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  • The developed method was used to quantify RBC membrane


    The developed method was used to quantify RBC membrane transport of the anomers of three monofluorinated analogs of glucose in a modified medium designed to provide stable metabolic properties of the cells over the lifetime of the experiment. This allowed us to evaluate the specific interaction (specificity constants) of the carrier individually for both anomers of each of the studied fluorosugars. The estimated specificity constants showed faster transport of the α-anomer versus the β-anomer for all investigated substrates, with FDG-4 featuring the largest anomeric preference. A qualitative interpretation of the differences in the transmembrane exchange rates of FDG-2, FDG-3, and FDG-4 in terms of the perturbation of binding of these monosaccharides to GLUT1, caused by specific F/OH substitutions, has been provided. Our developed approach and mathematical analysis could become important for a variety of applications such as drug development and systems biology. In turn, such studies can be used to probe responses of membrane proteins in their native environment, e.g., in testing whether disease conditions lead to altered permeability of particular carbohydrates or to changes in cell-membrane integrity (22). Fluorosugars are also of great interest as imaging agents. Radiolabeled FDG-2 is currently the most used PET (positron emission tomography)-imaging substrate for cancer diagnosis (66), whereas fluorinated fructose analogs have recently been shown to hold promise as imaging agents for GLUT5 expression in breast cancer tissue (67).
    Author Contributions
    Introduction Genetic alterations in PURA or Pur-alpha (purine-rich element binding protein A) have been documented in humans as the origin of neurologic syndromes [1] and the cause for the 5q31.3 Microdeletion Syndrome phenotype [2], [3]. PURA is expressed in brain, muscle, heart and blood and it is known to be essential for normal tpca synthesis development [4], [5]. Up to now, this disease has been documented to be caused by de novo, dominant mutations [1], [2]. Patients with this disorder have been described with hypotonia, feeding difficulties, severe developmental delay, respiratory difficulties, pituitary dysfunction, and epileptic/non-epileptic encephalopathy associated with delayed myelination [1], [6], [7], [8], [9], [10]. As in most neurologic diseases, these symptoms overlap with genetic and acquired encephalopathies of diverse origins, making diagnosis often a challenge. PURA is a single-exon gene, that encodes a highly conserved multifunctional protein, member of the PUR family (Pur-alpha, Pur-beta and Pur-gamma) [11]. It is a DNA and RNA binding protein that plays an important role in cell proliferation, transcriptional regulation and mRNA trafficking [12], [11]. As a member of the PUR family, it has three conserved sequence-specific repeats: PUR domains I, II and III that are responsible for the protein's main functions [11]. Each PUR amino acid repeat consists of a β-sheet domain and an α-helical domain arranged in a “whirly fold,” structure in which the convex β-sheets form a surface for interaction with nucleic acids and the remaining helix portions are involved in protein-protein interactions [12], [13]. PUR I and II motifs are proposed to form intramolecular peptide-peptide bonds between each other, while the PUR III domain is responsible for homo-heterodimerization with another PUR protein or interaction with other proteins [14], [13] (Fig. 1). It has been shown that specifically PURA can regulate gene expression by binding directly to DNA promoters, or to different mRNAs and non-coding RNAs. It can also form DNA-mRNA-protein complexes, all features that make it an important transcriptional and translational regulator [15], [16]. SLC2A1 gene (clinically better known as GLUT1) is a member of the GLUT family of facilitative glucose transporters, which includes 13 genes. SLC2A1 was the first cloned and sequenced gene of the group and it encodes for GLUT1 protein [17]. GLUT1 is ubiquitously expressed in most tissues, but selectively higher in erythrocytes, brain microvessels and astroglia. Glucose is the essential substrate for brain metabolism and its transport across the blood-brain barrier depends on GLUT1 [18]. It is also important for glucose uptake in red blood cells since these cells´ metabolism is strictly glycolytic [19], [20]. GLUT1 deficiency syndrome classically presents with infantile seizures (often resistant to antiepileptic drugs), developmental delay, acquired microcephaly, hypotonia, spasticity, dystonia and in some cases hemolytic anemia all associated to its key biomarker: hypoglycorrhachia [21].