GlycoBio: Clinical Flashcards
HbA1C and Type II Diabetes
Most common gylcated Hb = HbA1C
HbA1C forms spontaneously proportional to the blood glucose conc.
Good indicator for blood glucose over the preceding 6-8 weeks
Normal levels = 5%
Pre-diabetic = 5.7-6.4
Diabetic > 6.5
Hemaggulinin
Sialic acid binding lectin
Found in envelope protein of H1N1
Along with neuraminidase
Mechanism of H1N1 (swine flu)
Interaction #1:
Hemagglutinin on the viral surface with a host receptor (sialic acid) on host membrane surface….respiratory epithelial cell
Result = cell entry
Interaction #2: inside cell
Replicates
Eventually the cell will rupture and virus can escape
(H) on new viral particle attaches to dead cell membrane (SA)
(N) cleaves SA from membrane…so the virus can leave that area and infect other cells
Oseltamivir (Tamiflu) and Zanamivir (Relenza)
Neuraminidase inhibitors
So H1N1virus cannot spread after rupturing cell
So stops spreading…not initial infection
Mucopolysacchardoses (MPS)
General
Caused by deficiency of enzymes for the degradation of GAGs
Symptoms:
Coarse facial features
Hepatospenomegaly
Bone deformity
Mental retardation
Most common types:
Hurler/Schei (MPS I) - AR
Hunter (II) - X-link
Sanfilippo (III) - AR
Morquio (IV) - AR
Hurler Syndrome (MPS I)
GAGs: DS and HS
Enzyme: alpha-L-Iduronidase
Reaction: 2nd step in the degradation process of these GAGs
Involves the removal of the Iduronic acid after the sulfate group was removed (1st step)
TREATMENT: ERT (adlurazyme, laronidase) - non-neuro symptoms only
Hunter Syndrome (MPS II)
GAGs: DS and HS
Enzyme: Iduronate sulfatase
Reaction: removal of the sulfate group on the 2-S-L-IdoA….need to do this in order to remove that acid all together
TREATMENT: enzyme replacement therapy (Elaprase, idusulfase)…only non-neuro symptoms
Sanfillipo Syndrome (MPS III)
GAGs: HS (2-S-L-IdoA successfully cleaved away)
Enzyme: Heparan N-sulfatase (Type A), Acetyl-CoA acetyl transferase (Type C), alpha-N-acetylglucosaminidase (Type B)
1st reaction: removal of sulfate group
2nd reaction: acetyl group is added to the xposed NH2 group to form a terminal GlcNAc
3rd reaction: GlcNAc removed
Morquio Syndrome (MPS IV)
GAGs: KS (terminal Gal-6S)
Enzyme: N-acetylgalactosamine-6-sulfatase (Type A), beta-galactosidase (Type B)
1st reaction: removal of sulfate group generating a terminal galactose residue
2nd reaction: terminal galactose is removed
Morquio Type B
Vs.
Krabbe Disease
Both are a due to a defect in a galactosidase
But the enzymes are from 2 different loci, distinct from one another
—> so enzymes are not the same…active sites and substrates are not the same
Morquio Type B:
- substrate = KS
- terminal galactose connected to a N-acetylglucosamine in a GAG (MPS)
Krabbe:
- substrate = galactocerebroside
- terminal galactose is bound to ceramide (lipid)
Morquio Type B
Vs.
GM1-gangliosidosis
Defect in cleaving a terminal galactose (beta1,3) is the issue in both
ALSO, in both KS (Morquio) and GM1…
The terminal galactose is bound to a GalNAc
(N-acetylgalactosamine)
THEREFORE, the same enzyme is involved in both….so if that enzyme is defective…can cause a buildup in both KS and GM1
Still considered two separate diseases though
The 4 common sphingolipidoses (abnormal GSLs)
Fabry
Gaucher
Krabbe
Tay-Sachs
**all recessive except Fabry (X-linked)
Fabry Disease
Gb3 catabolism disorder…accumulation in kidney, heart, skin, and other visceral organs
Symptoms: hemizygous male with skin lesions, fever, burning pain
Death occurs in adult life from renal and cardiac failure
Mutation of alpha-galactosidase A
ERT (Fabrazyme)= may be good for slowing progression….otherwise dialysis or kidney transplants
Gaucher disease
Most common LSD
Deficiency in glucocerebrosidase (beta-glucosidase)
Accumulation of GlcCer is tissue macrophages…which become engorge Gaucher Cells
Type 1 = adult form, non neuropathic
Type 2 = acute neuropathic form
Type 3 = subacture neuropathic form
ERT = only effective for Type 1 because no neuro
General symptoms
Hepatosplenomegaly
Osteoporesis of long bones
CNS impairment in rare infantile and juvenile forms
Krabbe Disease
= globoid cell leukodystrophy
Severe demyelination of the CNS and PNS
Deficiency in lysosomal galactocerebrosidase (GALC or beta-galastosidase)
Needed to catabolize GalCer —> Gal + Cer
***NO accumulation of GalCer
Instead the galactosylsphingosine (psychosine) is elevated in the brain
—> leads to early destruction of oligodendroglia (which produce much of the GalCer)
GALC degrades psychosine too…
Symptoms:
Mental and motor retard
Blindness and deafness
Near total loos of myelin
Globoid bodes in white matter of brain
Classical Tay Sachs (GM2-gangliosidosis)
The terminal GalNAc in GM2 is hydrolyzed by HexA (not HexB)
Therefore caused by a HexA deficiency…which is a heterodimer (Hex B is a homodimer
Variants of TAY can be caused by deficiency in Hex A, B, or GM2 activator
Symptoms:
- rapid progessive neuro shit
- blindness
- cherry red macula
- muscular weakness
- seizures
Tay Sachs Variant B
Defect in alpha chain…so HexA is only one affected
Cannot digest GM2
HexB and cofactor are fine
Tay Sachs variant O (Sandoff)
Beta chain —> both HexA and B are affected
cofactor is fine
…cannot digest both Gb4 and GM2
Can also have issues digesting GalNAc from glycoproteins as well as GalNAc containing GSLs
More severe than classical but similar symptoms
- same neuro as classical…but now visceral is involved as well
Variant AB
Tay sachs
GM2 activator fucked
HexA and B are fine
Cannot digest GM2
Can digest Gb4
Blood group A
Possess the A antigen on RBC surface
Antibodies against antigen B
Can accept from A or with apcked RBCs (no plamsa) from O
Blood group B
Antigen B on surface
Anti-antigen A antibodies
Can accept from B or O (no plasma)
Blood group AB
Possess A and B on surface
Neither antibody
Accept from AB and packed RBCs from A, B, and O
‘Universal recepient’
Blood group O
Possess H antigens on the surface
Both antibodies expressed
Can only accept from O
Can donate to any (universal donor)
The major phosphoglycerides involved in neonatal respiratory distress syndrome (RDS)
DPPC and PC
-give mother an injection of glucocorticoids to promote surfactant production
How is surfactant production measured clinically
Look at the Lecithin:Sphingomyelin ration
Control lipid = SM
Measured in fetal amniotic fluid
<1.5 = lungs still immature
1.5-1.9 = transitional
> 2.0 = mature
Primary vs secondary RDS
Primary = not enough production (usually neonatal)
Secondary = surfactant not allowed to work properly…could be due to edema…surfactant too diluted
Zellweger syndrome
Defect in peroxisome biogenesis…
Where plasmalogens are made, so their production is compromised
Usually leads to death in 6mo-1yr
Sphingomyelinase
Cleaves between the ceramide and phosphocholine
Involved in Niemann Pick Type A and B
Niemann Pick Type A
Most severe
Enlarged liver and spleen
Mental retard
Neurodegeneration
Early death
Excessive build up of SM in CNS
Niemann Pick Type B
Less severe
Still some sphingomyelinase activity
Usually survive into adulthood
Farber disease
Ceramidase deficiency
(Cer —> sphingosine + FA)
Accumulation of ceramides
SYMPTOMS:
- Painful, progressive joint shit
- subcutaneous nodules of lipid cells
- hoarse cry
- tissues show granulomas
GM1 gangliosidosis
Enzyme: beta-galactosidase
GM1 and KS accumulation
SYMPTOMS:
Neuro shit
Hepatosplenomegaly
Skeletal deformities
Cherry red macula
Metachromatic leukodystrophy
Arylsulfatase deficiency
(Sulfatide —> desulfation fo galactosylcerbroside)
Accumulations of sulfatide
Symptoms:
Cognitive shit
Demyelination
Progressive paralysis
Dementia in adult form
Nerves stain yellowish brown with cresyl violet (metachromasia)
