Fish odour syndrome: Verification of carrier detection test

Zhang, A. Q.; Mitchell, Stephen C.; Smith, Robert L.

doi:10.1007/bf02436755

Cited by 40 publications

(28 citation statements)

References 12 publications

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“…However, obligate heterozygotes (parents of fish odor-affected children) on a normal diet oxidize more than 90% of the TMA to TMAO, but after a 600-mg TMA base load they N-oxidize only 76 6 3% to TMAD, clearly different than normal (96 6 2%.) (Zhang et al, 1995). Furthermore in a study of one-hundred volunteers challenged with a 600-mg base TMA, only one was within the range found among obligate heterozygotes (Zhang et al, 1995).…”

Section: New Informationmentioning

confidence: 84%

“…(Zhang et al, 1995). Furthermore in a study of one-hundred volunteers challenged with a 600-mg base TMA, only one was within the range found among obligate heterozygotes (Zhang et al, 1995). Interestingly, in three normal Japanese women during menstruation, the ratio of TMA to TMAO in the urine increased to levels seen in obligate heterozygotes, suggesting a hormonal effect (Shimizu et al, 2007).…”

Section: New Informationmentioning

confidence: 88%

“…To avoid the odor, such patients avoid TMA-containing foods. In normal humans, TMA is almost completely N-oxidized to TMAO after a 600-mg TMA base "load" (Zhang et al, 1995). However, obligate heterozygotes (parents of fish odor-affected children) on a normal diet oxidize more than 90% of the TMA to TMAO, but after a 600-mg TMA base load they N-oxidize only 76 6 3% to TMAD, clearly different than normal (96 6 2%.)…”

Section: New Informationmentioning

confidence: 98%

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New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Spector¹

2016

Journal of Pharmacology and Experimental Therapeutics

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At present, the guideline approach to the medical treatment and prevention of atherosclerotic cardiovascular disease (ASCVD) is to classify patients by risk and treat the known risk factors (contributory causes), e.g., hypertension, diabetes, obesity, smoking, and poor diet, as appropriate. All high-risk patients should receive statins. This approach has had substantial success but ASCVD still remains the number one cause of death in the United States. Until recently, the underlying cause of ASCVD remained unknown, although a potential dietary cause was suggested by the fact that vegetarians, especially vegans, have a much lower incidence of ASCVD than animal flesh eaters. Recently, consistent with the vegetarian data, substantial evidence for a cause of ASCVD in animals and humans has been discovered. Trimethylamine (TMA)-containing dietary compounds in meat, milk, and other animal foods (e.g., lecithin, choline, and carnitine) are converted by closely related gut bacterial TMA lyases to TMA, which is absorbed and converted predominantly by flavin mono-oxygenase 3 to the toxic trimethylamine N-oxide (TMAO). TMAO causes atherosclerosis in animals and is elevated in patients with coronary heart disease. Inhibition of bacterial lyases in mice prevents TMA and secondarily TMAO formation and atherosclerosis, strong evidence for the TMAO hypothesis. At present, the challenge for the pharmaceutical industry is to discover and develop a potent "broad spectrum" bacterial lyase inhibitor that, along with diet and exercise, could, if the TMAO hypothesis is correct, revolutionize the preventive treatment of ASCVD.

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Section: New Informationmentioning

confidence: 84%

Section: New Informationmentioning

confidence: 88%

Section: New Informationmentioning

confidence: 98%

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New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Spector¹

2016

Journal of Pharmacology and Experimental Therapeutics

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“…Twenty picomoles of holo-FMO3 were used in initial studies with incubation times ranging from [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] minutes. Metabolic reactions with enzymes that exhibited low substrate turnover (N61S, M66I, P153L, and R492W) were repeated using 50-100 pmol of FMO for 20 minutes to facilitate product quantitation.…”

Section: Microsomal Incubationsmentioning

confidence: 99%

“…Normally, TMA metabolism in humans is an efficient process and individuals will typically excrete more than 18 μmol of TMA/μmol creatinine daily in the urine with a TMA:TMAO ratio less than 5:95 [8,9]. However, in cases of the metabolic disorder, trimethylaminuria (TMAU), greater than 46 μmol urinary TMA/μmol creatinine is excreted daily [10], and the TMA: TMAO ratio changes dramatically to greater than 80:20 [11].…”

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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