Glycolysis and the Hexosamine Biosynthetic Pathway as Novel Targets for Upper and Lower Airway Inflammation

Abstract

Glycolysis is a process that rapidly converts glucose to lactate to produce adenosine triphosphate (ATP) under anaerobic conditions and occurs in all eukaryotic and prokaryotic cells. On the other hand, the hexosamine biosynthetic pathway (HBP) converts glucose to intermediate products like UDP-N-acetylglucosamine, which is critical for post-translational modifications of proteins, such as protein glycosylation. These 2 pathways are well known to contribute to glucose metabolism, but recent studies indicate modulation of these pathways can alter immune system function. In this review article, the authors present results suggesting how cellular metabolism, including glycolysis and the HBP, occurs in immune cells, and the immunologic significances of such activities. In addition, they provide a review of the literature on the effects of glycolysis and the HBP on various autoimmune, immunologic, and allergic diseases. Finally, the authors briefly introduce the results of their research on the immunologic effects of HBP supplementation (glucosamine) in animal models of allergic disease.

Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling

“…However, we cannot exclude that ammonia generated from GlcN catabolism might also contribute to its effect [9]. GlcN can be taken up by glucose transporters and phosphorylated by hexokinase, and there is a competitive relationship between the HBP and glycolysis [34]. Although a portion of glucosamine enters the HBP, GlcN also enters glycolysis after glucosamine-6-phosphate (GlcN-6-P) is deaminated by GNPDA1 (glucosamine-6-phosphate deaminase 1), resulting in ammonia production [34].…”

“…GlcN can be taken up by glucose transporters and phosphorylated by hexokinase, and there is a competitive relationship between the HBP and glycolysis [34]. Although a portion of glucosamine enters the HBP, GlcN also enters glycolysis after glucosamine-6-phosphate (GlcN-6-P) is deaminated by GNPDA1 (glucosamine-6-phosphate deaminase 1), resulting in ammonia production [34]. Ammonia can cause autophagosome accumulation by interfering with lysosomal function [35].…”

Hyaluronan‐CD44/RHAMM interaction‐dependent cell proliferation and survival in lung cancer cells

“…The supply of UDP‐ N ‐Acetylglucosamine (UDP‐GlcNAc) and UDP glucuronic acid (UDP‐GlcUA), the substrates of HAS enzymes, could also be a limiting factor for HA synthesis . Accumulating evidence indicates that aerobic glycolysis, the hallmark of cancer, increases levels of UDP‐GlcNAc and UDP‐GlcUA and these effects are under the control of various oncogenic signals. In particular, oncogenic Kras , the most common oncogenic event in NSCLC, plays a vital role in the regulation of aerobic glycolysis, which suggests that Kras mutant cells could overproduce HA.…”

Metabolic control of gene transcription in non-alcoholic fatty liver disease: the role of the epigenome

“…Disruption of the OGT binding site in TET1 reduces genomic 5hmC levels, with a concurrent reduction in gene expression [117]. The post-translational addition of O -GlcNAcylation to proteins is promoted by the hexosamine biosynthetic pathway (HBP), which synthesises N -GlcNAc from glucose, linking elevated intracellular glucose to increased O -GlcNAcylation [118]. This generates a positive feedback loop, whereby the HBP diverts glucose away from glycolysis, and lowers αKG levels.…”