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Review
. 2015 Jun 25:5:138.
doi: 10.3389/fonc.2015.00138. eCollection 2015.

Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Developing of Drugs Against Cancer

Andréia Vasconcelos-Dos-Santos  1 , Isadora A Oliveira  1 , Miguel Clodomiro Lucena  1 , Natalia Rodrigues Mantuano  1 , Stephen A Whelan  2 , Wagner Barbosa Dias  1 , Adriane Regina Todeschini  1
Affiliations
Review

Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Developing of Drugs Against Cancer

Andréia Vasconcelos-Dos-Santos et al. Front Oncol. .

Abstract

Cancer cells depend on altered metabolism and nutrient uptake to generate and keep the malignant phenotype. The hexosamine biosynthetic pathway is a branch of glucose metabolism that produces UDP-GlcNAc and its derivatives, UDP-GalNAc and CMP-Neu5Ac and donor substrates used in the production of glycoproteins and glycolipids. Growing evidence demonstrates that alteration of the pool of activated substrates might lead to different glycosylation and cell signaling. It is already well established that aberrant glycosylation can modulate tumor growth and malignant transformation in different cancer types. Therefore, biosynthetic machinery involved in the assembly of aberrant glycans are becoming prominent targets for anti-tumor drugs. This review describes three classes of glycosylation, O-GlcNAcylation, N-linked, and mucin type O-linked glycosylation, involved in tumor progression, their biosynthesis and highlights the available inhibitors as potential anti-tumor drugs.

Keywords: N-linked glycan; O-linked glycan; cancer; glycans; glycoconjugate; glycosyltransferases; hexosamine biosynthetic pathway; inhibitors.

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Figures

Figure 1
Figure 1
The synthesis of glycoconjugates from glucose through the hexosamine biosynthetic pathway (HBP). After glucose entry into the cell via the glucose transport, it is phosphorylated into glucose-6-phosphate (Glc-6P) by hexokinase (HK), mainly proceeding into glycolysis through conversion into fructose-6­-phosphate (Fru-6P) by Glc-6P isomerase. Alternatively, Glc-6P may be utilized by the pentose phosphate pathway (PPP). Glc-6P can also be diverted to glucosamine-6-phosphate by the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT) (c). The end product of this pathway, uridinediphosphoglucose-N-acetylglucosamine (UDP-GlcNAc) (d) serves to build extracellular glycoconjugates (a), as well as, it is used for the biosynthesis of intracellular O-linked glycoproteins (b) by the enzyme O-GlcNAc transferase. Alternatively, UDP-GlcNAc can undergo epimerization to generate UDP-GalNAc (e) and CMP-Neu5Ac (f) which can be used for the extracellular biosynthesis of glycoproteins and glycolipids (a) UDP-GlcNAc and its derivatives are extremely responsive to variations in cell nutrients as its synthesis depends on products of the metabolism of glucose (green), amino acids (blue), fatty acids (red), and nucleotides (orange). Thus, glycosylation can serve as a reporter for the functional status of multiple pathways and considered a metabolic sensor.
Figure 2
Figure 2
Schematic representation of biosynthesis and processing of N-linked oligosaccharides showing known inhibitors and key targets for inhibition. Inhibitors of the lipid-linked saccharide pathway (LSPi), tunicamycin, castanopermine (Cast), 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (DMJ), swansonine, and indolizidine (Indol).
Figure 3
Figure 3
Schematic representation of biosynthesis and processing of O-linked oligosaccharides showing known inhibitors and key targets for inhibition.
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