Flavin-containing monooxygenases: mutations, disease and drug response

NOTICE: this is the author’s version of a work that was accepted for publication in Trends in Pharmacological Sciences. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Trends in Pharmacological Sciences, [VOL 29, ISSUE 6, (2008)] DOI: 10.1016/j.tips.2008.03.00

Trimethylaminuria

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Drug metabolism by flavin-containing monooxygenases of human and mouse

Introduction: Flavin-containing monooxygenases (FMOs) play an important role in drug metabolism. / Areas covered: We focus on the role of FMOs in the metabolism of drugs in human and mouse. We describe FMO genes and proteins of human and mouse; the catalytic mechanism of FMOs and their significance for drug metabolism; differences between FMOs and CYPs; factors contributing to potential underestimation of the contribution of FMOs to drug metabolism; the developmental and tissue-specific expression of FMO genes and differences between human and mouse; and factors that induce or inhibit FMOs. We discuss the contribution of FMOs of human and mouse to the metabolism of drugs and how genetic variation of FMOs affects drug metabolism. Finally, we discuss the utility of animal models for FMO-mediated drug metabolism in humans. / Expert opinion: The contribution of FMOs to drug metabolism may be underestimated. As FMOs are not readily induced or inhibited and their reactions are generally detoxifications, the design of drugs that are metabolized predominantly by FMOs offers clinical advantages. Fmo1(-/-),Fmo2(-/-),Fmo4(-/-) mice provide a good animal model for FMO-mediated drug metabolism in humans. Identification of roles for FMO1 and FMO5 in endogenous metabolism has implications for drug therapy and initiates an exciting area of research

Flavin-containing monooxygenases: new structures from old proteins

A study reports the structures of membrane-bound flavin-containing monooxygenases (FMOs), solved using reconstructed ancestral mammalian FMOs. The models provide a structural basis for these enzymes’ mechanism of action and show how the proteins interact with membranes and how substrates access their active sites

Trimethylamine and trimethylamine N-oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host-microbiome metabolic axis implicated in health and disease

Flavin-containing monooxygenase 3 (FMO3) is known primarily as an enzyme involved in the metabolism of therapeutic drugs. However, on a daily basis we are exposed to one of the most abundant substrates of the enzyme, trimethylamine, which is released from various dietary components by the action of gut bacteria. FMO3 converts the odorous trimethylamine to non-odorous trimethylamine N-oxide, which is excreted in urine. Impaired FMO3 activity gives rise to the inherited disorder primary trimethylaminuria. Affected individuals cannot produce trimethylamine N-oxide and, consequently, excrete large amounts of trimethylamine. A dysbiosis in gut bacteria can give rise to secondary trimethylaminuria. Recently, there has been much interest in FMO3 and its catalytic product trimethylamine N-oxide. This is because trimethylamine N-oxide has been implicated in various conditions affecting health, including cardiovascular disease, reverse cholesterol transport and glucose and lipid homeostasis. In this review, we consider the dietary components that can give rise to trimethylamine, the gut bacteria involved in the production of trimethylamine from dietary precursors, the metabolic reactions by which bacteria produce and utilize trimethylamine and the enzymes that catalyze the reactions. Also included is information on bacteria that produce trimethylamine in the oral cavity and vagina, two key microbiome niches that can influence health. Finally, we discuss the importance of the trimethylamine/trimethylamine N-oxide microbiome-host axis in health and disease, considering factors that affect bacterial production and host metabolism of trimethylamine, the involvement of trimethylamine N-oxide and FMO3 in disease and the implications of the host-microbiome axis for management of trimethylaminuria

Spectral decompositions and nonnormality of boundary integral operators in acoustic scattering - extended version

Understanding the spectral properties of boundary integral operators in acoustic scattering has important practical implications, such as for the analysis of the stability of boundary element discretisations or the convergence of iterative solvers as the wavenumber k grows. Yet little is known about spectral decompo- sitions of the standard boundary integral operators in acoustic scattering. Theoretical results are mainly available on the unit disk, where these operators diagonalise in a simple Fourier basis. In this paper we investigate spectral decompositions for more general smooth domains. Based on the decomposition of the acoustic Green’s function in elliptic coordinates we give spectral decompositions on ellipses. For general smooth domains we show that approximate spectral decompositions can be given in terms of circle Fourier modes transplanted onto the boundary of the domain. An important underlying question is whether or not the operators are normal. Based on previous numerical investigations it appears that the standard boundary integral operators are normal only when the domain is a ball and here we prove that this is indeed the case for the acoustic single layer potential. We show that the acoustic single, double and conjugate double layer potential are normal in a scaled inner product on the ellipse. On more general smooth domains the operators can be split into a normal component plus a smooth perturbation. Numerical computations of pseudospectra are presented to demonstrate the nonnonnormal behaviour on general domains

A highly sensitive liquid chromatography electrospray ionization mass spectrometry method for quantification of TMA, TMAO and creatinine in mouse urine

Our method describes the quantification in mouse urine of trimethylamine (TMA), trimethylamine N-oxide (TMAO) and creatinine. The method combines derivatization of TMA, with ethyl bromoacetate, and LC chromatographic separation on an ACE C18 column. The effluent was continuously electrosprayed into the linear ion trap mass spectrometer (LTQ), which operated in selective ion monitoring (SIM) modes set for targeted analytes and their internal standards (IS). All validation parameters were within acceptable ranges of analytical method validation guidelines. Intra- and inter-day assay precision and accuracy coefficients of variation were <3.1%, and recoveries for TMA and TMAO were 97–104%. The method developed uses a two-step procedure. Firstly, TMA and TMAO are analyzed without a purification step using a 5-min gradient cap-LC- SIMs analysis, then creatinine is analyzed using the same experimental conditions. The method is robust, highly sensitive, reproducible and has the high-throughput capability of detecting TMA, TMAO and creatinine at on-column concentrations as low as 28 pg/mL, 115 pg/mL and 1 ng/mL, respectively. The method is suitable for analysis of TMA, TMAO and creatinine in both male and female mouse urine. / The key benefits of the method are: The small sample volume of urine required, which overcomes the difficulties of collecting sufficient volumes of urine at defined times. / No sample pre-treatment is necessary. / The quantification of TMA, TMAO and creatinine using the same cap-LC-MS method

Patients Receiving Palliative Care and Their Families' Experiences of Participating in a "Patient-Centered Family Meeting": A Qualitative Substudy of the Valuing Opinions, Individual Communication, and Experience Feasibility Trial.

Background: Family meetings are used in palliative care to facilitate discussion between palliative patients, their families, and the clinical team. However, few studies have undertaken qualitative assessment of the impact of family meetings on patients and their families. Objectives: To explore inpatients receiving palliative care and their families' experiences of participation in a patient-centered family meeting ("Meeting"), where the patient sets the Meeting agenda. Design: This qualitative study used the constant comparative method for thematic content analysis of the data. Setting/Participants: The setting was a specialist palliative care (SPC) inpatient unit in Australia. Nine palliative care inpatients and nine family members were interviewed. Measurements: Semistructured interviews were used evaluate the patients' and their families' experiences and perceptions of the Meeting. Results: Three overarching themes described the experiences of participating in a patient-focused family meeting, namely that the Meeting: (1) provides a forum for inpatients receiving SPC to speak openly about their end-of-life concerns, clarify issues, and is of comfort to patients; (2) provides the family members with a voice, and an opportunity to discuss their concerns and have their needs addressed; and (3) helps to ensure that everyone is "on the same page" and patient care plans can be discussed. Conclusions: These Meetings are a potentially effective means of supporting certain palliative care patients and their families to articulate, confront, and address end-of-life issues in the presence of the interdisciplinary team. It is important to undertake further research to further examine the evidence for this Meeting model and to identify the patients and families who would most benefit from this type of Meeting

Sleep disturbances in caregivers of patients with advanced cancer: A systematic review.

© Cambridge University Press 2017. Objective: Sleep disturbances are a common issue for those who provide informal care to someone with a life-limiting condition. The negative consequences of poor sleep are well documented. The purpose of the present study was to determine the sleep patterns of caregivers of patients with advanced cancer. Method: An extensive systematic review of studies reporting empirical sleep data was undertaken in 2015 in accordance with the PRISMA Statement. A total of eight electronic databases were searched, with no date restrictions imposed. Additionally, a search of the bibliographies of the studies identified during the electronic search was conducted. Search terms included: Sleep, insomnia, sleep disturbance, circadian rhythm, caregiver, carer, advanced cancer, palliative cancer, and MESH suggestions. The inclusion criteria required studies to be in English and to report primary qualitative and/or quantitative research that examined sleep in caregivers of patients with advanced cancer. Unpublished studies, conference papers, and dissertations were excluded. Results: Overall, 10 studies met the inclusion criteria and were included in the review. Two major findings emerged from the data synthesis. First, at least 72% of caregivers reported moderate to severe sleep disturbance as measured by the Pittsburgh Sleep Quality Index. Second, objective measurement of caregivers' sleep identified that some caregivers experienced up to a 44% reduction in their total sleep time compared to the recommended eight hours. Significance of Results: Reduction in total sleep time appears to be the biggest issue facing caregivers' sleep. Future studies need to explore the specific factors that cause these sleep disturbances and thus help to identify interventions to optimize sleep

Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from Hypotaurine

Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as an NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that human FMO1 catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic- or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1-catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, and the pathogenesis of obesity and skeletal muscle disorders