Unit 6 - Complex Lipids in Health and Disease Flashcards
what are the 3 families of lipids, and their subgroups?
- glycerolipids: TGs, glycerophospholipids, and ether glycerolipids
- phospholipids: glycerophospholipids, ether glycerolipids, and sphingophospholipids
- sphingolipids: sphingophospholipids and glycolipids
structure of glycerophospholipids
predominant phospholipids/glycerolipids in cell membranes
- amphipathic polar (alcohol) head group attached to DAG via phosphodiester bond to C3
- 2 nonpolar FA chains form ester bonds to C1/2
- -C2 FA often unsaturated
- -embedded in hydrophobic core of bilayer
what is the simplest glycerophospholipid?
phosphatidic acid
what are the 3 major glycerophospholipids in cell membranes?
phosphatidylserine
phosphatidylethanolamine
phosphatidylcholine
what is cardiolipin (diphosphatidyl glycerol)? where is it found? what does it do?
2 molecules of phosphatidic acid are esterified thru phosphate to a glycerol
- found in membranes of bacteria and eukaryotic cells, in IMM
- supports structure and function of certain respiratory complexes in ETC
structure of plasmalogens
FA at C1 has unsaturated alkyl group via ether linkage (unsaturated ether glycerophospholipids)
what are the 2 major plasmalogens (unsaturated ether glycerophospholipids) in mammals?
phosphatidalcholine (enriched in heart muscle)
phosphatidalserine
what is platelet activating factor?
has saturated alkyl group linked by ether linkage to C1 (saturated ether glycerolipid) and acetyl group at C2
-made by many cells, and binds to specific surface receptors stimulating thrombotic and acute inflammatory responses
what is sphingomyelin structure? what is special about sphingomyelin?
backbone is amino alcohol sphingosine
-LCFA attached to amino group, to make ceramide
-alcohol group at C1 of sphingosine becomes esterified to phosphoryl choline to make sphingomyelin
(ceramide = sphingosine + LCFA)
(sphingomyelin = ceramide + choline)
-SM is the only major spingophospholipid in humans, and found in many membranes
-highly enriched in myelin sheath
structure of glycosphingolipids
similar to sphingomyelin, except don’t have a phosphate group, but a sugar attached by an O-glycosidic bond
-the sugar is the polar head group, and the ceramide is the hydrophobic tail that inserts into hydrophobic core of membranes
what are cerebrosides? where are they found most
simple uncharged glycosphingolipids with one galactose or glucose
- found mostly in CNS and PNS tissue
- -enriched in myelin sheath
what are globosides?
ceramide oligosaccharides (attach monosaccharides to glucocerebroside) -include substituted sugars like N-acetyl galactosamine
what are gangliosides? what is their structure? where are they found?
derivatives of globosides, in that they have negatively charged acidic glycosphingolipids
- have one or more sialic acid residues and named M(ono), D(i), T(ri), Q(uatro), etc.
- -additional numbers designate sequence of sugars attached to ceramide
- found mostly in ganglion cells of CNS (enriched at nerve endings)
what are lipid rafts?
specialized choelsterol, sphingolipid, and glycolipid rich domains within membrane leaflets that regulate activity of membrane enzymes and receptors
-diverse assembly of signaling molecules, involvement in membrane PRO and receptor trafficking, regulating neurotransmission
what are the 2 pathways for phospholipid synthesis? where does it start?
both start with phosphatidic acid in SER
- Pi cleaved by phosphatase to make DAG, which reacts with activated CDP-head group to make glycerophospholipid and release CMP
- PA reacts with CTP to release PPi and CDP-DAG, which interacts with G3P (makes phosphatidylglycerol) or PG (makes cardiolipid or inositol to make phosphatidylinositol)
what are interconversions that can occur between phospholipids?
- PS formed by base exchange RXN from PE, and converted back by decarboxylase with PLP (B6) coenzyme
- PE converted to PC by 3 methylations of head group, by N-methyltransferase with SAM methyl donor
what is dipalmitoylphosphatidylcholine and how is it related to respiratory distress syndrome?
DPPC is PC with C1 and C2 esterified to palmitate
- produced and secreted by type II pneumocytes, and major lipid component of surfactant (along with apo-PRO Sp-A/B/C, PG, and cholesterol
- deficiency will caues RDS in neonates
how are cardiolipin and PI (glyceroPLs) made?
phosphatidic acid + CTP –> CDP-DAG
- if inositol is added, PI is made, which can make PIP2
- if phosphatidylglycerol is made, cardiolipin is made
how is plasmalogen made?
DHAP (from glycolysis) C1 reacts with fatty acyl
- FA exchanged for fatty alcohol made by reduction of FA by 2 NADPH to make ether linkage
- keto gorup of C2 is reduced to alcohol, and FA esterified into C2
- polar head groups added as normal
- final reduction of alkyl group in ether linkage to C1 makes alkenyl group of plasmologen (DB between C1 and C2)
what is Zellweger’s syndrome?
decreased plasmalogen causes decreased peroxisomes
how is ceramide made?
serine + PCoA –> dihydrosphingosine + CoA + CO2
- 22 C FA-CoA acylated at amino group to make amide bond
- product is oxidized, DB is formed, and ceramide created
what is ceramide the precursor of?
sphingolipids
what do glycosyl transferases do?
add CHO monomers to ceramide to make globosides (more than 1 CHO)
what do sulfotransferases do?
use sulfate carrier PAPS to convert galactocerebroside to sulfatide (negative charge)
how are glycerophospholipids degraded?
phospholipases in all tissues and pancreatic juice (also snake/bee venom, pathogenic bacteria)
where and what does phospholipase A1 do?
present in mammalian tissues
-cleaves off FA at C1 and C2, leaving behind lysophospholipids
what are lysophospholipids?
phopsholipids that lack 1 acyl group
where and what does phopsholipase A2 do? what does it act on and what inhibits it?
in mammalian tissues, pancreatic juice, snack, bee venoms
- proenzyme is activated by trypsin, and needs bile salts for activity
- acts on PI to release arachidonic acid
- inhibited by glucocorticoids like cortisol
where and what does phospholipase C do?
found in liver lysosomes and alpha-toxin of clostridia and other bacilli
- membrane-bound is activated by PIP2, so plays role in making 2nd messengers
- cleaves off phosphorylated head gropu to make DAG
where and what does phospholipase D do?
in signal transduction to make phoshatidic acid from PC, and DAG from PA
-IOW, cleaves off head group
how is phosphatidylinositol related in cell signaling?
PI most frequently has stearic acid associated with C1, and arachidonic acid on C2
- serves as reservoir for AA, b/c released by phospholipase A2
- phosphorylation of PI makes PIP2, which is cleaved after hormone binds to GPCR, to activate PLC
- PIP2 –> DAG and IP3
- -DAG stimulates PKC, and IP3 increases Ca++ release
what does “last on, first off” mean?
specific lysosomal enzymes cleave specific glycosidic bonds in “last on, first off” order
what happens when a specific lysosomal hydrolase is deficient or defective? what are these diseases called?
sphingolipids accumulate (only one per disease)
- sphingolipidoses are lysosomal storage diseases caused by defects or diminishment
- -cause premature death and neurologic problems, since nerve tissue are enriched in glycospohingolipids
how are sphingolipidoses diagnosed?
- enzyme assays in cultured fibroblasts or peripheral leukocytes
- histologic examination of affected tissue
- analysis of DNA
which diseases are more frequent in Ashkenazi Jewish population?
Gaucher, Tay-Sachs, and Niemann-Pick disease
what are treatments for some sphingolipidoses?
- gene therapy (Gaucer, Fabry)
- bone marrow transplantation (Gaucher)
- substrate reduction therapy (Gaucher)
what accumulates and happens in Tay-Sachs disease?
accumulation of gangliosides (GM2) due to deficiency of GM2 activator PRO or beta-hexosaminidase A
- rapid, progressive, and fatal neurodegeneration
- blindness
- cherry-red macula
- muscular weakness
- seizures
what accumulates and happens in Gaucher disease?
accumulation of glucocerebrosides due to deficiency of beta-glucosidase/glucocerebrosidase
- most common lysosomal storage disease
- hepatosplenomegaly
- osteoporosis of long bones
- CNS involvement in rare infantile and juvenile forms
- enzyme replacement therapy as treatment
what accumulates and happens in metachromatic leukodystrophy?
accumulation of sulfatides due to arylsulfatase A, or activator PRO saposin B, deficiency
- cognitive deterioration (demyelination)
- progressive paralysis and dementia in infantile form
- nerves stain yellow-brown with cresyl violet
what accumulates and happens in Krabbe disease (globoid cell leukodystrophy)?
accumulation of galactocerebrosides due to beta-galactosidase/galactocerebrosidase deficiency
- mental/motor deterioration
- blindness/deafness
- near total loss of myelin
- globoid bodies (glycolipid-laden macrophages) in white matter of brain
what accumulates and happens in Farber disease?
accumulation of ceramide due to ceraminidase deficiency
- painful and progressive joint deformity
- subcutaneous nodules of lipid laden cells
- hoarse cry
- tissues show granulomas
what accumulates and happens in Nieman-Pick disease
in both A and B type, accumulation of sphingomyelin due to deficiency in sphingomyelinase
- hepatosplenomegaly
- cherry red macula
- neurodegeneration in A
what accumulates and happens in Fabry disease?
X-linked accumulation of globosides
- red-purple skin rash
- kidney and heart failure
- burning pain in lower extremeties
- enzyme replacement therapy treatment
what accumulates and happens in GM1 gangliosidosis?
accumulation of GM1 and keratan sulfate due to beta-galactosidase deficiency
- neurologic deterioration
- hepatosplenomegaly
- skeletal deformities
- cherry-red macula in infantile form
