Métabolite secondaire | EPFL Graph Search

vignette|Coca érythroxylum Un métabolite secondaire est une molécule qui, par exclusion, n'appartient pas au métabolisme primaire. Ce dernier est indispensable à la nutrition, il assure la croissance, le développement d'un organisme. Les métabolites primaires rassemblent les acides aminés, les lipides, les sucres ou les acides nucléiques, par exemple. Les métabolites secondaires sont historiquement plus spécifiques aux plantes, bactéries et champignons, mais on découvre également des métabolismes spécifiques à certains groupes animaux, que l'on peut donc qualifier des métabolismes secondaires. On les retrouve dans des compartiments particuliers ou à des moments précis de la vie. Contrairement aux métabolites primaires, ils ne participent pas directement à l’assimilation des nutriments et donc, au développement de l'organisme (la plante, typiquement). Cependant, ces composés ne sont pas totalement différents des métabolites primaires. En effet, ils dérivent parfois des mêmes voies de

The role of sulfated metabolites in the wound response of siphonous green algae

Matthew Anthony Welling

The giant unicellular macroalgae exhibit an extraordinary wound repair mechanism. The rapid assimilation of cellular contents into an insoluble wound plug prevents detrimental cytoplasmic loss and limits the intrusion of extracellular components which could otherwise prove fatal. Using chemical and biochemical investigations in conjunction with ultra performance liquid chromatography mass spectrometry (UPLC-MS) and MS/MSanalysis, we demonstrate that biopolymerization reactions are adopted by the organism to assist in the assembly of the wound plug. We found that wounding of the cell initiates biopolymerisation by the rapid hydrolysis of a novel secondary metabolite, 6,7-dihydroxycoumarin-3-sulfate (DHCS) via cellular sulfatases to produce 3,6,7-trihydroxycoumarin (THC). Our results further substantiate the hypothesis that, upon generation, THC immediately undergoes oxidation mediated by an oxidative burst to produce o- and p-quinones. These may subsequently form multiple covalent bonds with thiol or amino functionalities present in a number of proteins, proteoglycans or other small molecules located within the wounded region. The resulting matrix of crosslinked proteins reinforces the structural integrity of the wound plug. Preliminary results suggest that DHCS may also function as a metallophore. Hydroxycoumarin analogues and deuterium labeled amino acid incubations were used to probe the biosynthetic pathway for DHCS assembly. We propose that C3-hydroxyl group introduction proceeds via an α-hydroxy-2-hydroxycaffeic acid intermediate. Subsequent spontaneous ring cyclization followed by sulfate transfer mediated by a sulfotransferase yields DHCS. Following secondary metabolite profile screening, we used a combination of analytical techniques to identify new sulfated metabolites in selected species of the Dasycladales and the seagrass Zostera marina.

EPFL2010

Methods to Enhance Nuclear Magnetic Resonance Sensitivity at High Magnetic Field

Claudia Christina Zanella

MR is a well-established technique routinely used in preclinical and clinical studies. This thesis focussed on the improvement of sensitivity of different methods in MR. Hyperpolarized 129Xe gas is used for studying pulmonary disease or cerebral perfusion. When hyperpolarization is conducted inside a polarizer, the achieved solid state polarization is currently limited to a few percent. One aim of this thesis was to counteract this bottleneck by investigating the effect of microwave frequency modulation for different spin systems. An increase in nuclear 129Xe spin polarization up to 14.5% was achieved compared to the polarization obtained without frequency modulation. Electron spin-lattice relaxation times T1S, as short as 5 ms, correlated directly with the gain in 129Xe nuclear polarization due to microwave frequency modulation, irrespective of the solvent or its deuteration. Simulations of the electron spin system confirmed that microwave frequency modulation could be an efficient method to considerably enhance nuclear spin polarization in short T1S matrices or in the presence of large linewidth radicals by promoting spectral diffusion. DNP matrices can also be hyperpolarized through non-persistent radicals generated by UV-irradiation. They have the advantage of quenching upon dissolution, yielding a hyperpolarized solution with no need for radical filtration. Radical precursors researched up to date either yielded low 13C polarization, contained toxic matrix components or interfered with metabolic processes. Therefore, the two novel endogenously-occurring precursors, alpha-ketovalerate (akV) and alpha-ketobutyrate (akB) were investigated. Liquid state polarization of the metabolic substrate glucose increased to 16.3% using akB compared with 13.3% obtained with pyruvate. [1-13C]butyric acid was polarized to 12.1% for akV and 12.9% for akB and used for in vivo hyperpolarized cardiac MRS. Hyperpolarized [1-13C]butyrate metabolism in the heart revealed label incorporation into a wide range of metabolites. This study demonstrated the potential of using UV-induced radicals generated in the endogenously-occurring metabolites akV and akB as polarizing agents, enabling high polarization without requiring radical filtration for radical-free hyperpolarized MRI. While MRI requires RF coils that generate high B1 homogeneity, MRS strongly depends on high sensitivity and potentially high B1 efficiency to allow for short-TE acquisitions. Two custom-made 1H coils resonating at 600 MHz, a single-channel saddle coil and an 8-leg quadrature birdcage coil, were investigated with respect to those criteria for applications at ultra-high field (14.1 T). The saddle coil yielded a 54% higher transmit field efficiency with a 20% higher SNR compared to the birdcage coil after full-FOV corrections. Using the saddle coil in glycoCEST imaging of a homogeneous phantom resulted in an MTR asymmetry coefficient of variation as small as 5.2% over an 11 mm diameter ROI. Overall, the saddle coil provided a good compromise between globally homogeneous excitation and high sensitivity. Finally, it was successfully used to map skeletal muscle glycogen content in vivo. This thesis focused on improving MR sensitivity by means of adequate custom-made RF coils as well as DNP through the implementation of a method capitalizing on electronic spin properties and the development of novel endogenous precursors for in vivo hyperpolarized MRI.

EPFL2021

Total Synthesis of Fijiolide A via an Atropselective Paracyclophane Formation

Christoph Heinz

The natural product fijiolide A is a secondary metabolite isolated from a marine-derived actinomycete of the genus Nocardiopsis. It displays inhibitory activity against TNF-Î±-induced activation of NFÎºB, an important transcription factor and a potential target for the treatment of different cancers and inflammation related diseases. Structurally, fijiolide A impresses by its highly complex molecular architecture, featuring a polychlorinated and rotationally restricted [2.6]paracyclophane core. The embedded highly unsaturated cyclopenta[a]indene framework is glycosylated with an amino ribopyranose unit. Fijiolide A is related to the Bergman cycloaromatization product of the C-1027 chromophore and is proposed to stem from a similar biosynthetic enediyne precursor. This thesis outlines a total synthesis of fijiolide A. Our synthetic approach features an intermolecular ruthenium-catalyzed [2+2+2] cycloaddition of three different alkynes to assemble the heavily substituted central arene core. Only 10 further steps were required to build up the strained [2.6]paracyclophane core of the fijiolide A aglycone. For this purpose we engineered an unprecedented macroetherification process that proceeds with remarkably high regio- and atropselectivity via a templated nucleophilic substitution. A late-stage glycosylation of the sterically encumbered tertiary alcohol enabled, for the first time, access to fijiolide A. Overall, the natural product fijiolide A was synthesized in a longest linear sequence of 18 steps from commercially available starting material.

EPFL2016

Methods to Enhance Nuclear Magnetic Resonance Sensitivity at High Magnetic Field

Claudia Christina Zanella

EPFL2021