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

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

nonsulfated glycosaminoglycan– Neisseria meningitidis: homopolymeric sialic 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 excellular polysaccahride (EPS) matrix can bind and inactivate the defense molecules, contributing to the persistence of the biofilm and difficulty in medical treatment of biofilm infections.

Polymicrobial biofilm (dental plaque)

Bacterial toxins binding to glycans and entering the host cell

Microorganism ToxinProposed receptor sequence Target tissue

Bacillus thuringiensis crystal toxins(killing plant-pathogenic insects)

Galβ1–3/6Galα/β1–3(±Glcβ1–6)GalNAcβ GlcNAcβ1–3Manβ1–4GlcβCer

intestinal epithelia of insects(only conserved in invertebrates, from nematode to insects)

Clostridium botulinum botulinum toxins (A–E) gangliosides GT1b, GQ1b

nerve membrane

Clostridium difficile toxin A GalNAcβ1–3Galβ1–4GlcNAcβ1–3Galβ1–4GlcβCer

large intestine

Clostridium tetani tetanus toxin ganglioside GT1b nerve membrane

Escherichia coli heat-labile toxin GM1 intestine

Shigella dysenteriae Shiga toxin Galα1–4GalβCer Galα1–4Galβ1–4GlcβCer

large intestine

Vibrio cholerae cholera toxin GM1 small intestine

Mechanism of virus entering the cell

Viral infection: glycan-GBP interaction

Virus Lectin Glycan receptor specificity Site of infection

Influenza A and B (human) hemagglutinin Neu5Acα2–6Gal upper respiratory tract mucosa

Influenza A and B (avian and porcine)

hemagglutinin Neu5Acα2–3Gal intestinal mucosa

Influenza C hemagglutinin-esterase 9-O-acetyl-Neu5Acα-

Newcastle disease hemagglutinin-neuraminidase Neu5Acα2–3Gal-

Sendai hemagglutinin-neuraminidase Neu5Acα2–8Neu5Ac-

Polyoma ? Neu5Acα2–3Gal-, etc

Herpes simplex glycoproteins gB, gC, gD 3-O-sulfated heparan sulfate mucosal surfaces of mouth, eyes, genital and respiratory tracts

Foot-and-mouth disease caspid proteins heparan sulfate

HIV gp120 V3 loop heparan sulfate CD4 lymphocytes

Dengue envelope protein heparan sulfate macrophages?

Glycan-GBP binding in parasite infectionParasite Stage Protein Specificity

Plasmodium falciparum merozoite EBA-175 Neu5Acα2-3Gal/glycophorin A

(causing malaria) merozoite EBA-140 sialic acid/glyco phorin B?

merozoite EBA-180 sialic acid (erythrocytes)

sporozoite circumsporozoite protein heparan sulfate (hepatocytes)

Trypanosoma cruzi trypomastigote trans-sialidase Neu5Acα2-3Gal

trypomastigote penetrin heparan sulfate

Entamoeba histolytica trophozoite Gal/GalNAc lectin Gal/GalNAc

Entamoeba invadens (a reptilian pathogen)

cyst cyst wall protein (Jacob lectin) chitin

Giardia lamblia trophozoite taglin (α-1 giardin) Man-6-phosphate heparan sulfate

Cryptosporidium parvum sporozoite Gal/GalNAc lectin Gal/GalNAc

sporozoite Cpa135 protein ?

Acanthamoeba keratitis trophozoite 136-kD mannose-binding protein

mannose

Toxocara canis larval TES-32 ?

Haemonchus contortus gut-localized galectin β-galactosides

Defects in glycoprotein degradation (in lysosomes) Disorder Defect Glycoprotein Glycolipid Clinical symptomsα-Mannosidosis (types I and II)

α-mannosidase major none type I: infantile onset, progressive mental retardation, hepatomegalytype II: juvenile/adult onset, milder, slowly progressive

β-Mannosidosis β-mannosidase major none severe quadriplegia; mild cases have mental retardation, angiokeratoma, facial dysmorphism

Aspartylglucosaminuria aspartyl-glucosaminidase

major none progressive, coarse facies, mental retardation

Sialidosis (mucolipidosis I)

sialidase major minor progressive, severe mucopolysaccharidosis-like features, mental retardation

Schindler (types I and II) α-N-acetyl-galactosaminidase

yes ? type I: infantile onset, neuroaxonal dystrophy, etctype II: mild intellectual impairment, angiokeratoma, etc

Galactosialidosis protective protein

major minor coarse facies, skeletal dysplasia, early death

Fucosidosis α-fucosidase major minor spectrum of severities includes psychomotor retardation, coarse facies

GM1 gangliosidosis β-galactosidase minor major progressive neurological disease and skeletal dysplasia in severe infantile form

GM2 gangliosidosis β-hexosaminidase

minor major slower onset of symptoms and variable symptoms, all relating to various parts of the central nervous system

Defects in glycosaminoglycan degradation—the mucopolysaccharidoses

Number Common name Enzyme deficiency Glycosamino-glycan affected

MPS I H Hurler, Hurler/Scheie, Scheie α-L-iduronidase DS, HS

MPS II Hunter iduronate-2-sulfatase DS, HS

MPS III A Sanfilippo A heparan N-sulfatase HS

MPS III B Sanfilippo B α-N-acetylglucos aminidase HS

MPS III C Sanfilippo C acetyl CoA: α-glucosaminide acetyltransferase

HS

MPS III D Sanfilippo D N-acetylglucosamine 6-sulfatase

HS

MPS IV A Morquio A galactose-6-sulfatase KS, CS

MPS IV B Morquio B β-galactosidase KS

MPS VI Maroteaux-Lamy N-acetylgalactosamine 4-sulfatase

DS

MPS VII Sly β-glucuronidase DS, HS, CS

multiple sulfatase deficiency sulfatase modifying factor converts cysteine→formyl glycine

all sulfated glycans

Defects in glycolipid degradationDisease name Enzyme or protein deficiency Clinical symptoms

Tay–Sachs β-hexosaminidase A severe: neurodegeneration, death by 4 years less severe: slower onset of symptoms, variable symptoms all relating to parts of the nervous system

Sandhoff β-hexosaminidase A and B same as Tay–Sachs

GM1 gangliosidosis β-galactosidase

Sialidosis sialidase

Fabry α-galactosidase severe pain, angiokeratoma, corneal opacities, death from renal or cerebrovascular disease

Gaucher’s β-glucoceramidase severe: childhood or infancy onset, hepatosplenomegaly, neurodegeneration mild: child/adult onset, no neurodegenerative course

Krabbe β-galactoceramidase early onset with progression to severe mental and motor deterioration

Metachromatic leukodystrophy arylsulfatase A (cerebroside sulfatase) infantile, juvenile, and adult forms can include mental regression, peripheral neuropathy, seizures, dementia

Saposin deficiency saposin precursor similar to Tay–Sachs and Sandhoff

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 sialyl Tn

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.