Trimethylaminuria

Viewed on: 14.6.2011Viewed on: 14.6.2011Viewed on: 14.6.201

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

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

Molecular footprints of the Holocene retreat of dwarf birch in Britain

© 2014 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

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

Terahertz imaging through emissivity control

This is the final version. Available on open access from Optica Publishing Group via the DOI in this recordData availability: Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.Electromagnetic radiation in the terahertz (THz) frequency band has unique potential for future communication and imaging applications.However, the adoption of THz technologies is hindered by the lack of cost-effective THz sources. Here we demonstrate a way to generate and control THz radiation, via spatio-temporal emissivity modulation. By patterning the optical photoexcitation of a surface-passivated silicon wafer, we locally control the free-electron density, and thereby pattern the wafer's emissivity in the THz part of the electromagnetic spectrum.We show how this unconventional source of controllable THz radiation enables a form of incoherent computational THz imaging.We use it to image various concealed objects, demonstrating that this scheme has the penetrating capability of other THz imaging approaches, without the requirement of femtosecond pulsed laser sources. Furthermore, the incoherent nature of thermal radiation also ensures the obtained images are free of interference artifacts. Our spatio-temporal emissivity control could enable a family of long-wavelength structured illumination, imaging, and spectroscopy systems.Engineering and Physical Sciences Research Council (EPSRC)European Research Council (ERC)Royal Academy of Engineering (RAE

Towards strange metallic holography

We initiate a holographic model building approach to `strange metallic' phenomenology. Our model couples a neutral Lifshitz-invariant quantum critical theory, dual to a bulk gravitational background, to a finite density of gapped probe charge carriers, dually described by D-branes. In the physical regime of temperature much lower than the charge density and gap, we exhibit anomalous scalings of the temperature and frequency dependent conductivity. Choosing the dynamical critical exponent $z$ appropriately we can match the non-Fermi liquid scalings, such as linear resistivity, observed in strange metal regimes. As part of our investigation we outline three distinct string theory realizations of Lifshitz geometries: from F theory, from polarised branes, and from a gravitating charged Fermi gas. We also identify general features of renormalisation group flow in Lifshitz theories, such as the appearance of relevant charge-charge interactions when $z \geq 2$. We outline a program to extend this model building approach to other anomalous observables of interest such as the Hall conductivity.Comment: 71 pages, 8 figure