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Journal articles on the topic 'Hexosamine biosynthesis pathway'

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Published: 10 December 2022

Last updated: 28 January 2023

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1

Lockhart, Deborah E. A., Mathew Stanley, Olawale G. Raimi, David A. Robinson, Dominika Boldovjakova, Daniel R. Squair, Andrew T. Ferenbach, Wenxia Fang, and Daan M. F. van Aalten. "Targeting a critical step in fungal hexosamine biosynthesis." Journal of Biological Chemistry 295, no. 26 (April 27, 2020): 8678–91. http://dx.doi.org/10.1074/jbc.ra120.012985.

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Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.

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2

Frank, L. A., M. L. Sutton-McDowall, D. L. Russell, X. Wang, D. K. Feil, R. B. Gilchrist, and J. G. Thompson. "Effect of varying glucose and glucosamine concentration in vitro on mouse oocyte maturation and developmental competence." Reproduction, Fertility and Development 25, no. 8 (2013): 1095. http://dx.doi.org/10.1071/rd12275.

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The effects of hyper- and hypo-glycaemic conditions during the in vitro maturation of mouse cumulus–oocyte complexes on developmental competence were examined, with an emphasis on the role of the hexosamine biosynthesis pathway. A low (1 mM) glucose concentration achieved optimal oocyte competence (3-fold higher blastocyst development rate compared with high (30 mM) glucose, P < 0.05). In addition, glucose supplementation during only the first hour after release from the follicle was necessary and sufficient to support oocyte maturation and embryo development to the blastocyst stage. Glucosamine (a known hyperglycaemic mimetic and specific activator of the hexosamine pathway) was able to substitute for glucose during this first hour, indicating that flux through the hexosamine pathway is essential for oocyte competence. In the absence of glucose throughout the maturation period, glucosamine was not able to increase developmental competence, and at higher concentrations (2.5 and 5 mM) had a detrimental effect on MII and blastocyst development rates, compared with controls (P < 0.05). These experiments underscore the importance of glucose metabolic pathways during in vitro maturation and support the concept that excess flux through the hexosamine pathway has detrimental consequences.

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3

FILIPPIS, Anthony, Stella CLARK, and Joseph PROIETTO. "Increased flux through the hexosamine biosynthesis pathway inhibits glucose transport acutely by activation of protein kinase C." Biochemical Journal 324, no. 3 (June 15, 1997): 981–85. http://dx.doi.org/10.1042/bj3240981.

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The hexosamine biosynthesis pathway and protein kinase C (PKC) activation mediate hyperglycaemia-induced impaired glucose transport, but the relative role of each pathway is unknown. Following a 2 h preincubation of rat adipocytes in the presence of either high glucose (30 mM) plus insulin (0.7 nM) or glucosamine (3 mM), both high glucose and glucosamine inhibited subsequent basal and insulin-stimulated glucose transport, measured at 5.0 mM glucose. Azaserine, an inhibitor of the enzyme glutamine:fructose-6-phosphate aminotransferase, abolished the effect of high glucose, but not that of glucosamine. Ro-31-8220, an inhibitor of PKC, reversed the effects of both high glucose and glucosamine, suggesting that flux through the hexosamine biosynthesis pathway impaired glucose transport acutely by activating PKC. Both high glucose and glucosamine caused a 3-fold increase in PKC activity; this effect of high glucose, but not that of glucosamine, was partially decreased by azaserine. Neither high glucose nor glucosamine altered basal or insulin-stimulated plasma membrane GLUT1 levels, whereas both treatments decreased basal, but not insulin-stimulated, GLUT4 levels. Azaserine abolished the effect of high glucose, but not that of glucosamine, on basal plasma membrane GLUT4 levels. Ro-31-8220, which returned glucose transport to control values, caused a further decrease in plasma membrane GLUT4 levels. It is concluded that, in rat adipocytes, an acute increase in flux through the hexosamine biosynthesis pathway inhibits glucose transport by activation of PKC.

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4

Filippis, Christine, Anthony Filippis, Stella Clark, and Joseph Proietto. "Activation of PI 3-kinase by the hexosamine biosynthesis pathway." Molecular and Cellular Endocrinology 194, no. 1-2 (August 2002): 29–37. http://dx.doi.org/10.1016/s0303-7207(02)00213-7.

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5

Willems, Anke P., Baziel G. M. van Engelen, and Dirk J. Lefeber. "Genetic defects in the hexosamine and sialic acid biosynthesis pathway." Biochimica et Biophysica Acta (BBA) - General Subjects 1860, no. 8 (August 2016): 1640–54. http://dx.doi.org/10.1016/j.bbagen.2015.12.017.

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6

Przybyl, Joanna, Angela Tolwani, Sushama Varma, and Matt van de Rijn. "Abstract B015: Targeting hexosamine biosynthesis pathway for the treatment of desmoid tumors." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): B015. http://dx.doi.org/10.1158/1557-3265.sarcomas22-b015.

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Abstract Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. The three main glucose metabolism pathways that support growth of cancer cells are: a) the glycolysis pathway for energy production; b) the pentose phosphate pathway for biomass production; and c) the hexosamine biosynthesis pathway (HBP) for protein glycosylation. It is known that the activation of HBP leads to altered glycosylation of oncogenes, transcription factors and kinases in many types of cancer. These aberrations may lead to increased proliferation and survival of tumor cells, and may be associated with resistance to therapy. A better understanding of the role of HBP in malignancies has the potential for clinical implications. Several studies demonstrated that pharmacological inhibition of GFPT2 (glutamine-fructose-6-phosphate transaminase 2, the first and rate-limiting enzyme in HBP) and the enzymes that act downstream of HBP may exhibit anti-tumorigenic effect both in vitro and in vivo, and may modulate sensitivity to chemo-, radio- and immunotherapy. Most of these studies focused on carcinomas and the role of HPB in sarcoma has not been studied. We recently reported a remarkable enrichment of genes involved in HBP in a subset of leiomyosarcoma (LMS) and demonstrated that expression of GFPT2 in LMS is associated with poor clinical outcome. We identified the c-Myc oncoprotein as a potential target of HPB that may be stabilized by aberrant glycosylation in LMS. Here we show the results of a large-scale screening of 260 primary specimens of 33 types of soft tissue lesions. In addition to expression in a subset of LMS, we observed near universal expression of GFPT2 in 34 of 35 desmoid type fibromatosis (DTF), independent of the mutation type of the CTNNB1 gene. Gene Set Enrichment Analysis of a previously published 3SEQ transcriptomic dataset composed of DTF and 9 other types of fibrotic lesions identified significant enrichment of other genes implicated in HBP and multiple glycosylation-associated pathways in DTF compared to the other types of fibrotic lesions. Our analysis identified ATF6 (activating transcription factor 6) as a possible target regulated by aberrant glycosylation as a consequence of HBP activation in DTF. ATF6 is a glycoprotein that has been demonstrated to underlie the resistance to chemotherapy in osteosarcoma, to have a pro-oncogenic role in primary liver cancers and has been proposed as a therapeutic target in cystic fibrosis. Others have shown that targeting HBP can provide therapeutic benefit in a number of preclinical models of carcinoma. Our studies offer new insights into the mechanisms of DTF tumorigenesis and, when confirmed by in vitro studies, will provide a rationale to explore the potential of therapeutic targeting of HBP in DTF. Citation Format: Joanna Przybyl, Angela Tolwani, Sushama Varma, Matt van de Rijn. Targeting hexosamine biosynthesis pathway for the treatment of desmoid tumors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B015.

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7

Filhoulaud, Gaëlle, Ghislaine Guillemain, and Raphaël Scharfmann. "The Hexosamine Biosynthesis Pathway Is Essential for Pancreatic Beta Cell Development." Journal of Biological Chemistry 284, no. 36 (July 7, 2009): 24583–94. http://dx.doi.org/10.1074/jbc.m109.025288.

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8

Adeyemo, Adelola O., Dulce H. Gomez, Maitha A. Aldokhayyil, and Michael D. Brown. "Is The Hexosamine Biosynthesis Pathway Affected By Inflammation In Endothelial Cells?" Medicine & Science in Sports & Exercise 52, no. 7S (July 2020): 567. http://dx.doi.org/10.1249/01.mss.0000680392.11336.c3.

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9

Beriault, D., Y. Shi, and G. Werstuck. "Investigating the Role of the Hexosamine Biosynthesis Pathway in Diabetic Atherosclerosis." Canadian Journal of Cardiology 29, no. 10 (October 2013): S254. http://dx.doi.org/10.1016/j.cjca.2013.07.417.

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10

Penque, Brent A., April M. Hoggatt, B. Paul Herring, and Jeffrey S. Elmendorf. "Hexosamine Biosynthesis Impairs Insulin Action via a Cholesterolgenic Response." Molecular Endocrinology 27, no. 3 (March 1, 2013): 536–47. http://dx.doi.org/10.1210/me.2012-1213.

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Abstract Plasma membrane cholesterol accumulation has been implicated in cellular insulin resistance. Given the role of the hexosamine biosynthesis pathway (HBP) as a sensor of nutrient excess, coupled to its involvement in the development of insulin resistance, we delineated whether excess glucose flux through this pathway provokes a cholesterolgenic response induced by hyperinsulinemia. Exposing 3T3-L1 adipocytes to physiologically relevant doses of hyperinsulinemia (250pM–5000pM) induced a dose-dependent gain in the mRNA/protein levels of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR). These elevations were associated with elevated plasma membrane cholesterol. Mechanistically, hyperinsulinemia increased glucose flux through the HBP and O-linked β-N-acetylglucosamine (O-GlcNAc) modification of specificity protein 1 (Sp1), known to activate cholesterolgenic gene products such as the sterol response element-binding protein (SREBP1) and HMGR. Chromatin immunoprecipitation demonstrated that increased O-GlcNAc modification of Sp1 resulted in a higher binding affinity of Sp1 to the promoter regions of SREBP1 and HMGR. Luciferase assays confirmed that HMGR promoter activity was elevated under these conditions and that inhibition of the HBP with 6-diazo-5-oxo-l-norleucine (DON) prevented hyperinsulinemia-induced activation of the HMGR promoter. In addition, both DON and the Sp1 DNA-binding inhibitor mithramycin prevented the hyperinsulinemia-induced increases in HMGR mRNA/protein and plasma membrane cholesterol. In these mithramycin-treated cells, both cortical filamentous actin structure and insulin-stimulated glucose transport were restored. Together, these data suggest a novel mechanism whereby increased HBP activity increases Sp1 transcriptional activation of a cholesterolgenic program, thereby elevating plasma membrane cholesterol and compromising cytoskeletal structure essential for insulin action.

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11

Coussement, Pieter, David Bauwens, Gert Peters, Jo Maertens, and Marjan De Mey. "Mapping and refactoring pathway control through metabolic and protein engineering: The hexosamine biosynthesis pathway." Biotechnology Advances 40 (May 2020): 107512. http://dx.doi.org/10.1016/j.biotechadv.2020.107512.

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12

McClain, Donald, Rodrick Taylor, Yudi Soesanto, and Bai Luo. "Metabolic Regulation by the Hexosamine Biosynthesis/O-Linked N-Acetyl Glucosamine Pathway." Current Signal Transduction Therapy 5, no. 1 (January 1, 2010): 3–11. http://dx.doi.org/10.2174/157436210790226474.

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13

Dang, V. T., C. I. Petlura, D. R. Beriault, Y. Shi, and G. H. Werstuck. "METABOLOMIC INVESTIGATION OF THE HEXOSAMINE BIOSYNTHESIS PATHWAY IN HYPERGLYCEMIA-INDUCED ACCELERATED ATHEROSCLEROSIS." Canadian Journal of Cardiology 30, no. 10 (October 2014): S271. http://dx.doi.org/10.1016/j.cjca.2014.07.478.

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14

Taparra, K. T., H. Wang, R. Malek, K. Nugent, J. Groves, G. Yildirir, B. Simons, D. Felsher, N. Zachara, and P. T. Tran. "SNAI1 Regulates the Hexosamine Biosynthesis Pathway to Promote Kras Mutant Lung Tumorigenesis." International Journal of Radiation Oncology*Biology*Physics 96, no. 2 (October 2016): S54—S55. http://dx.doi.org/10.1016/j.ijrobp.2016.06.142.

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15

Beriault, D. R., Y. Shi, M. Khan, and G. H. Werstuck. "032 Investigating the Role of the Hexosamine Biosynthesis Pathway in Diabetic Atherosclerosis." Canadian Journal of Cardiology 28, no. 5 (September 2012): S96—S97. http://dx.doi.org/10.1016/j.cjca.2012.07.045.

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16

Nelson, B. A., K. A. Robinson, J. S. Koning, and M. G. Buse. "Effects of exercise and feeding on the hexosamine biosynthetic pathway in rat skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 272, no. 5 (May 1, 1997): E848—E855. http://dx.doi.org/10.1152/ajpendo.1997.272.5.e848.

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Products of the hexosamine biosynthesis pathway (HSNP) have been implicated in glucose-induced insulin resistance. We measured the major products of HSNP, UDP-N-acetyl hexosamines (UDP-HexNAc), and the activity of L-glutamine: D-fructose-6-phosphate amidotransferase (GFAT, rate-limiting enzyme) in rat hindlimb muscles immediately after exercise and 1, 3, and 16 h postexercise (swimming) in fed and fasted rats and sedentary controls. Muscle glycogen decreased by 50-75% postexercise. In sedentary rats, muscle GFAT activity decreased by approximately 30% (P < 0.002) after an 18-h fast. GFAT activity was not affected by exercise under any condition. Muscle UDP-HexNAc increased approximately 30% postexercise (P < 0.01) in ad libitum-fed but not in fasted rats. UDP-HexNAc remained elevated (approximately 30%, P < 0.002) for 16 h if animals were fed postexercise. Concentrations of UDP-hexoses, GDP-mannose, and UDP were unchanged postexercise. Conclusions are that muscle GFAT activity is regulated by the nutritional state but not by acute exercise. Glucose flux via HNSP may be increased postexercise in muscles of ad libitum-fed rats. Increased HSNP products may serve as negative feedback regulators to limit excessive muscle glycogen deposition postexercise.

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17

Chen, Yabing, Xinyang Zhao, and Hui Wu. "Metabolic Stress and Cardiovascular Disease in Diabetes Mellitus." Arteriosclerosis, Thrombosis, and Vascular Biology 39, no. 10 (October 2019): 1911–24. http://dx.doi.org/10.1161/atvbaha.119.312192.

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Mammalian cells metabolize glucose primarily for energy production, biomass synthesis, and posttranslational glycosylation; and maintaining glucose metabolic homeostasis is essential for normal physiology of cells. Impaired glucose homeostasis leads to hyperglycemia, a hallmark of diabetes mellitus. Chronically increased glucose in diabetes mellitus promotes pathological changes accompanied by impaired cellular function and tissue damage, which facilitates the development of cardiovascular complications, the major cause of morbidity and mortality of patients with diabetes mellitus. Emerging roles of glucose metabolism via the hexosamine biosynthesis pathway (HBP) and increased protein modification via O -linked β- N -acetylglucosamine ( O -GlcNAcylation) have been demonstrated in diabetes mellitus and implicated in the development of diabetic cardiovascular complications. This review will discuss the biological outcomes of the glucose metabolism via the hexosamine biogenesis pathway and protein O -GlcNAcylation in regulating cellular homeostasis, and highlight the regulations and contributions of elevated O -GlcNAcylation to the pathogenesis of diabetic cardiovascular disease.

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18

Zraika, Sakeneh, Marjorie Dunlop, Joseph Proietto, and Sofianos Andrikopoulos. "The hexosamine biosynthesis pathway regulates insulin secretion via protein glycosylation in mouse islets." Archives of Biochemistry and Biophysics 405, no. 2 (September 2002): 275–79. http://dx.doi.org/10.1016/s0003-9861(02)00397-1.

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19

Huang, Ji-Biao, Andrea J. Clark, and Howard R. Petty. "The hexosamine biosynthesis pathway negatively regulates IL-2 production by Jurkat T cells." Cellular Immunology 245, no. 1 (January 2007): 1–6. http://dx.doi.org/10.1016/j.cellimm.2007.03.006.

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20

Singh, Lalit P., Kenneith Green, Michelle Alexander, Shira Bassly, and Errol D. Crook. "Hexosamines and TGF-β1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells." American Journal of Physiology-Renal Physiology 286, no. 2 (February 2004): F409—F416. http://dx.doi.org/10.1152/ajprenal.00007.2003.

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Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix (ECM) protein accumulation are seen in diabetic glomerulopathy. Transforming growth factor-β1 (TGF-β1) mediates high-glucose-induced matrix production in the kidney. Recent studies demonstrated that some of the effects of high glucose on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP) in which fructose-6-phosphate is converted to glucosamine (GlcN) 6-phosphate. We previously showed that the high-glucose-mediated fibronectin and laminin synthesis in MES cells is mediated by the HBP and that GlcN is more potent than glucose in inducing TGF-β1 promoter luciferase activity. In this study, we investigated the hypothesis that the effects of glucose on MES matrix production occur via hexosamine regulation of TGF-β1. Culturing simian virus (SV)-40-transformed rat kidney MES cells in 25 mM glucose (HG) for 48 h increases cellular fibronectin and laminin levels about twofold on Western blots compared with low glucose (5 mM). GlcN (1.5 mM) or TGF-β1 (2.5-5 ng/ml) for 24-48 h also increases ECM synthesis. However, the effects of HG or GlcN with TGF-β1 are not additive. The presence of anti-TGF-β1 antibodies (20 μg/ml) blocks both TGF-β1- and GlcN-induced fibronectin synthesis. TGF-β1 increased ECM levels via PKA (laminin and fibronectin) and PKC (fibronectin) pathways. Similarly, TGF-β1 and hexosamines led to nonadditive increases in phosphorylation of the cAMP responsive element binding transcription factor. These results suggest that the effects of excess glucose on MES ECM synthesis occur via HBP-mediated regulation of TGF-β1.

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21

Penque, Brent A., Lixuan Tackett, and Jeffrey S. Elmendorf. "Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance." Open Journal of Endocrine and Metabolic Diseases 03, no. 04 (2013): 1–8. http://dx.doi.org/10.4236/ojemd.2013.34a1001.

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22

Kim, Jiyeon, Hyun Min Lee, Feng Cai, Bookyung Ko, Chendong Yang, Elizabeth L. Lieu, Nefertiti Muhammad, et al. "The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer." Nature Metabolism 2, no. 12 (November 30, 2020): 1401–12. http://dx.doi.org/10.1038/s42255-020-00316-0.

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23

Laczy, Boglárka, Norbert Fülöp, Arzu Onay-Besikci, Christine Des Rosiers, and John C. Chatham. "Acute Regulation of Cardiac Metabolism by the Hexosamine Biosynthesis Pathway and Protein O-GlcNAcylation." PLoS ONE 6, no. 4 (April 11, 2011): e18417. http://dx.doi.org/10.1371/journal.pone.0018417.

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24

Bouché, Clara, Shanti Serdy, C. Ronald Kahn, and Allison B. Goldfine. "The Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes." Endocrine Reviews 25, no. 5 (October 1, 2004): 807–30. http://dx.doi.org/10.1210/er.2003-0026.

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Type 2 diabetes is a complex disorder with diminished insulin secretion and insulin action contributing to the hyperglycemia and wide range of metabolic defects that underlie the disease. The contribution of glucose metabolic pathways per se in the pathogenesis of the disease remains unclear. The cellular fate of glucose begins with glucose transport and phosphorylation. Subsequent pathways of glucose utilization include aerobic and anaerobic glycolysis, glycogen formation, and conversion to other intermediates in the hexose phosphate or hexosamine biosynthesis pathways. Abnormalities in each pathway may occur in diabetic subjects; however, it is unclear whether perturbations in these may lead to diabetes or are a consequence of the multiple metabolic abnormalities found in the disease. This review is focused on the cellular fate of glucose and relevance to human type 2 diabetes.

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25

Robinson, Katherine A., Steven M. Willi, Sarah Bingel, and Maria G. Buse. "Decreased hexosamine biosynthesis in GH-deficient dwarf rat muscle. Reversal with GH, but not IGF-I, therapy." American Journal of Physiology-Endocrinology and Metabolism 276, no. 3 (March 1, 1999): E435—E442. http://dx.doi.org/10.1152/ajpendo.1999.276.3.e435.

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Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measuredl-glutamine:d-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP- N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30–60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls ( P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles ( P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle.

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26

Orzechowska-Licari, Emilia J., Joseph F. LaComb, Aisharja Mojumdar, and Agnieszka B. Bialkowska. "SP and KLF Transcription Factors in Cancer Metabolism." International Journal of Molecular Sciences 23, no. 17 (September 1, 2022): 9956. http://dx.doi.org/10.3390/ijms23179956.

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Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic pathways such as glycolysis, oxidative phosphorylation, lipid metabolism, and hexosamine biosynthesis pathway are crucial to sustain increased redox, bioenergetic, and biosynthesis demands of a tumor cell. Transcription factors (oncogenes and tumor suppressors) play crucial roles in modulating these alterations, and their functions are tethered to major metabolic pathways under homeostatic conditions and disease initiation and advancement. Specificity proteins (SPs) and Krüppel-like factors (KLFs) are closely related transcription factors characterized by three highly conserved zinc fingers domains that interact with DNA. Studies have demonstrated that SP and KLF transcription factors are expressed in various tissues and regulate diverse processes such as proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. This review highlights the role of SP and KLF transcription factors in the metabolism of various cancers and their impact on tumorigenesis. A better understanding of the role and underlying mechanisms governing the metabolic changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment.

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27

Ferreira, Érika Elias, Isadora de Araújo Oliveira, Adriane Regina Todeschini, and Julio Cesar de Freitas-Junior. "Abstract 2387: The impact of beta 1,6-GlcNAc branched N-glycan synthesis on hexosamine pathway and UDP-GlcNAc demands in colorectal cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2387. http://dx.doi.org/10.1158/1538-7445.am2022-2387.

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Abstract Metabolic changes are commonly seen in cancer. Tumor cells present a high rate of glucose and glutamine uptake and part of these nutrients supplies the hexosamine biosynthesis pathway (HBP), whose exacerbation has been related to solid tumors progression, including colorectal cancer. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end product of HBP, serves as the donor for several enzymes involved in glycan biosynthesis. Aberrant glycosylation is known to affect cellular and molecular mechanisms related to the malignant phenotype. Beta 1,6-GlcNAc branches on N-glycans (products of the MGAT5 enzyme) are associated with greater stability of transmembrane glycoproteins, as glutamine and glucose transporters, and growth factor receptors. Furthermore, changes in the availability of UDP-GlcNAc can affect the levels of hyaluronic acid (HA) and O-GlcNAc-modified proteins. The interplay between different direct demands for UDP-GlcNAc is not well understood and may help to better understand tumor metabolism. Therefore, we intend to evaluate in colorectal cancer cells how changes in levels of branched beta1,6-GlcNAc N-glycans can affect both the hexosamine pathway and the different processes which demand UDP-GlcNAc (such as O-GlcNAcylation and hyaluronic acid synthesis). For this, two experimental strategies were performed. The first focused on the inhibition of complex N-glycans using swainsonine, and the second focused on the MGAT5 inactivation using CRISPR-Cas9. The levels of UDP-GlcNAc were also manipulated using DON, an inhibitor of the GFAT enzyme. Initially, it was found that both the pharmacological inhibition of complex N-glycan biosynthesis and the specific inactivation of MGAT5 lead to significantly reduced levels of hexosamine pathway intermediates, activated monosaccharides, and proteins modified by O-GlcNAc. Furthermore, it was also observed that MGAT5 inactivation enhances the expression of genes encoding HA synthases (HAS2 and HAS3). Upon detection of metabolites by LC-MS, a multivariate analysis was performed using the statistical method of Partial Least-Squares Discriminant Analysis (PLS-DA), and it was observed that KO MGAT5 cells formed a metabolically distinct population from MOCK cells. Interestingly, after pharmacological inhibition of GFAT, an increase in the levels of beta 1,6-GlcNAc branched N-glycans and a reduction in O-GlcNAcylation were observed. Treatment with DON was also able to reduce HAS2 expression however an increased in HAS3 expression was observed. These data suggest that there is a relationship among different demands for UDP-GlcNAc in tumor cells and a possible regulatory role played by beta 1,6-GlcNAc branched N-glycans in this issue. This work contributes to a better understanding of interconnections between biochemical processes that demand UDP-GlcNAc in the context of colorectal cancer. Citation Format: Érika Elias Ferreira, Isadora de Araújo Oliveira, Adriane Regina Todeschini, Julio Cesar de Freitas-Junior. The impact of beta 1,6-GlcNAc branched N-glycan synthesis on hexosamine pathway and UDP-GlcNAc demands in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2387.

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Sage, Andrew T., Lisa A. Walter, Yuanyuan Shi, Mohammad I. Khan, Hideaki Kaneto, Alfredo Capretta, and Geoff H. Werstuck. "Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells." American Journal of Physiology-Endocrinology and Metabolism 298, no. 3 (March 2010): E499—E511. http://dx.doi.org/10.1152/ajpendo.00507.2009.

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There is increasing evidence that endoplasmic reticulum (ER) stress contributes to the development of atherosclerosis in diabetes mellitus. The purpose of this study was to determine the effects of increased hexosamine biosynthesis pathway (HBP) flux on ER stress levels and the complications of ER stress associated with diabetes and atherosclerosis in hepatic cells. Glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of the HBP, was overexpressed in HepG2 cells by use of an adenoviral expression system. The ER stress response and downstream effects, including activation of lipid and inflammatory pathways, were determined using real-time PCR, immunoblot analysis, and cell staining techniques. GFAT overexpression resulted in increased expression of ER stress markers, including Grp78, Grp94, calreticulin, and GADD153, relative to cells infected with an empty adenoviral vector. In addition, GFAT overexpression promoted lipid, but not cholesterol, accumulation in hepatic cells as well as inflammatory pathway activation. Treatment with 6-diazo-5-oxo-norleucine, a GFAT antagonist, blocked the effects of GFAT overexpression. Consistent with our in vitro data, hyperglycemic mice presented with elevated markers of hepatic ER stress, glucosamine and lipid accumulation. Together, these data suggest that HBP flux-induced ER stress plays a role in the development of hepatic steatosis and atherosclerosis under conditions of hyperglycemia.

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Rajapakse, Angana Gupta, Xiu-Fen Ming, João M. Carvas, and Zhihong Yang. "The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 3 (March 2009): H815—H822. http://dx.doi.org/10.1152/ajpheart.00756.2008.

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Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-α (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-α. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-α. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway.

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Olson, Aaron K., Bertrand Bouchard, Wei Zhong Zhu, John C. Chatham, and Christine Des Rosiers. "First characterization of glucose flux through the hexosamine biosynthesis pathway (HBP) in ex vivo mouse heart." Journal of Biological Chemistry 295, no. 7 (January 8, 2020): 2018–33. http://dx.doi.org/10.1074/jbc.ra119.010565.

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The hexosamine biosynthesis pathway (HBP) branches from glycolysis and forms UDP-GlcNAc, the moiety for O-linked β-GlcNAc (O-GlcNAc) post-translational modifications. An inability to directly measure HBP flux has hindered our understanding of the factors regulating protein O-GlcNAcylation. Our goals in this study were to (i) validate a LC-MS method that assesses HBP flux as UDP-GlcNAc (13C)-molar percent enrichment (MPE) and concentration and (ii) determine whether glucose availability or workload regulate cardiac HBP flux. For (i), we perfused isolated murine working hearts with [U-13C6]glucosamine (1, 10, 50, or 100 μm), which bypasses the rate-limiting HBP enzyme. We observed a concentration-dependent increase in UDP-GlcNAc levels and MPE, with the latter reaching a plateau of 56.3 ± 2.9%. For (ii), we perfused isolated working hearts with [U-13C6]glucose (5.5 or 25 mm). Glycolytic efflux doubled with 25 mm [U-13C6]glucose; however, the calculated HBP flux was similar among the glucose concentrations at ∼2.5 nmol/g of heart protein/min, representing ∼0.003–0.006% of glycolysis. Reducing cardiac workload in beating and nonbeating Langendorff perfusions had no effect on the calculated HBP flux at ∼2.3 and 2.5 nmol/g of heart protein/min, respectively. To the best of our knowledge, this is the first direct measurement of glucose flux through the HBP in any organ. We anticipate that these methods will enable foundational analyses of the regulation of HBP flux and protein O-GlcNAcylation. Our results suggest that in the healthy ex vivo perfused heart, HBP flux does not respond to acute changes in glucose availability or cardiac workload.

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Zhou, Fuxing, Junwei Huo, Yu Liu, Haixia Liu, Gaowei Liu, Ying Chen, and Biliang Chen. "Elevated glucose levels impair the WNT/β-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer." Journal of Steroid Biochemistry and Molecular Biology 159 (May 2016): 19–25. http://dx.doi.org/10.1016/j.jsbmb.2016.02.015.

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Riegger, Jana, Julia Baumert, Frank Zaucke, and Rolf E. Brenner. "The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model." International Journal of Molecular Sciences 22, no. 14 (July 6, 2021): 7247. http://dx.doi.org/10.3390/ijms22147247.

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The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

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Hsieh, Tusty-Jiuan, Pierre Fustier, Shao-Ling Zhang, Janos G. Filep, Shiow-Shih Tang, Julie R. Ingelfinger, I. George Fantus, Pavel Hamet, and John S. D. Chan. "High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells." Endocrinology 144, no. 10 (October 1, 2003): 4338–49. http://dx.doi.org/10.1210/en.2003-0220.

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The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and β-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.

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Xu, Xiaofang, Dianhua Qiao, Lang Pan, Istvan Boldogh, Yingxin Zhao, and Allan R. Brasier. "RELA∙8-Oxoguanine DNA Glycosylase1 Is an Epigenetic Regulatory Complex Coordinating the Hexosamine Biosynthetic Pathway in RSV Infection." Cells 11, no. 14 (July 15, 2022): 2210. http://dx.doi.org/10.3390/cells11142210.

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Respiratory syncytial virus (RSV), or human orthopneumovirus, is a negative-sense RNA virus that is the causative agent of severe lower respiratory tract infections in children and is associated with exacerbations of adult lung disease. The mechanisms how severe and/or repetitive virus infections cause declines in pulmonary capacity are not fully understood. We have recently discovered that viral replication triggers epithelial plasticity and metabolic reprogramming involving the hexosamine biosynthetic pathway (HBP). In this study, we examine the relationship between viral induced innate inflammation and the activation of hexosamine biosynthesis in small airway epithelial cells. We observe that RSV induces ~2-fold accumulation of intracellular UDP-GlcNAc, the end-product of the HBP and the obligate substrate of N glycosylation. Using two different silencing approaches, we observe that RSV replication activates the HBP pathway in a manner dependent on the RELA proto-oncogene (65 kDa subunit). To better understand the effect of RSV on the cellular N glycoproteome, and its RELA dependence, we conduct affinity enriched LC-MS profiling in wild-type and RELA-silenced cells. We find that RSV induces the accumulation of 171 N glycosylated peptides in a RELA-dependent manner; these proteins are functionally enriched in integrins and basal lamina formation. To elaborate this mechanism of HBP expression, we demonstrate that RSV infection coordinately induces the HBP pathway enzymes in a manner requiring RELA; these genes include Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT)-1/2, Glucosamine-Phosphate N-Acetyltransferase (GNPNAT)-1, phosphoglucomutase (PGM)-3 and UDP-N-Acetylglucosamine Pyrophosphorylase (UAP)-1. Using small-molecule inhibitor(s) of 8-oxoguanine DNA glycosylase1 (OGG1), we observe that OGG1 is also required for the expression of HBP pathway. In proximity ligation assays, RSV induces the formation of a nuclear and mitochondrial RELA∙OGG1 complex. In co-immunoprecipitaton (IP) experiments, we discover that RSV induces Ser 536-phosphorylated RELA to complex with OGG1. Chromatin IP experiments demonstrate a major role of OGG1 in supporting the recruitment of RELA and phosphorylated RNA Pol II to the HBP pathway genes. We conclude that the RELA∙OGG1 complex is an epigenetic regulator mediating metabolic reprogramming and N glycoprotein modifications of integrins in response to RSV. These findings have implications for viral-induced adaptive epithelial responses.

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Johswich, Anita, Christine Longuet, Judy Pawling, Anas Abdel Rahman, Michael Ryczko, Daniel J. Drucker, and James W. Dennis. "N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway." Journal of Biological Chemistry 289, no. 23 (April 17, 2014): 15927–41. http://dx.doi.org/10.1074/jbc.m114.563734.

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Daniels, M. C. "Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway." Molecular Endocrinology 7, no. 8 (August 1, 1993): 1041–48. http://dx.doi.org/10.1210/me.7.8.1041.

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Daniels, M. C., P. Kansal, T. M. Smith, A. J. Paterson, J. E. Kudlow, and D. A. McClain. "Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway." Molecular Endocrinology 7, no. 8 (August 1993): 1041–48. http://dx.doi.org/10.1210/mend.7.8.8232303.

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Marsh, Susan A., Louis J. Dell’Italia, and John C. Chatham. "Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice." Amino Acids 40, no. 3 (July 30, 2010): 819–28. http://dx.doi.org/10.1007/s00726-010-0699-8.

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Sutton-McDowall, Melanie L., Robert B. Gilchrist, and Jeremy G. Thompson. "The pivotal role of glucose metabolism in determining oocyte developmental competence." REPRODUCTION 139, no. 4 (April 2010): 685–95. http://dx.doi.org/10.1530/rep-09-0345.

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The environment that the cumulus oocyte complex (COC) is exposed to during eitherin vivoorin vitromaturation (IVM) can have profound effects on the success of fertilisation and subsequent embryo development. Glucose is a pivotal metabolite for the COC and is metabolised by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP) and the polyol pathway. Over the course of oocyte maturation, a large proportion of total glucose is metabolised via the glycolytic pathway to provide substrates such as pyruvate for energy production. Glucose is also the substrate for many cellular functions during oocyte maturation, including regulation of nuclear maturation and redox state via the PPP and for the synthesis of substrates of extracellular matrices (cumulus expansion) andO-linked glycosylation (cell signalling) via the HBP. However, the oocyte is susceptible to glucose concentration-dependent perturbations in nuclear and cytoplasmic maturation, leading to poor embryonic development post-fertilisation. For example, glucose concentrations either too high or too low result in precocious resumption of nuclear maturation. This review will discuss the relevant pathways of glucose metabolism by COCs duringin vivomaturation and IVM, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism. The consequences of exposing COCs to abnormal glucose concentrations will also be examined, either during IVM or by altered maternal environments, such as during hyperglycaemia induced by diabetes and obesity.

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Daniels, Marc C., Donald A. McClain, and Errol D. Crook. "Transcriptional Regulation of Transforming Growth Factor β1 by Glucose: Investigation into the Role of the Hexosamine Biosynthesis Pathway." American Journal of the Medical Sciences 319, no. 3 (March 2000): 138–42. http://dx.doi.org/10.1016/s0002-9629(15)40711-6.

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Daniels, Marc C., Donald A. McClain, and Errol D. Crook. "Transcriptional Regulation of Transforming Growth Factor β1 by Glucose: Investigation into the Role of the Hexosamine Biosynthesis Pathway." American Journal of the Medical Sciences 359, no. 2 (February 2020): 79–83. http://dx.doi.org/10.1016/j.amjms.2019.12.013.

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Bhonagiri, Padma, Guruprasad R. Pattar, Emily M. Horvath, Kirk M. Habegger, Alicia M. McCarthy, and Jeffrey S. Elmendorf. "Hexosamine Biosynthesis Pathway Flux Contributes to Insulin Resistance via Altering Membrane Phosphatidylinositol 4,5-Bisphosphate and Cortical Filamentous Actin." Endocrinology 150, no. 4 (November 26, 2008): 1636–45. http://dx.doi.org/10.1210/en.2008-1102.

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Daniels, Marc C., Donald A. McClain, and Errol D. Crook. "Transcriptional Regulation of Transforming Growth Factor ??1 by Glucose: Investigation into the Role of the Hexosamine Biosynthesis Pathway." American Journal of the Medical Sciences 319, no. 3 (March 2000): 138–42. http://dx.doi.org/10.1097/00000441-200003000-00002.

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Maucieri, Abigail M., and David H. Townson. "Evaluating the impact of the hexosamine biosynthesis pathway and O-GlcNAcylation on glucose metabolism in bovine granulosa cells." Molecular and Cellular Endocrinology 564 (March 2023): 111863. http://dx.doi.org/10.1016/j.mce.2023.111863.

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Greig, Kylie T., Jennifer Antonchuk, Donald Metcalf, Phillip O. Morgan, Danielle L. Krebs, Jian-Guo Zhang, Douglas F. Hacking, et al. "Agm1/Pgm3-Mediated Sugar Nucleotide Synthesis Is Essential for Hematopoiesis and Development." Molecular and Cellular Biology 27, no. 16 (June 4, 2007): 5849–59. http://dx.doi.org/10.1128/mcb.00802-07.

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ABSTRACT Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.

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Singh, Lalit P., Docia Gennerette, Shakisha Simmons, and Errol D. Crook. "Glucose-induced insulin resistance of phosphatidylinositol 3′-OH kinase and AKT/PKB is mediated by the hexosamine biosynthesis pathway." Journal of Diabetes and its Complications 15, no. 2 (March 2001): 88–96. http://dx.doi.org/10.1016/s1056-8727(00)00140-9.

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Rajapakse, Angana Gupta, Xiu-Fen Ming, João M. Carvas, and Zhihong Yang. "O-linked β-N-acetylglucosamine During Hyperglycemia Exerts Both Anti-Inflammatory and Pro-Oxidative Properties in the Endothelial System." Oxidative Medicine and Cellular Longevity 2, no. 3 (2009): 172–75. http://dx.doi.org/10.4161/oxim.2.3.8482.

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Elevated cellular levels of proteinO-linked β-N-acetylglucosamine (O-GlcNAc) through hexosamine biosynthesis pathway (HBP) are suggested to contribute to cardiovascular adverse effects under chronic hyperglycemic condition associated with oxidative stress and inflammation. Conversely, enhancingO-GlcNAc levels have also been demonstrated being protective against myocardial ischemia/reperfusion injury. We recently demonstrated that hyperglycemia increases oxidative stress and HBP flux in endothelial cells and enhances endothelial expression of vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in response to tumor necrosis factor-α (TNFα) through oxidative stress rather than HBP pathway. Here we present further complementary data showing that enhancingO-GlcNAc levels by glucosamine does not mimic hyperglycemia's effect on TNFα-induced endothelial VCAM-1 and ICAM-1 expression. Glucosamine however inhibits ICAM-1 (not VCAM-1) expression and induces superoxide generation in the cells. The results further suggest that increasedO-GlcNAc levels do not mediate the enhancing effect of hyperglycemia on the endothelial inflammatory responses to TNFα. In contrast, it exerts certain anti-inflammatory effects accompanied by pro-oxidative properties. Further work should delineate the exact role of HPB pathway in different aspects of cardiovascular functions, especially those of diabetic cardiovascular complications.

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Schelbach, C., M. Lane, K. L. Kind, and J. G. Thompson. "235. Abberant murine embryonic development following glucosamine exposure during IVM or embryo culture." Reproduction, Fertility and Development 17, no. 9 (2005): 92. http://dx.doi.org/10.1071/srb05abs235.

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The hexosamine biosynthesis pathway is an alternate fate for glucose metabolism providing glycosylation moieties and is significantly upregulated by addition of glucosamine, a common dietary supplement. Here we determined the impact of glucosamine addition to cumulus oocyte complex (COC) maturation or during embryo culture on subsequent embryonic development. COCs were collected from 23-day-old mice 46 h post-eCG, and matured under several conditions prior to being fertilized and cultured: (1) 10mL/COC a MEM (5.56mM glucose) + 0, 1.25 or 5mM glucosamine; (2) 10mL/COC a MEM (20mM glucose) + 0, 1.25 or 5mM glucosamine; (3) 100mL/COC G2.3 (5mM glucose) + 0, 1.25 or 2.5mM glucosamine. One-cell embryos were also flushed from age-matched donors 24 h after mating and cultured in 0, 1.25 or 2.5mM glucosamine in G 1.3/2.3 sequential media. No differences in rates of embryonic development were detected between COCs matured in 10mL of media with 5.56mM glucose with glucosamine. However, blastocyst formation was significantly impaired (P<0.001) when COC maturation occurred in equivalent volumes of media that contained 20mM glucose + 1.25mM (49.98%) or 5mM glucosamine (44.7%) v. control (86.55%). Intriguingly, embryonic viability was significantly (P<0.001) reduced in COCs matured in 100mL G2.3 containing 5mM glucose + 1.25mM (44.6%) or 2.5mM glucosamine (40.1%) v. control (79.81%), suggesting a volume × glucose concentration interaction. In contrast, embryonic development was significantly reduced (34%, P < 0.002) and completely ablated when 1-cell embryos were cultured in media containing 1.25mM and 2.5mM glucosamine, respectively (control = 88.57%). These results suggest that glucosamine up-regulated hexosamine pathway activity in both COCs and early embryos impairs subsequent embryonic development by as yet undescribed mechanisms. Funded by NIH and NHMRC

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Li, Siqiang, Yun Li, Fujia Chen, Yurong Yang, Li Song, Chaoying Liu, Baogen Wang, Yuanhong Xu, Mingguang Shao, and Enzhong Li. "Metabolomics analysis reveals metabolic changes associated with trans-resveratrol treatment in experimental cryptorchidism mice." Reproduction, Fertility and Development 33, no. 5 (2021): 328. http://dx.doi.org/10.1071/rd20189.

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This study aimed to analyse global metabolomic changes associated with trans-resveratrol (RSV) treatment in mice with cryptorchidism using untargeted metabolomics. Cryptorchidism was established surgically in Kunming mice, which were then treated with 20µg g–1 day–1, s.c., RSV for 35 consecutive days. Typical manifestations of spermatogenesis arrest were seen in mice with cryptorchidism, and RSV treatment for 35 days restored spermatogenesis. Liquid chromatography–tandem mass spectrometry was used to profile the metabolome of testes from mice in the control (non-cryptorchid, untreated), cryptorchid and RSV-treated cryptorchid groups. In all, 1386 and 179 differential metabolites were detected in the positive and negative modes respectively. Seven and six potential biomarkers were screened for spermatogenesis arrest and restoration respectively. Pathway analysis showed changes in 197 metabolic pathways. The hexosamine biosynthesis pathway was inhibited in the cryptorchid group, which probably resulted in a decrease in the end product, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Immunoblot analysis showed that total testicular protein O-linked β-N-acetylglucosamine glycosylation was related to spermatogenesis arrest, further indicating a decrease in UDP-GlcNAc in the cryptorchid group. Thus, untargeted metabolomics revealed the biochemical pathways associated with the restoration of metabolic status in the cryptorchid group following RSV treatment and the findings could be used to monitor the response to RSV treatment. This study provides a meaningful foundation for the future clinical application of RSV in the treatment of spermatogenesis dysfunction.

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Wang, Qiming, Peining Fang, Rui He, Mengqi Li, Haisheng Yu, Li Zhou, Yu Yi, et al. "O-GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5." Science Advances 6, no. 16 (April 2020): eaaz7086. http://dx.doi.org/10.1126/sciadv.aaz7086.

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In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.

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