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GLUT7 is a Class II glucose transporter predominantly expressed at the apical membrane of enterocytes in the small intestine. Here, we report the cryo-EM structure of nanodisc-reconstituted human GLUT7 in the apo state at 3.3 Å resolution. Our atomic model reveals a typical major facilitator superfamily fold, with the substrate-binding site open to the extracellular side of the membrane. Despite the nearly identical conformation to its closest family member, rat GLUT5, our structure unveils distinct features of the substrate-binding cavity that may influence substrate specificity and binding mode. A homology model of the inward-open human GLUT7 indicates that similar to other members of the GLUT family, it may undergo a global rocker-switch-like reorientation of the transmembrane bundles to facilitate substrate translocation across the membrane. Our work enhances the current structural understanding of the GLUT family, and lays a foundation for rational design of regulators of GLUTs and other sugar transporters.

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BACKGROUND: Selective deprivation of glutamine has been shown to accelerate the generation of reactive oxygen species (ROS) and to impair the activity of a specific pentose phosphate pathway (PPP) located within the endoplasmic reticulum (ER). The consequent oxidative damage suggests that glucose flux through this reticular pathway might contribute to the redox stress of breast cancer cells. We thus evaluated whether this response is reproduced when the glutamine shortage is coupled with the glucose deprivation. METHODS: Cancer growth, metabolic plasticity and redox status were evaluated under saturating conditions and after 48 h starvation (glucose 2.5 mM, glutamine 0.5 mM). The Seahorse technology was used to estimate adenosine triphosphate (ATP)-linked and ATP-independent oxygen consumption rate (OCR) as well as proton efflux rate (PER). 18F-fluoro-deoxy-glucose (FDG) uptake was evaluated through the LigandTracer device. Proliferation rate was estimated by the carboxyfluorescein-diacetate-succinimidyl ester (CFSE) staining, while cell viability by the propidium iodide exclusion assay. RESULTS: Starvation reduced the proliferation rate of MCF-7 cells without affecting their viability. It also decreased lactate release and PER. Overall OCR was left unchanged although ATP-synthase dependent fraction was increased under nutrient shortage. Glutaminolysis inhibition selectively impaired the ATP-independent and the oligomycin-sensitive OCR in control and starved cultures, respectively. The combined nutrient shortage decreased the cytosolic and mitochondrial markers of redox stress. It also left unchanged the expression of the reticular unfolded protein marker GRP78. By contrast, starvation decreased the expression of hexose-6P-dehydrogenase (H6PD) thus decreasing the glucose flux through the ER-PPP as documented by the profound impairment in the uptake rate of FDG. CONCLUSIONS: When combined with glucose deprivation, glutamine shortage does not elicit the expected enhancement of ROS generation in the studied breast cancer cell line. Combined with the decreased activity of ER-PPP, this observation suggests that glutamine interferes with the reticular glucose metabolism to regulate the cell redox balance.

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The 'assimilates inhibition hypothesis' posits that accumulation of nonstructural carbohydrates (NSCs) in leaves reduces leaf net photosynthetic rate, thus internally regulating photosynthesis. Experimental work provides equivocal support mostly under controlled conditions without identifying a particular NSC as involved in the regulation. We combined 3-yr in situ leaf gas exchange observations (natural dynamics) in the upper crown of mature Betula pendula simultaneously with measurements of concentrations of sucrose, hexoses (glucose and fructose), and starch, and similar measurements during several one-day shoot girdling (perturbation dynamics). Leaf water potential and water and nitrogen content were measured to account for their possible contribution to photosynthesis regulation. Leaf photosynthetic capacity (A/Ci) was temporally negatively correlated with NSC accumulation under both natural and perturbation states. For developed leaves, leaf hexose concentration explained A/Ci variation better than environmental variables (temperature history and daylength); the opposite was observed for developing leaves. The weaker correlations between NSCs and A/Ci in developing leaves may reflect their strong internal sink strength for carbohydrates. By contrast, the strong decline in photosynthetic capacity with NSCs accumulation in mature leaves, observed most clearly with hexose, and even more tightly with its constituents, provides support for the role of assimilates in regulating photosynthesis under natural conditions.

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Most of the carbon found in fruits at harvest is imported by the phloem. Imported carbon provide the material needed for the accumulation of sugars, organic acids, secondary compounds, in addition to the material needed for the synthesis of cell walls. The accumulation of sugars during fruit development influences not only sweetness but also various parameters controlling fruit composition (fruit "quality"). The accumulation of organic acids and sugar in grape berry flesh cells is a key process for berry development and ripening. The present review presents an update of the research on grape berry development, anatomical structure, sugar and acid metabolism, sugar transporters, and regulatory factors.

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As a leaf vegetable, Gynura bicolor DC (G. bicolor) experiences a rapid deterioration after harvest including insufficient supply of sugar and destruction of cell membranes. In this research, four treatments were experimented on G. bicolor including the control (CK), 12% (g/g) sucrose (ST), 10 µL L-1 1-MCP (MT), and the combination of sucrose and 1-MCP (SMT). The results showed that three treated groups reduced respiratory rate, inhibited hexose consumption and promoted the decrease of starch and sucrose, which was converted into hexose including glucose and fructose to maintain cell membrane integrity. Meanwhile, the activities of AI, NI, SS-C, amylase, and corresponding gene expression levels were significantly up-regulated in three treated groups at 1 d, among which AI played a crucial role in regulating the accumulation of hexose. Furthermore, ST exerted a pronounced effect on hexose accumulation at the beginning while MT reduced hexose consumption through lowered respiratory metabolism during storage. Notably, SMT exhibited an optimum preservation effect on inhibited respiratory metabolism, maintaining cell membrane integrity, enhancing the retention of hexose, indicating that a synergistic effect of ST and MT were developed during storage.

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Introduction: The positive effect of intercropping on host plant growth through plant-soil feedback has been established. However, the mechanisms through which intercropping induces interspecific competition remain unclear. Methods: In this study, we selected young apple trees for intercropping with two companion plants: medium growth-potential Mentha haplocalyx Briq. (TM) and high growth-potential Ageratum conyzoides L. (TA) and conducted mixed intercropping treatment with both types (TMA) and a control treatment of monocropping apples (CT). Results: Our findings revealed that TM increased the under-ground biomass of apple trees and TA and TMA decreased the above-ground biomass of apple trees, with the lowest above-ground biomass of apple trees in TA. The above- and under-ground biomass of intercrops in TA and TMA were higher than those in TM, with the highest in TA, suggesting that the interspecific competition was the most pronounced in TA. TA had a detrimental effect on the photosynthesis ability and antioxidant capacity of apple leaves, resulting in a decrease in above-ground apple biomass. Furthermore, TA led to a reduction in organic acids, alcohols, carbohydrates, and hydrocarbons in the apple rhizosphere soil (FRS) compared to those in both soil bulk (BS) and aromatic plant rhizosphere soil (ARS). Notably, TA caused an increase in pentose content and a decrease in the hexose/pentose (C6/C5) ratio in FRS, while ARS exhibited higher hexose content and a higher C6/C5 ratio. The changes in exudates induced by TA favored an increase in taxon members of Actinobacteria while reducing Proteobacteria in FRS compared to that in ARS. This led to a higher eutrophic/oligotrophic bacteria ratio relative to TM. Discussion: This novel perspective sheds light on how interspecific competition, mediated by root exudates and microbial community feedback, influences plant growth and development.

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BACKGROUND: It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells. AIM OF REVIEW: Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field. KEY SCIENTIFIC CONCEPTS OF REVIEW: Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.

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Sugar transport proteins (STPs) are high-affinity H+-coupled hexose symporters. Recently, the contribution of STP13 to bacterial and fungal pathogen resistance across multiple plant species has garnered significant interest. Quantitative PCR analysis of source leaves, developing embryos, and seed coats of Phaseolus vulgaris L. (common bean) revealed that PvSTP13.1 was expressed in source leaves and seed coats throughout seed development. In contrast, PvSTP13.1 transcripts were detected at exceedingly low levels in developing embryos. To characterize the transport mechanism, PvSTP13.1 was expressed in Xenopus laevis oocytes, and inward-directed currents were analyzed using two-electrode voltage clamping. PvSTP13.1 was shown to function as an H+-coupled monosaccharide symporter exhibiting a unique high affinity for hexoses and aldopentoses at depolarized membrane potentials. Specifically, of the 31 assessed substrates, which included aldohexoses, deoxyhexoses, fructose, 3-O-methyl-D-glucose, aldopentoses, polyols, glycosides, disaccharides, trisaccharides, and glucuronic acid, PvSTP13.1 displayed the highest affinity (K 0.5) for glucose (43 µM), mannose (92 µM), galactose (145 µM), fructose (224 µM), xylose (1.0 mM), and fucose (3.7 mM) at pH 5.6 at a depolarized membrane potential of -40 mV. The results presented here suggest PvSTP13.1 contributes to retrieval of hexoses from the apoplasmic space in source leaves and coats of developing seeds.

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Hexose transporters (HXT) play a crucial role in the pathogenicity of Magnaporthe oryzae, serving not only as key facilitators for acquiring and transporting sugar nutrients to support pathogen development, but also as sugar sensors which receive transduction signals. The objective of this study is to investigate the impact of MoHXT1-3 on rice pathogenicity and hexose affinity. MoHXT1-3 deletion mutants were generated using CRISPR/Cas9 technology, and their affinity for hexose was evaluated through yeast complementation assays and electrophysiological experiments in Xenopus oocytes. The results suggest that MoHXT1 does not contribute to melanin formation or hexose transportation processes. Conversely, MoHXT2, despite displaying lower affinity towards the hexoses tested in comparison to MoHXT3, is likely to have a more substantial impact on pathogenicity. The analysis of the transcription profiles demonstrated that the deletion of MoHXT2 caused a decrease in the expression of MoHXT3, whereas the knockout of MoHXT3 resulted in an upregulation of MoHXT2 transcription. It is noteworthy that the MoHXT2M145K variant displayed an incapacity to transport hexoses. This investigation into the functional differences in hexose transporters in Magnaporthe oryzae provides insights into potential advances in new strategies to target hexose transporters to combat rice blast by blocking carbon nutrient supply.

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Glucose, which plays an essential role in carbon and energy metabolism in eukaryotes, is vital in directing various energy-consuming cellular processes. In S. cerevisiae, transcription factors involved in regulating hexose transporters and their mechanisms of action under different carbon sources were revealed in detail. However, there is limited information on these processes in S. pombe. In this study, the effect of SPCC320.03 (named SpRgt1), the ortholog of ScRgt1 whose molecular mechanism is known in detail in S. cerevisiae, on the transcriptional regulation of hexose transporters (ght1-8) dependent on different carbon sources was investigated. We measured the transcript levels of ght1-8 using the qPCR technique and performed relative evaluation in S. pombe strains (parental, rgt1 deleted mutant, rgt1 overexpressed, and vectoral rgt1 carrying mutant). We aimed to investigate the transcriptional changes caused by the protein product of the rgt1 (SPCC320.03) gene in terms of ght1-8 genes in strains that are grown in different carbon sources (2% glucose, 2% glycerol + 0.1% glucose, and 2% gluconate). Here, we show that SpRgt1 is involved in the regulation of the ght3, ght4, ght6, and ght7 genes but that the ght1, ght2, ght5, and ght8 gene expression vary depending on carbon sources, independently of SpRgt1.

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Lipophilic marine biotoxin azaspiracids (AZAs) are produced by dinoflagellates Azadinium and Amphidoma. Recently, several strains of Azadinium poporum were isolated from Japanese coastal waters, and detailed toxin profiles of two strains (mdd421 and HM536) among them were clarified by several detection techniques on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-quadrupole time of flight mass spectrometry (LC-QTOFMS). In our present study, AZA analogues in seven strains of A. poporum from Japanese coastal waters (including two previously reported strains) were determined by these detection techniques. The dominant AZA in the seven strains was AZA2 accompanied by small amounts of several known AZAs and twelve new AZA analogues. Eight of the twelve new AZA analogues discovered in our present study were detected as bi-charged ions on the positive mode LC/MS/MS. This is the first report describing AZA analogues detected as bi-charged ions with hexose and sulfate groups in their structures.

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KEY MESSAGE: OsSWEET1b is a hexose transporter protein, which localized in cell membranes and interacting with itself to form homodimer and knockout of OsSWEET1b resulted in reduced leaves sugar content and accelerating leaf senescence. In the rice genome, the SWEET gene family contains 21 homologous members, but the role of some of them in rice growth and development is still unknown. The function of the sugar transporter OsSWEET1b protein in rice was identified in this research. Expression analysis showed that the expression levels of OsSWEET1b in leaves were higher than that in other tissues. The hexose transport experiment confirmed that OsSWEET1b has glucose and galactose transporter activity in yeast. Subcellular localization indicates that OsSWEET1b protein was targeted to the plasma membrane and BiFC analysis showed that OsSWEET1b interacts with itself to form homodimers. Functional analysis demonstrated that the ossweet1b mutant plants were have reduced the sucrose, glucose, fructose, starch and galactose contents, and induced carbon starvation-related gene expression, which might lead to carbon starvation in leaves at filling stage. The ossweet1b knockout plants showed decreased chlorophyll content and antioxidant enzyme activity, and increased ROS accumulation in leaves, leading to leaf cell death and premature senescence phenotype at filling stage. In ossweet1b mutants, the leaf senescence-related gene expression levels were increased and the abundance of photosynthesis-related proteins was decreased. Loss of OsSWEET1b were affected the starch, sucrose metabolism and carbon fixation in photosynthetic organelles pathway by RNA-seq analysis. The destruction of OsSWEET1b function will cause sugar starvation, decreased photosynthesis and leaf senescence, which leading to reduced rice yield. Collectively, our results suggest that the OsSWEET1b plays a key role in rice leaves carbohydrate metabolism and leaf senescence.

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Pollen cells require large amounts of sugars from the anther to support their development, which is critical for plant sexual reproduction and crop yield. Sugars Will Eventually be Exported Transporters (SWEETs) have been shown to play an important role in the apoplasmic unloading of sugars from anther tissues into symplasmically isolated developing pollen cells and thereby affect the sugar supply for pollen development. However, among the 17 CsSWEET genes identified in the cucumber (Cucumis sativus L.) genome, the CsSWEET gene involved in this process has not been identified. Here, a member of the SWEET gene family, CsSWEET5a, was identified and characterized. The quantitative real-time PCR and ß-glucuronidase expression analysis revealed that CsSWEET5a is highly expressed in the anthers and pollen cells of male cucumber flowers from the microsporocyte stage (stage 9) to the mature pollen stage (stage 12). Its subcellular localization indicated that the CsSWEET5a protein is localized to the plasma membrane. The heterologous expression assays in yeast demonstrated that CsSWEET5a encodes a hexose transporter that can complement both glucose and fructose transport deficiencies. CsSWEET5a can significantly rescue the pollen viability and fertility of atsweet8 mutant Arabidopsis plants. The possible role of CsSWEET5a in supplying hexose to developing pollen cells via the apoplast is also discussed.

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Specialized pollination systems frequently match a particular set of floral characteristics. Vincetoxicum spp. (Apocynaceae, Asclepiadoideae) have disk-shaped flowers with open access to rewards and reproductive organs. Flowers with these traits are usually associated with generalized pollination. However, the highly modified androecium and gynoecium that characterize asclepiads are thought to be associated with specialized pollinators. In V. sangyojarniae, we investigated floral biology, pollination, and the degree of pollinator specialization in two localities in Thailand. We examined floral traits that target legitimate pollinators. Flowers of V. sangyojarniae opened only at night, emitted floral scents containing mainly (E)-ß-ocimene, 1-octen-3-ol, (E)-4,8-dimethyl-1,3,7-nonatriene (E-DMNT) and N-(3-methylbutyl)acetamide, and provided sucrose-dominated nectar openly to insect visitors. Assessment of pollinator effectiveness indicated that V. sangyojarniae is functionally specialized for pollination by cecidomyiid flies. Although various insects, particularly cockroaches, frequently visited flowers, they did not carry pollinaria. Our results suggest that V. sangyojarniae attracts its fly pollinators by emitting floral volatiles bearing olfactory notes associated with the presence of fungi or, less likely, of prey captured by predatory arthropods (food sources of its pollinators) but offers a nectar reward upon insect arrival. Hence, there is a mismatch between the advertisement and the actual reward. Our results also suggest that the size of floral parts constitutes a mechanical filter where reciprocal fit between flower and insect structures ensures that only suitable pollinators can extract the pollinaria, a prerequisite for successful pollination.

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In plants under drought stress, sugar content in roots increases, which is important for drought resistance. However, the molecular mechanisms for controlling the sugar content in roots during response to drought remain elusive. Here, we found that the MdDOF3-MdHT1.2 module-mediated glucose influx into the root is essential for drought resistance in apple (Malus × domestica). Drought induced glucose uptake from the rhizosphere and up-regulated the transcription of hexose transporter MdHT1.2. Compared with the wild-type plants, overexpression of MdHT1.2 promoted glucose uptake from the rhizosphere, thereby facilitating sugar accumulation in root and enhancing drought resistance, whereas silenced plants showed the opposite phenotype. Furthermore, ATAC-seq, RNA-seq and biochemical analysis demonstrated that MdDOF3 directly bound to the promoter of MdHT1.2 and was strongly up-regulated under drought. Overexpression of MdDOF3 in roots improved MdHT1.2-mediated glucose transport capacity and enhanced plant resistance to drought, but MdDOF3-RNAihr apple plants showed the opposite phenotype. Moreover, overexpression of MdDOF3 in roots did not attenuate drought sensitivity in MdHT1.2-RNAi plants, which was correlated with a lower glucose uptake capacity and glucose content in root. Collectively, our findings deciphered the molecular mechanism through which glucose uptake from the rhizosphere is mediated by MdDOF3-MdHT1.2, which acts to modulate sugar content in root and promote drought resistance.

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Fungal infections are emerging as major health challenges in recent years. The development of resistance against existing antifungal agents needs urgent attention and action. The limited classes of antifungal drugs available, their tendency to cause adverse effects, lack of effectiveness, etc., are the major limitations of current therapy. Thus, there is a pressing demand for new antifungal drug classes to cope with the present circumstances. Glucose is the key source of energy for all organisms, including fungi. Glucose plays a crucial role as a source of carbon and energy for processes like virulence, growth, invasion, biofilm formation, and resistance development. The glucose transport and sensing mechanisms are well developed in these organisms as an important strategy to sustain survival. Modulating these transport or sensor mechanisms may serve as an important strategy to inhibit fungal growth. Moreover, the structural difference between human and fungal glucose transporters makes them more appealing as drug targets. Limited literature is available for fungal glucose entry mechanisms. This review provides a comprehensive account of sugar transport mechanisms in common fungal pathogens.

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In the endoplasmic reticulum (ER) lumen, glucose-6-phosphatase catalytic subunit 1 and 2 (G6PC1; G6PC2) hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate whereas hexose-6-phosphate dehydrogenase (H6PD) hydrolyzes G6P to 6-phosphogluconate (6PG) in a reaction that generates NADPH. 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) utilizes this NADPH to convert inactive cortisone to cortisol. HSD11B1 inhibitors improve insulin sensitivity whereas G6PC inhibitors are predicted to lower fasting blood glucose (FBG). This study investigated whether G6PC1 and G6PC2 influence G6P flux through H6PD and vice versa. Using a novel transcriptional assay that utilizes separate fusion genes to quantitate glucocorticoid and glucose signaling, we show that overexpression of H6PD and HSD11B1 in the islet-derived 832/13 cell line activated glucocorticoid-stimulated fusion gene expression. Overexpression of HSD11B1 blunted glucose-stimulated fusion gene expression independently of altered G6P flux. While overexpression of G6PC1 and G6PC2 blunted glucose-stimulated fusion gene expression, it had minimal effect on glucocorticoid-stimulated fusion gene expression. In the liver-derived HepG2 cell line, overexpression of H6PD and HSD11B1 activated glucocorticoid-stimulated fusion gene expression but overexpression of G6PC1 and G6PC2 had no effect. In rodents, HSD11B1 converts 11-dehydrocorticosterone (11-DHC) to corticosterone. Studies in wild-type and G6pc2 knockout mice treated with 11-DHC for 5 weeks reveal metabolic changes unaffected by the absence of G6PC2. These data suggest that HSD11B1 activity is not significantly affected by the presence or absence of G6PC1 or G6PC2. As such, G6PC1 and G6PC2 inhibitors are predicted to have beneficial effects by reducing FBG without causing a deleterious increase in glucocorticoid signaling.

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The use of kinetic modeling and metabolic control analysis (MCA) to identify possible therapeutic targets and to investigate the controlling and regulatory mechanisms in cancer glycolysis is here reviewed. The glycolytic pathway has been considered a target to decrease cancer cell growth; however, its occurrence in normal cells makes it difficult to design therapeutic strategies that target this pathway in pathological cells. Notwithstanding, the over-expression of all enzymes and transporters, as well as the expression of isoenzymes with different kinetic and regulatory properties in cancer cells, suggested a different distribution of the control of glycolytic flux than that observed in normal cells. Kinetic models of glycolysis are constructed with enzyme kinetics experimental data, validated with the steady-state metabolite concentrations and glycolytic fluxes; applying MCA, permitted us to identify the steps with the highest control of glycolysis in cancer cells, but low control in normal cells. The cancer glycolysis main controlling steps under several metabolic conditions were: glucose transport, hexokinase and hexose-6-phosphate isomerase (HPI); whereas in normal cells were: the first two and phosphofructokinase-1. HPI is the best therapeutic target because it exerts high control in cancer glycolytic flux, but not in normal cells. Furthermore, kinetic modeling also contributed to identifying new feed-back and feed-forward regulatory loops in cancer cells glycolysis, and to understanding the mode of metabolic action of glycolytic inhibitors. Thus, MCA and metabolic modeling allowed to propose new strategies for inhibiting glycolysis in cancer cells.

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Snf1, the fungal homologue of mammalian AMP-dependent kinase (AMPK), is a key protein kinase coordinating the response of cells to a shortage of glucose. In fungi, the response is to activate respiratory gene expression and metabolism. The major regulation of Snf1 activity has been extensively investigated: In the absence of glucose, it becomes activated by phosphorylation of its threonine at position 210. This modification can be erased by phosphatases when glucose is restored. In the past decade, two additional independent mechanisms of Snf1 regulation have been elucidated. In response to glucose (or, surprisingly, also to DNA damage), Snf1 is SUMOylated by Mms21 at lysine 549. This inactivates Snf1 and leads to Snf1 degradation. More recently, glucose-induced proton export has been found to result in Snf1 inhibition via a polyhistidine tract (13 consecutive histidine residues) at the N-terminus of the Snf1 protein. Interestingly, the polyhistidine tract plays also a central role in the response to iron scarcity. This review will present some of the glucose-sensing mechanisms of S. cerevisiae, how they interact, and how their interplay results in Snf1 inhibition by three different, and independent, mechanisms.

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We applied raw human liver microsome lysate to a holey carbon grid and used cryo-electron microscopy (cryo-EM) to define its composition. From this sample we identified and simultaneously determined high-resolution structural information for ten unique human liver enzymes involved in diverse cellular processes. Notably, we determined the structure of the endoplasmic bifunctional protein H6PD, where the N- and C-terminal domains independently possess glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase enzymatic activity, respectively. We also obtained the structure of heterodimeric human GANAB, an ER glycoprotein quality-control machinery that contains a catalytic α subunit and a noncatalytic ß subunit. In addition, we observed a decameric peroxidase, PRDX4, which directly contacts a disulfide isomerase-related protein, ERp46. Structural data suggest that several glycosylations, bound endogenous compounds, and ions associate with these human liver enzymes. These results highlight the importance of cryo-EM in facilitating the elucidation of human organ proteomics at the atomic level.

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