Summary
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved
across all vertebrates, whose cellular activity and pathway assignment are
unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with
reduced circulating B12 levels being the only and consistent
phenotype reported to date. Here, by combining enzymology, structural biology
and activity-based metabolomics we report that CLYBL operates as a
citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate
citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that
includes itaconate, a recently identified human antimicrobial metabolite and
immunomodulator. We report that CLYBL loss leads to a cell autonomous defect in
the mitochondrial B12 metabolism and that itaconyl-CoA is a
cofactor-inactivating, substrate-analogue inhibitor of the mitochondrial
B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans
the function of human CLYBL and reveals that a consequence of exposure to the
immunomodulatory metabolite itaconate is B12 inactivation.
Combining chemical looping with a traditional fuel conversion process yields a promising technology for low-CO2-emission energy production. Bridged by the cyclic transformation of a looping material (CO2 carrier or oxygen carrier), a chemical looping process is divided into two spatially or temporally separated half-cycles. Firstly, the oxygen carrier material is reduced by fuel, producing power or chemicals. Then, the material is regenerated by an oxidizer. In chemical looping combustion, a separation-ready CO2 stream is produced, which significantly improves the CO2 capture efficiency. In chemical looping reforming, CO2 can be used as an oxidizer, resulting in a novel approach for efficient CO2 utilization through reduction to CO. Recently, the novel process of catalyst-assisted chemical looping was proposed, aiming at maximized CO2 utilization via the achievement of deep reduction of the oxygen carrier in the first half-cycle. It makes use of a bifunctional looping material that combines both catalytic function for efficient fuel conversion and oxygen storage function for redox cycling. For all of these chemical looping technologies, the choice of looping materials is crucial for their industrial application. Therefore, current research is focused on the development of a suitable looping material, which is required to have high redox activity and stability, and good economic and environmental performance. In this review, a series of commonly used metal oxide-based materials are firstly compared as looping material from an industrial-application perspective. The recent advances in the enhancement of the activity and stability of looping materials are discussed. The focus then proceeds to new findings in the development of the bifunctional looping materials employed in the emerging catalyst-assisted chemical looping technology. Among these, the design of core-shell structured Ni-Fe bifunctional nanomaterials shows great potential for catalyst-assisted chemical looping.
Fe-modified MgAl2O4 makes a surprisingly
active catalyst support, likely linked to a structural effect of the
Fe incorporation. Two catalyst supports, MgAl2O4 and MgFeAlO4, have been studied in fresh and reduced
state to determine the effect of high-temperature H2 reduction
upon ion distribution in the lattices. To this end, an X-ray Raman
scattering study has been performed, focusing on the oxygen K edge
and magnesium and aluminum L2,3 and iron M2,3 soft edges. MgAl2O4 shows a random cation
distribution and only small changes occur at the Mg L2,3 and Al L2,3 edges upon reduction at 1073 K. The main
oxygen signal does lose intensity and its simulation points to a lower
O covalency and more confined state after reduction. Introducing 8.9
wt % Fe into the spinel pushes Mg towards mostly tetrahedral position
in the MgFeAlO4 lattice, whereas Fe and Al share the octahedral
sites. Concomitant lattice distortion is observable in the O signal.
Reduction of MgFeAlO4 leads to enhanced distortion visible
in the O and Al signals and the presence of 50% Fe2+. Both
disorder and reduction lead to partial segregation of MgFeO
x
from the MgFeAlO4 lattice. This combination
of distortion and phase restructuring in the Fe-modified MgFeAlO4 material facilitates the lattice oxygen mobility and hence
its catalytic activity.
The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.
Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.9b04505. Detailed experimental procedures for Western blot, bisulfite sequencing, Northern blot, structure-based docking, and electrophoretic mobility shift assay; LC-MS/MS quantification data; and Western blot images (PDF) A list of proteins with relative binding ratios toward m 5 C-over C-containing RNA identified from SILAC-based affinity screening experiments with the use of lysate of HeLa cells (XLSX) A list of proteins with relative binding ratios toward m 5 C-over C-containing RNA identified from SILAC-based affinity screening experiments with the use of lysate of HEK293T cells (XLSX) A list of m 5 C sites in HEK293T cells and the isogenic YTHDF2 knockout cells, as obtained from bisulfite sequencing analysis (XLSX) A list of m 5 C sites that are commonly identified from the current bisulfite sequencing experiment and from previously published miCLIP analysis (XLSX)
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