The peptide/histidine transporter PHT1 () is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H-coupled/histidine symporter that can transport a wide range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response.
View Article and Find Full Text PDFThe TransCure project entitled 'Iron Transporters DMT1 and FPN1' took an interdisciplinary approach combining structural biology, chemistry and physiology to gain new insights into iron transport. Proteins studied included Divalent Metal Transporter 1 (DMT1, SLC11A2), enabling the import of Fe2+ into the cytoplasm, and the iron efflux transporter Ferroportin (FPN1, SLC40A1). The physiology and pathophysiology, and the mechanisms underlying iron transport in the gut, across the placenta and in bone were investigated.
View Article and Find Full Text PDFAs the COVID-19 pandemic progresses, new variants of SARS-CoV-2 continue to emerge. This underscores the need to develop optimized tools to study such variants, along with new coronaviruses that may arise in the future. Such tools will also be instrumental in the development of new antiviral drugs.
View Article and Find Full Text PDFSLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup).
View Article and Find Full Text PDFThe metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed the transport properties of mutant ZIP8 A391T and investigated in mice the physiological effects of this polymorphism.
View Article and Find Full Text PDFBackground: Lignocellulose biomass has been investigated as a feedstock for second generation biofuels and other value-added products. Some of the processes for biofuel production utilize cellulases and hemicellulases to convert the lignocellulosic biomass into a range of soluble sugars before fermentation with microorganisms such as yeast Saccharomyces cerevisiae. One of these sugars is L-arabinose, which cannot be utilized naturally by yeast.
View Article and Find Full Text PDFSolute carrier proteins (SLCs) are membrane proteins controlling fluxes across biological membranes and represent an emerging class of drug targets. Here we searched for inhibitors of divalent metal transporters in a library of 1,676 commercially available 3D-shaped fragment-like molecules from the generated database GDB-17, which lists all possible organic molecules up to 17 atoms of C, N, O, S and halogen following simple criteria for chemical stability and synthetic feasibility. While screening against DMT1 (SLC11A2), an iron transporter associated with hemochromatosis and for which only very few inhibitors are known, only yielded two weak inhibitors, our approach led to the discovery of the first inhibitor of ZIP8 (SLC39A8), a zinc transporter associated with manganese homeostasis and osteoarthritis but with no previously reported pharmacology, demonstrating that this target is druggable.
View Article and Find Full Text PDFTrichoderma reesei is an ascomycete fungus known for its capability to secrete high amounts of extracellular cellulose- and hemicellulose-degrading enzymes. These enzymes are utilized in the production of second-generation biofuels and T. reesei is a well-established host for their production.
View Article and Find Full Text PDFOncogenic KRAS mutations develop unique metabolic dependencies on nutrients to support tumor metabolism and cell proliferation. In particular, KRAS mutant cancer cells exploit amino acids (AAs) such as glutamine and leucine, to accelerate energy metabolism, redox balance through glutathione synthesis and macromolecule biosynthesis. However, the identities of the amino acid transporters (AATs) that are prominently upregulated in KRAS mutant cancer cells, and the mechanism regulating their expression have not yet been systematically investigated.
View Article and Find Full Text PDFSolute carrier proteins (SLCs) control fluxes of ions and molecules across biological membranes and represent an emerging class of drug targets. SLC11A2 (hDMT1) mediates intestinal iron uptake and its inhibition might be used to treat iron overload diseases such as hereditary hemochromatosis. Here we report a micromolar (IC = 1.
View Article and Find Full Text PDFSodium glucose transporters (SGLTs) belong to the mammalian solute carrier family SLC5. This family includes 12 different members in human that mediate the transport of sugars, vitamins, amino acids, or smaller organic ions such as choline. The SLC5 family belongs to the sodium symporter family (SSS), which encompasses transporters from all kingdoms of life.
View Article and Find Full Text PDFIn humans, the divalent metal ion transporter-1 (DMT1) mediates the transport of ferrous iron across the apical membrane of enterocytes. Hence, its inhibition could be beneficial for the treatment of iron overload disorders. Here we characterize the interaction of aromatic bis-isothiourea-substituted compounds with human DMT1 and its prokaryotic homologue EcoDMT.
View Article and Find Full Text PDFSLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild-type SLC1A2 protein localization and function.
View Article and Find Full Text PDFThe transport and ion-coupling mechanisms of ZIP transporters remain largely uncharacterized. Previous work in our laboratory has revealed that the solute carrier family 39 member A2 (SLC39A2/ZIP2) increases its substrate transport rate in the presence of extracellular H Here, we used a combination of and techniques involving structural modeling, mutagenesis, and functional characterization in HEK293 cells to identify amino acid residues potentially relevant for both the ZIP2-H interaction and substrate binding. Our ZIP2 models revealed a cluster of charged residues close to the substrate-translocation pore.
View Article and Find Full Text PDFThe human zinc transporter SLC39A2, also known as ZIP2, was shown to mediate zinc transport that could be inhibited at pH <7.0 and stimulated by HCO, suggesting a Zn/HCO cotransport mechanism [Gaither, L. A.
View Article and Find Full Text PDFIn humans, the H-coupled Fe transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H-cotransport has remained elusive. Here, we used a combination of molecular dynamics simulations, in silico pK calculations and site-directed mutagenesis, followed by rigorous functional analysis, to discover two previously uncharacterized functionally relevant residues in hDMT1 that contribute to H-coupling.
View Article and Find Full Text PDFGlutamate transporters maintain synaptic concentration of the excitatory neurotransmitter below neurotoxic levels. Their transport cycle consists of cotransport of glutamate with three sodium ions and one proton, followed by countertransport of potassium. Structural studies proposed that a highly conserved serine located in the binding pocket of the homologous GltPh coordinates L-aspartate as well as the sodium ion Na1.
View Article and Find Full Text PDFGLUT12 is a member of the facilitative family of glucose transporters. The goal of this study was to characterize the functional properties of GLUT12, expressed in Xenopus laevis oocytes, using radiotracer and electrophysiological methods. Our results showed that GLUT12 is a facilitative sugar transporter with substrate selectivity: d-glucose ≥ α-methyl-d-glucopyranoside (α-MG) > 2-deoxy-d-glucose(2-DOG) > d-fructose = d-galactose.
View Article and Find Full Text PDFBackground: Recent studies proposed GLUT12 to be a major glucose transporter involved in the glycolytic metabolism of cancer cells.
Methods: GLUT12 expression was determined by immunohistochemistry in a selection of cancer cell lines and a tumour spheroid model.
Results: GLUT12 expression was high in A549 and RH-36; low in HT29; and absent in NB-EB cancer cell lines.
Alzheimer's disease (AD) might be conceptualized as a metabolic disease with progressive impairment of the brain's capacity to utilize glucose. One of the last glucose transporters discovered is GLUT12. The aim of the present work was to investigate the expression of GLUT12 in frontal cortex from AD patients.
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