Glycobiology II - Ullo 3/9/16 Flashcards
lipids basics
hydrophobic - allows them to serve as compartments in polar environment of the body
examples:
lipoproteins: transport of fats
TAGs: storage of fats
membrane lipids: structural/functional components of cells
classification of lipids
based on backbone (glycerol vs. sphingolipid)
glycerol lipids - neutral
- TAGs: adipose stores, lipoproteins
- *glyceroPLs: phosphotidylcholine, phosphotidylinositol
- ether glycerolipids: plasmalogens, platelet af
sphingolipids - polar
- *sphingoPLs: sphingomyelin
- *glycolipids: globosides, gangliosides
glycerophospholipids: structure, fx
structure: glycerol backbone + 2 FA tails + phosphatidic acid (PA)
PA has a P moeity that is esterified with other compounds
- PA + choline = phosphatidylcholine (lecithin)
- PA + inositol = phosphatidylinositol (PI)
fx
- membrane-related
- major const of cell membrane
- anchor proteins in membranes
- intracellular signaling (PI)
- other
- component of bile
- component of lipoprotein
- component of lung surfactant (lecithin)
phosphatidylcholine (PC)
aka
lecithin
can be synthesized de novo (choline + ethanolamine; liver PS), BUT de novo synth isn’t sufficient for our needs
dietary sources: meat, fish, eggs, soybean, wheat germ, broccoli, PB, milk choc
fx
- structural component of membranes
- mild detergent in bile : def can lead to poor solubilization → gallstones!
- part of alveolar surfactant : prevents alveolar collapse during expiration
lecithin : role in lungs
alveolar surfactant: reduces surface tension of fluid lining alveolar surface → prevents alveolar collapse during expiration
- if collapse occurs, need 10x pressure to reinflate
- bc surfactant is present, no collapse occurs, and you need less pressure to reinflate
respiratory distress syndrome (RDS)
infant: cause, diagnosis, tx
adult: cause
hyaline membrane disease
premature infants at risk bc they havent had time to produce/secrete req amts of PLs
- screen amniotic fluid via amniocentesis & chromatography for L/S ratio (lecithin:sphingomyelin) → more lecithin, better chance of good resp
- L/S 2 or more? good. L/S 1.5 or less? high risk for infant RDS
tx: mom given glucocorticoids before delivery to induce surfactant production; baby supplemented with nat/synth surfactant
can also occur in adults in cases of damage/destruction to pneumocytes (surfactant-producing cells) from infection, trauma, chemo, immunosuppression
glycolipids
sphingosine backbone + FA tail + carbohydrate tail
- derivatives of ceramides
- essential component of all membranes - esp high levels in nerve tissue
- located in outer leaflet → interact with extracellular environment
- roles in cellular interactions, growth and devpt
- antigenic blood group antigens; cell surface receptors for cholera, tetanus, others
synthesis of glycosphingo lipids
key types
synthesis occurs in Golgi
ceramide backbone with addition of glycosyl monomers from UDP-sugar donors [glycosyltransferases]
sulfatide: brain, nerve tissue, kidney
ganglioside: ganglion cells of CNS
degradation of glycosphingolipids
lysosomal degradation via acid hydrolases, “last on, first off” removal of residues
disorders in degradation: sphingolipidoses → accumulation in lysosomes
- dramatic effects in nerve tissues, possible neuro degen leading to early death
sphingophospholipid
sphingosine backbone (amino alcohol) + FA tail + P attached to head group
sphingomyelin is an imp component of nerve fiber myelin (insulates nerve cells and allow faster conduction)
- immediate precursor: ceramide
degradation of sphingophospholipids
(sphingomyelin)
sphingomyelinase is a lysosomal enzyme that (variant of phospholipase C) catalyzes release of phosphatidylcholine, release of ceramide
- defect in breakdown of sphingomyelin → diseases like Niemann Pick
sphingomyelin buildup has severe conseqs
- kidney, liver enlargment
- severe mental retardation
- death
Tay Sach’s disease
inability to break down:
GM2 → GM3 [→glucocerebroside → ceramide] due to beta hexosaminidase A deficiency
genetics: autosomal recessive, most common in E Euro Jewish families (Ashkenazi)
basic patho: beta hexosaminidase A deficiency → accumulation of gangliosides
diagnosis: assay showing decreased serum/leukocyte levels of beta hexosaminidase A
symptoms: normal at birth, progressive neuro dysfx with age (cherry red spot, seizures, loss of vision, poor growth, ataxia, motor retardation/weakness)
tx: none; supportive care until death (usually by 3)
Niemann Pick diease
inability to break down :
sphingomyelin → ceramide due to defect in sphingomyelinase, leading to accumulation of sphingomyelin
genetics: autosomal recessive, common in Ashkenazi Jews
basic patho: sphingomyelinase deficiency → accumulation of sphingomyelin
diagnosis: clinical presentation + DNA testing
symptoms: normal at birth, regression of acquired motor/social skills. progressive neuro dysfx concurrent with progressive demyelination
- cherry red spot on macula of eye (background pale due to lipid deposition, macula red bc doesn’t have much membrane on it)
-
hepato/splenomegaly: accumulation of macrophages (conc in liver, spleen, marrow) that have become enlarged due to buildup of sphingomyelin
- foamy-appearing cells containing sphingomyelin (bc not broken down)
- xanthomas
- pancytopenia (unique to NPD, along with hepatomegaly, as compared with TaySachs)
tx: none; supportive care until death (usually by 3)
Fabry disease
inability to break down:
ceramide trihexoside → glucocerebroside [→ ceramide] due to alpha galactosidase
genetics: X linked recessive
basic patho: alpha galactosidase A deficiency → accumulation of ceramide trihexoside
diagnosis: clinical presentation + alpha galactosidase activity
symptoms: varies with age of onset (worse over time)
- corneal clouding (vision unaffected)
- angiokeratoma (benign cutaneous lesions of caps) - painless papular rash
- acroparasthesia (tingling in fingers/toes) and pain
- kidney failure (high creatine, proteinuria, HTN)
- fatigue, cardiomyopathy
tx: enzyme replacement therapy with alpha galactosidase (Fabrazyme); male/female expectancy 58/75 due to cardiac and renal disease - less severe in females bc X linked.
F - febrile
A - alpha galactosidase
B - burning pain/neuropathy
R - renal failure
Y - youth disease
Krabbe disease
low levels of beta galactocerebrosidase activity
genetics: autosomal recessive
basic patho: beta galactocerebrosidase deficiency → accumulation of galactocerebroside
diagnosis: clinical presentation + brain imaging + DNA testing
symptoms: varies based on age of onset. gross neuro deficits, hyperactive reflexes, optic atrophy, devpt delay/regression
- classic histo finding: globoid cell (multinucleated macrophage) in intracranial tissue
tx: none; early stem cell replacement might help. supportive care until death (usually 2)
- adult-onset has slower progression, longer lifespan
