bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2025–05–11
two papers selected by
Silvia Radenkovic, UMC Utrecht



  1. Sci Rep. 2025 May 07. 15(1): 15929
      Phosphomannomutase-2 (PMM2) deficiency represents the most common congenital disorder of glycosylation (CDG). Currently, little is known about cell metabolic alterations occurring in these patients. Here, we quantified compounds connected to protein glycosylation (GDP-mannose, UDP-derivatives), energy metabolism (high-energy phosphates, nicotinic coenzymes, oxypurines), oxidative/nitrosative stress (GSH, nitrite, nitrate) and free amino acids in extracts of peripheral blood mononucleated cells (PBMCs), of seven PMM2-CDG patients and ten control healthy donors. Besides marked GDP-mannose decrease, PBMCs of PMM2-CDG patients had higher UDP-glucose (UDP-Glc), UDP-galactose (UDP-Gal) and UDP-Glucuronic levels, lower ATP, GTP and UTP levels, abnormal ATP/ADP, ATP/AMP and NAD+/NADH ratios, increased xanthine, uric acid and nitrite + nitrate levels, and decreased GSH and free amino acids concentrations. These results suggest a new, conceivable metabolic route leading to the increase of specific UDP-derivatives (UDP-Glc, UDP-Gal and UDP-Glucuronic), also potentially explaining the glycogen abnormalities recently found in PMM2-CDG patients. Altogether, this study highlighted various metabolic changes caused by PMM2 deficiency, illustrating the widespread effects of PMM2 mutations (beyond N-glycan biosynthesis) that may significantly vary depending on the cell line considered. Using PBMCs, as a cellular model of lower invasiveness than skin fibroblast, may advantage cell metabolism studies to investigate new therapies specifically targeted to PMM2 deficiency.
    Keywords:  Energy metabolism; HPLC; Peripheral blood mononucleated cells; Phosphomannomutase2 deficiency; Protein glycosylation; UDP-derivatives
    DOI:  https://doi.org/10.1038/s41598-025-98846-8
  2. Am J Physiol Gastrointest Liver Physiol. 2025 May 07.
      De novo lipogenesis (DNL) converts excess glucose into lipids, while the hexosamine biosynthetic pathway (HBP), a glycolytic branch, generates UDP-N-acetylglucosamine (UDP-GlcNAc) for protein glycosylation, including O-GlcNAcylation and N-linked glycosylation. Both pathways are active in hepatocytes and integral to glucose metabolism; however, their functional interplay remains unclear. Here, we investigated the role of HBP in hepatic DNL activation using both in vitro and in vivo models. AML12 hepatocytes were cultured in low- and high-glucose media with or without HBP blockade, both pharmacologically and genetically. For in vivo studies, male C57BL/6J mice were subjected to a fasting-refeeding regimen with or without intraperitoneal administration of azaserine, a competitive inhibitor of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), the rate-limiting enzyme of the HBP. Our results demonstrated that, in AML12 cells, glucose exposure activated both DNL and HBP, leading to triacylglycerol (TAG) accumulation, while HBP inhibition ameliorates DNL and TAG accumulation. In mice, refeeding after a 24-hour fasting induced hepatic DNL, which was abolished by HBP inhibition, indicating its mechanistic involvement in glucose-driven lipogenesis. Mechanistically, we identified ATF4 as a key regulator of GFPT1 upregulation under high-glucose conditions. As expected, both glucose-treated hepatocytes and livers from fasting-refed mice exhibited increased protein glycosylation. Notably, blocking N-linked glycosylation, but not O-GlcNAcylation, abolished glucose-induced DNL activation, indicating that HBP is essential for glucose-induced DNL pathway activation via promoting N-linked glycosylation, independent of O-GlcNAcylation. In conclusion, our findings establish that an intact HBP is required for glucose-induced hepatic DNL activation, primarily through promoting protein N-linked glycosylation.
    Keywords:  ATF4; GFPT1; GlcNAcylation; HBP; lipogenesis
    DOI:  https://doi.org/10.1152/ajpgi.00056.2025