains to be determined. Interestingly, one report describes a man developing fish-odour syndrome at 27 years of age, having had no previous history, and the authors suggested that this condition could be secondary to asymptomatic viral (A) hepatitis, as evidenced by the presence of serum antibodies (25). The overgrowth of intestinal microbes, Scand J Gastroenterol 1999 (5) associated with hepatic and kidney dysfunction, may also increase the liberation of trimethylamine from dietary precursors, leading to metabolic saturation.…”

Section: Discussionmentioning

confidence: 99%