Transcript Glycan and disease

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
Proposed receptor
sequence
Microorganism
Toxin
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
Foot-and-mouth disease
caspid proteins
heparan sulfate
HIV
gp120 V3 loop
heparan sulfate
CD4 lymphocytes
Dengue
envelope protein
heparan sulfate
macrophages?
mucosal surfaces of mouth,
eyes, genital and respiratory
tracts
Glycan-GBP binding in parasite infection
Parasite
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)
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
Trypanosoma cruzi
Defects in glycoprotein degradation (in lysosomes)
Disorder
Defect
Glycoprotein Glycolipid Clinical symptoms
α-Mannosidosis
(types I and II)
α-mannosidase
major
none
type I: infantile onset, progressive
mental retardation, hepatomegaly
type II: juvenile/adult onset, milder,
slowly progressive
β-Mannosidosis
β-mannosidase
major
none
severe quadriplegia; mild cases have
mental retardation, angiokeratoma,
facial dysmorphism
Aspartylglucosaminuria
aspartylglucosaminidase
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-acetylgalactosaminida
se
yes
?
type I: infantile onset, neuroaxonal
dystrophy, etc
type 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
βhexosaminidase
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 6sulfatase
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 4sulfatase
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 degradation
Disease 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.