Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin

Scimone, Concetta; Alibrandi, Simona; Donato, Luigi; Giofrè, Salvatore V.; Rao, Giacomo; Sidoti, Antonina; D’Angelo, Rosalia

doi:10.1111/jcpt.13315

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…Flavin-containing monooxygenase 3 (FMO3) is an endoplasmic reticulum-tethered protein primarily expressed in the liver of adult humans [1], which is known to induce Nor S-oxygenation of numerous drug substrates [1] and has recently gained much attention for its role in the formation of proatherogenic trimethylamine-N oxide (TMAO). Flavincontaining monooxygenases are a major class of enzymes responsible for oxidizing multiple substrates, including many commonly administered amine-and sulfate-containing drugs, including Clozapine, Ranitidine, Tamoxifen, Atazanavir, Abacavir, and Lamivudine [1,2]. Distinguished from the major xenobiotic detoxification enzymes, cytochrome P450s, which require their accessory proteins (CYP reductases) to transfer electrons from NADPH, FMO3 directly accepts electrons from NADPH [1,3].…”

Section: Introductionmentioning

confidence: 99%

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

Zhao

Stemmer

Petriello

2022

Toxics

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The hepatic xenobiotic metabolizing enzyme flavin-containing monooxygenase 3 (FMO3) has been implicated in the development of cardiometabolic disease primarily due to its enzymatic product trimethylamine-N oxide (TMAO), which has recently been shown to be associated with multiple chronic diseases, including kidney and coronary artery diseases. Although TMAO may have causative roles as a pro-inflammatory mediator, the possibility for roles in metabolic disease for FMO3, irrespective of TMAO formation, does exist. We hypothesized that FMO3 may interact with other proteins known to be involved in cardiometabolic diseases and that modulating the expression of FMO3 may impact on these interaction partners. Here, we combine a co-immunoprecipitation strategy coupled to unbiased proteomic workflow to report a novel protein:protein interaction network for FMO3. We identified 51 FMO3 protein interaction partners, and through gene ontology analysis, have identified urea cycle as an enriched pathway. Using mice deficient in FMO3 on two separate backgrounds, we validated and further investigated expressional and functional associations between FMO3 and the identified urea cycle genes. FMO3-deficient mice showed hepatic overexpression of carbamoylphosphate synthetase (CPS1), the rate-limiting gene of urea cycle, and increased hepatic urea levels, especially in mice of FVB (Friend leukemia virus B strain) background. Finally, overexpression of FMO3 in murine AML12 hepatocytes led to downregulation of CPS1. Although there is past literature linking TMAO to urea cycle, this is the first published work showing that FMO3 and CPS1 may directly interact, implicating a role for FMO3 in chronic kidney disease irrespective of TMAO formation.

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Section: Introductionmentioning

confidence: 99%

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

Zhao

Stemmer

Petriello

2022

Toxics

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“…The release of chemokines in neurodegenerative diseases with increased microglia proliferation and inflammation is similarly described in HIV, leading to synapto-dendritic alterations and neuronal loss supporting cognitive and motoric impairment [22]. Systematic immune response influenced by metabolic activities of the gut microbiota-neuroinflammation axis has been discussed as a potential underlying mechanism for HIV [23,24]. Moreover, HIV infection can lead to heterogeneous clinical abnormalities ranging from encephalitis, myelitis, polyneuropathy, and infiltrative nerve lymphocytosis [25].…”

Section: Introductionmentioning

confidence: 99%

Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

2021

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Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

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“…The FMO3 enzyme catalyses the NADPH-dependent oxidative metabolism of a wide range of exogenous chemicals, including drugs, dietary-derived compounds, and environmental pollutants [13]. As already cited, it is responsible for the conversion of TMA, synthesized from precursors introduced with diet, in its oxidized and odourless form TMAO.…”

Section: Introductionmentioning

confidence: 99%

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

et al. 2021

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Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.

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Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin

Cited by 7 publications

References 28 publications

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

Proteomics-Based Identification of Interaction Partners of the Xenobiotic Detoxification Enzyme FMO3 Reveals Involvement in Urea Cycle

Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

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