Biological functions of fucose in mammals

Abstract

Fucose is a 6-deoxy hexose in the l-configuration found in a large variety of different organisms. In mammals, fucose is incorporated into N-glycans, O-glycans and glycolipids by 13 fucosyltransferases, all of which utilize the nucleotide-charged form, GDP-fucose, to modify targets. Three of the fucosyltransferases, FUT8, FUT12/POFUT1 and FUT13/POFUT2, are essential for proper development in mice. Fucose modifications have also been implicated in many other biological functions including immunity and cancer. Congenital mutations of a Golgi apparatus localized GDP-fucose transporter causes leukocyte adhesion deficiency type II, which results in severe developmental and immune deficiencies, highlighting the important role fucose plays in these processes. Additionally, changes in levels of fucosylated proteins have proven as useful tools for determining cancer diagnosis and prognosis. Chemically modified fucose analogs can be used to alter many of these fucose dependent processes or as tools to better understand them. In this review, we summarize the known roles of fucose in mammalian physiology and pathophysiology. Additionally, we discuss recent therapeutic advances for cancer and other diseases that are a direct result of our improved understanding of the role that fucose plays in these systems.

Synthetic and Crystallographic Insight into Exploiting sp2 Hybridization in the Development of α‐l‐Fucosidase Inhibitors

“…[1] Reflecting the important roles of this carbohydrate motif, there are specific enzymes, termed a-l-fucosidases( which are part of al arger class of enzymes termedg lycoside hydrolases [2] ), that act to cleave a-l-fucose moieties from glycoconjugates. Enzymes hydrolyzing fucose from glycoconjugates, a-l-fucosidases, are important targets for inhibitor and probe development.H ere we describe the synthesis and evaluation of novel a-l-fucosidase inhibitors, with X-ray crystallographic analysisu sing an a-l-fucosidase from Bacteroides thetaiotamicron helping to lay af oundation for future developmento fi nhibitors for this important enzymec lass.…”

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

“…Terminal fucosylation is a common modification found on many N -glycans, mucin O -GalNAc glycans, and glycolipids (36). At least ten fucosyltransferases ( FUT1–7 and FUT9–11 ) can function to add terminal fucose to oligosaccharide chains on these molecules leading to diverse biological functions and as well as is considerable redundancy (37). Studies in mice have shown that Fut4 and Fut7 are functionally redundant, and the much weaker contribution of Fut4 to fucosylation of selectin ligands to form sLe x was only revealed in the context of Fut7 deficiency (13).…”

Recognition of Complex Core‐Fucosylated N‐Glycans by a Mini Lectin

“…[1] This posttranslational modification regulates many biological processes such as cell adhesion or innate immunity.I ti sa ssociated with pathologies like cancers,w here altered glycosylation is ah allmark. [1] This posttranslational modification regulates many biological processes such as cell adhesion or innate immunity.I ti sa ssociated with pathologies like cancers,w here altered glycosylation is ah allmark.…”

“…[1] This posttranslational modification regulates many biological processes such as cell adhesion or innate immunity.I ti sa ssociated with pathologies like cancers,w here altered glycosylation is ah allmark. [3] Several core-fucosylated glycoproteins,s uch as alpha-fetoprotein (AFP-L3), [1,2] prostate-specific antigen (PSA), [4] or haptoglobin [5] are used as serological biomarkers for the detection of hepatocellular carcinoma, prostate,a nd pancreatic cancers, respectively.Core fucosylation strongly affects the bioactivity of therapeutical N-glycoproteins.Its presence in the Fc region of monoclonal antibodies (mABs) impairs their recognition by FcgRIIIA receptors and thus,l owers their efficacy in antibody-dependent cellular cytotoxicity (ADCC). [3] Several core-fucosylated glycoproteins,s uch as alpha-fetoprotein (AFP-L3), [1,2] prostate-specific antigen (PSA), [4] or haptoglobin [5] are used as serological biomarkers for the detection of hepatocellular carcinoma, prostate,a nd pancreatic cancers, respectively.Core fucosylation strongly affects the bioactivity of therapeutical N-glycoproteins.Its presence in the Fc region of monoclonal antibodies (mABs) impairs their recognition by FcgRIIIA receptors and thus,l owers their efficacy in antibody-dependent cellular cytotoxicity (ADCC).…”

“…Ac leavable and His6-tagged N-terminal fusion comprising the disulfide isomerase DsbA with its signal sequence was introduced to promote export into the periplasmic space,i ntroduce disulfide bonds into the nascent protein, and improve protein folding [11] (Figure 1a). Core-fucosylated biantennary oligosaccharide azides (1)(2)(3) used in this study. Core-fucosylated biantennary oligosaccharide azides (1)(2)(3) used in this study.…”