The Hexosamine Biosynthesis Pathway: Regulation and Function

Abstract

The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.

Synthesis and anti-inflammatory activities of two new N-acetyl glucosamine derivatives

“…A single pair of enzymes, β-N-acetylglucosaminyl transferase (O-GlcNAc transferase, OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA), are involved in regulation of the dynamic cycling of this protein modification. OGT transfers the GlcNAc moiety from uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of serine or threonine residues, while OGA cleaves the GlcNAc from the modified protein 23 . Dysregulation of O-GlcNAcylation is associated with a variety of human diseases, including cancer, diabetes and neurodegenerative diseases.…”

“…Dysregulation of O-GlcNAcylation is associated with a variety of human diseases, including cancer, diabetes and neurodegenerative diseases. Therefore, emerging evidence suggests that protein O-GlcNAcylation would be a promising therapeutic target 23 , 24 .…”

Metabolism-driven glycosylation represents therapeutic opportunities in interstitial lung diseases

“…The main building block for glycans is uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), synthesized in the hexosamine biosynthetic pathway (HBP) ( 97 ) ( Figure 2 ). This pathway requires several substrates such as fructose-6-phosphate (from glucose metabolism), glutamine (from amino acids metabolism), acetyl-CoA (from fatty acids metabolism) and UDP (from nucleotide metabolism).…”

Selective analysis of intracellular UDP-GlcNAc and UDP-GalNAc by hydrophilic interaction liquid chromatography-mass spectrometry

“…[1][2][3][4] UDP-GlcNAc is particularly important in living organisms since it serves as the key donor substrate for the post-translational modication of protein O-GlcNAcylation. This molecule is synthesized as the end product of a glucose metabolism pathway (the hexosamine biosynthetic pathway) 5 and is subsequently interconverted by an epimerase to UDP-GalNAc, which acts as a sugar donor initiating mucin-type O-linked glycosylation 6 (Fig. 1).…”