Glycan and disease. Classification of human diseases known to be related to glycans. Infectious disease Bacterial and viral infection Parasite infection Genetic disorders Glycan synthesis/degradation related Glycosylation related Acquired diseases Cancer.
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Classification of human diseases known to be related to glycans • Infectious disease • Bacterial and viral infection • Parasite infection • Genetic disorders • Glycan synthesis/degradation related • Glycosylation related • Acquired diseases • Cancer
Polysaccharides on bacterial surface • Polysaccharide capsule • Covers bacterial surface • Targets of immune clearance • Human’s ability to generate antibody responses against bacteria diminished at extremes of age • Certain bacteria avoid antibody defenses through molecular mimicry of common host glycan structure • group A Streptococcus (GAS): capsule of hyaluronan, identical to the nonsulfatedglycosaminoglycan • Neisseriameningitidis: homopolymericsialic acid capsules • Certain pathogens has the great diversity of capsular structures • Can be used to classify different “serotype” strains • Individuals can be repeatedly infected over their lifetime by different serotype strains of the same bacterial pathogen • Genetic exchange of capsule biosynthetic genes among serotype strains of a specific species (e.g., the polysialyltransferase gene in meningococcus) can lead to capsule switching in vivo
Glycan adhesins and receptors • Most microorganisms express more than one type of adhesins (mainly lectins) • mediated through terminal sugars or internal motifs.
Polymicrobial biofilm • Biofilm formation is a mechanism that promotes bacterial attachment to host surfaces; • Bacteria within biofilms communicate with one another through soluble signaling molecules in a process known as “quorum sensing” to optimize gene expression for survival; • In biofilms, bacteria live under nutrient limitation and in a dormant state in which defense molecules (e.g., antimicrobial peptides) produced by the immune system and pharmacologic antibiotics are less effective; • The excellularpolysaccahride (EPS) matrix can bind and inactivate the defense molecules, contributing to the persistence of the biofilm and difficulty in medical treatment of biofilm infections.
Defects in glycosaminoglycan degradation—the mucopolysaccharidoses
Therapies of lysosomal enzyme deficiency • Enzyme replacement therapy (ERT) • Injection of defective enzymes • Enzyme enhancement therapy (EET) • The inhibitors of the enzymes behave as molecular chaperones to stabilize the mutated enzymes in the endoplasmic reticulum to prevent their misfolding and proteasomal degradation • Even though SRT seems promising, the expected benefits to date have been minimal. • Substrate reduction therapy (SRT) • Reducing a glycan’s synthetic rate by can offset the effects of low glycosidase activity
Genetic disorder of glycosylations • Inherited disorders occurred in all major glycan synthesis • N-glycan assembly: congenital disorders of glycosylation (CDG) • Galactose metabolism: Galactosemia • Synthesis of the core region of xylose-based GAG chains: Ehlers–Danlos Syndrome • Defects in the formation of heparan sulfate (HS): hereditary multiple exostosis
Altered glycosylation in cancer • Increased β1-6GlcNAc branching of N-glycans; • Changes in the amount, linkage, and acetylation of sialic acids; • Truncation of O-glycans, leading to expression of Tn and sialylTn antigens; • Expression of the nonhuman sialic acid N-glycolylneuraminic acid, likely incorporated from dietary sources; • Expression of sialylated Lewis structures and selectin ligands; • Altered expression and enhanced shedding of glycosphingolipids; • Increased expression of galectins and poly-N-acetyllactosamines; • Altered expression of ABH(O) blood-group-related structures; • Alterations in sulfation of glycosaminoglycans; • Increased expression of hyaluronan • Loss of expression of GPI lipid anchors.