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MS 1 Unit VI MCP > Complex Lipids in Health and Disease > Flashcards

Complex Lipids in Health and Disease Flashcards

1
Q

Types of Glycerolipids and Sphingolipids

A
  • glycerolipids (which include triacylglycerol, glycerophospholipids and ether glycerolipids)
  • phospholipids (again including glycerophospholipids and ether glycerolipids but also sphingophospholipid called sphingomyelin
  • spingolipids (include sphingomelin and various glycolipids
  • glycolipids are built on a glycerol backbone while the sphingolipids are built on a sphingosine backbone. The phospholipids all contain polar head groups which are linked by a phosphodiester bond to carbon 3 of the glycerol or spingosine backbone
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2
Q

Structure of Glycerophospholipids

A
  • predominant phospholipids in cell membranes
  • amphipathic with a polar head group attached through a phosphodiester bond to carbon 3 of diacylglycerol. The two fatty acid chains form an ester bond to carbon 1 and 2 of the glycerol backbone are the non-polar portion of the PL and are imbedded within the hydrophobic core of the bilayer
  • phosphatidic acid is the simplest glcerophospholipid
  • in membranes the hydrophobic polar head groups of the glycerophospholipids and sphingomyelin face the aqueous environment, while the hydrophobic non-polar fatty acid chains are imbedded within the hydrophobic core of each leafleft of the bilayer
  • phosphate group is esterified to another compound containing an alchol forming phosphatidylserine, phosphatidylethanolamine, and phospatidylcholine
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3
Q

Cardiolipid

A
  • two molecules of phosphatidic acid esterieid through their phosphate to a glycerol is called cardiolipin or diphophatidyl glycerol
  • found in the membranes of bacteria and eukaryotic cells
  • within eukaryotes cardiolipin is found in the inner mitochondria membrane
  • it supports the structure and function of certain respiratory complexes in the elkctron transport chain
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4
Q

Ether Glycerophospholipids

A
  • in plasmalogens the fatty acid at carbon 1 of the glycerophosphospholipid contrains an unsaturated alkyl group attached to glycerol by an ether linkage
  • Phosphatidal ethanolamine which is abundant in nerve tissue
  • platelet activating factor, also an ether glycerolipid. It has a saturated alkyl group linked by an ether linkage to carbon 1 of the glycerol. It also has an acetyl group at carbon 2. PAF is synthesized by many cells and binds to specific surface receptors stimulating thrombotic and acute inflammatory response
  • another plasmalogen, phosphatidalcholine is enriched in heart muscle
  • phosphatidalserine and phosphatidal choline are two most abundant ether lipids in mammals
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5
Q

Sphingomyelin

A
  • backbone of sphingmyelin is the amino alcohol sphingosine
  • a long chain fatty acid is attached to the amino group in sphingosine, through an amide bond, to form ceramide
  • the alcohol group at carbon 1 of sphingosine becomes esterified to phophoryl choline forming sphingomyelin
  • sphingomyelin is the only major sphingophospholipid in humans and is found in many membranes. It is highly enriched in the myelin sheath wrapped around axons
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6
Q

Galactocerebroside

A
  • the glycosphingolipids differ from sphinomyelin in not having a phosphate group. Instead a sugar is attached to ceramide by an O-glycosidic bond
  • the sugar is the polar head group and the ceramide represents the hydrophobic tail that inserts into the hydrophobic core of membranes
  • simple uncharged glycosphingolipids with one galactose or glucose are called cerebrosides
  • they are in found predominantly in central and peripheral nervous tissue and are enriched in the myelin sheath
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7
Q

Globosides

A
  • ceramide oligosaccharides are produced by attaching monosaccharides to a glycocerbroside (ex. ceramide-glucose-galactose or lactosyl ceramide)
  • they are called globisides
  • they can include substituted sugars (ex N-acetyl galactosamine
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8
Q

Gangliosides (GM2)

A
  • negatively charged acidic glycosphingolipids include the gangliosides (contain NANA/Sialic Acid) and the sulfatides (contain sulfate)
  • the gangliosides are derivative of ceramide oligosaccarides (globosides)
  • the gangliosides contain one or more sialic acid residues and are named accordingly: mono (M), di (D), tri (T), quantro (Q). Additional numbers and letter as a subscript designate the sequence of sugars attached to ceramide
  • these complex glycosphingolipids are found primarily in the ganglion cells of the CNS and are enriched at nerve endings
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9
Q

Role of Complex Lipids in Membrane Structure and Function

A
  • phospholipids tend to bury the non-polar fatty acyl chains within the hydrophobic core of the bilayer or a micelle
  • there is asymmetric distribution of lipids with choline containing phospholipids (PC and SM) and glycolipids primarily in the outer leaflet and amine containing phospholipids and Phosphatidylinositol in the inner leaflet
  • phospholipids are capable of lateral mobility and slower flip-flop across membranes
  • lipid rafts are involved in functions as diverse as assembly of signaling molecules, involvement in membrane protein trafficking, regulating neurotransmission and receptor trafficking
  • PL and SM flipping against their concentration gradient requires ATP-dependent flippases. PL and SM flopping down their concentration gradient require scamblases or floppases
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10
Q

Strategies for Adding the Head groups for Glycerophospolipids

A
  • in the synthesis of glycerophospholipids the first step is addition of two activated fatty acyl chains to glycerol-3-phosphate forming phosphatidic acid (PA)
  • the head groups are added to C3 of PA throgh one of two mechanisms
  • mechanism 1L used for synthesis of PC, PE and PS, the phosphate is cleaved from PA by a phosphatase creating DAG, DAG reacts with the activated CDP-Head group to form the glycerophospholipid with release of CMP
  • mechanism 2- PA reacts with CTP to form CDP-Diacylglycerol with release of PPi. This activated CDP-DAG can interact with glycerol-3-P to form PG or with PG to form cardiolipin or inositol to form PI
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11
Q

Synthesis of PE, PC and PS

A
  • several interconversions can occur between the phospholipids: PS can be formed by a base exchange reaction from PE
  • PS can be reconverted to PE by a decarboxylase which requires pyridoxal phosphate (PLP) as a coenzyme
  • PE can be converted to PC by 3 methylation of the head group. This is carried out by N-methyltransferases with S-adenosyl methionine (SAM) serving as the methyl donor
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12
Q

Lung surfactant and respiratory distress syndrome

A
  • DPPC is PC with C1 and C2 esterified to palmitate
  • DPPC produced and secreted from type II pneumocytes is the major lipid component of surfactant the extracellular fluid layer lining the alveoli
  • the other components of lung surfactant are PG; apo-proteins Sp-A, Sp-B and Sp-C and cholesterol
  • lung surfactant reduces the surface tension of the alveoli of the lung preventing their collapse
  • deficiency in the synthesis of the components of lung surfactant leads to respiratory distress syndrome
  • DPPC is the major component of lung surfactant involved in reducing the surface pressure of the fluid layer in the alveoli
  • reducing the pressure needed to reinflate alveoli prevents their collapse
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13
Q

Synthesis of Cardiolipin and PI

A
  • once PI is formed through the addition of Inositol to CDP-DAG then PI can be phosphorylated by kinases to form polyphosphinositides
  • one such product is phosphatidylinositol biphosphate PIP2 a phospholipid enriched on the cytoplasmic facing leaflet of membrane bilayers
  • important role in signal transduction across membranes
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14
Q

Synthesis of Plasmalogen

A
  • the ether PLs are synthesized from the glycolytic intermediate dihydroxyacetone phosphate
  • a fatty acyl reacts with C1 of DHAP by an ester bond
  • this fatty acyl group is exchanged for a fatty alcohol produced by reduction of the fatty acyl by 2NADPH. This creates the ether linkage
  • then the keto group on C2 is reduced to an alchol and a fatty acid is esterified onto C2
  • the polar head groups are added as previously described for PC, PS, or PE
  • finally reduction of the alkyl group in ether linkage to C1 creates the alkenyl group of plasmalogen. There is a double bond between carbon 1 and 2 of the alkenyl group
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15
Q

Synthesis of Ceramide

A
  • the synthesis of all sphingolipids begins with the formation of ceramide. Serine and palmitoyl CoA condense with a loss of as CoA and CO2 are lost to form a product which is then reduced to dihydrosphingosine
  • fatty acyl CoA then is acylated at the amino group to form an amide bond. The product is then oxidized, a double carbon bond is formed, and ceramide is created
  • ceramide is the precursor of sphingomyelin and the other sphinolipids
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16
Q

Synthesis of Sphingolipids

A
  • ceramide interacts with phosphatidyl choline, with loss of DAG, to form Sphingomyelin
  • synthesis of glycosphingolipids occurs primarily in the Golgi. With sequential addition of glycosyl monomers by glycosyl transferases
  • the addition UDP-Galactose or UDP-glucose to Ceramide yields Galacto and Gluco-cerebrosides
  • a sulfotransferase, utilizing the sulfate carrier PAPS, converts Galactocerebroside to sulfatide (- charged)
  • glubosides are ceramide oligosaccharides. Each additional sugar is added by glycosyl transferases
  • in the gangliosides N-acetyl neuraminic acid (sialic acid, negatively charged) are added, via CMP-NANA to the oligosaccharide chains
17
Q

Phospholipases

A
  • the degradation of glycerophospholipids is catalyzed by phospholipases found in all tissues and pancreatic juice. Phospholipases are also found in snake and bee venoms and are produced by some pathogenic bacteria
  • there are a number of major phospholipases each having its own specificity: A1 and A2 cleave off fatty acids at C1 and C2 leaving behind lysophospholipids. C cleaves off the phosphorylated head group yielding DAG. D cleaves off head group leaving phosphatidic acid
  • phospholipases are also used to remodel phospholipids. A1 and A2 can remove fatty acid chains from membrane associated phospholipids. These chains can then be replaced with new ones by fatty acyl CoA transferase. This is how the surfactant component DPPC is enriched in lung. It is also how carbon 2 of PI is often associated with arachidonic acid
18
Q

Phospatidylinositol and Cell Signaling Across membranes

A
  • PI most frequently has stearic acid associated with C1 and arachidonic acid on C2. It serves as a reservoir for arachidonic acid which can be released by phospholipase A2
  • the phosphorylation of PI creates poly phosphoinosides such as PIP2
  • cleavage of membrane associated PIP2 occurs after a hormone binds to a specific G protein coupled receptor causing the activation of phospholipase C
  • the products of PIP2 cleavage are DAG and IP3
  • IP3 stimulates Ca2+ release from intracellular compartments
  • DAG stimulates cellular protein kinase C
19
Q

Properties of Sphingolipidoses

A
  • a specific lysosomal hydrolytic enzyme is diminished in activity for each disease
  • therefore only one sphingolipid substrate accumulates
  • although some of these diseases lead to death in childhood most demonstrate phenotypic and genetic variability and have different types (Niemann-Pick’s Disease A and B)

Diagnoses- based on enzme assays in cultred fibroblasts or peripheral leukocytes, histologic examination of affected tissues and/or analysis of DNA
-Gaucher, Tay-Sachs, and Niemann-Pick disease show high frequency in the Ashkenazi Jewish Population

-Treatment: gene therapy for gaucher and fabry disease, bone marrow transplantation for Gaucher, substrate reduction therapy for Gaucher

20
Q

Tay Sachs Disease

A
  • accumulation of gangliosides
  • rapid, progressive, and fatal neurodegeneration
  • blindness
  • cherry-red macula
  • muscular weakness
  • seizures
  • deficiency of activator protein (Gm activator) in some cases
  • Beta-hexosaminidase A (alpha subunit)
21
Q

Gm1 gangliosidosis

A 
-accumulation of gangliosides
GM1 and keratan sulfate
-neurologic deterioration
-hepatosplenomegaly
-skeletal deformities
-cherry-red macula in infantile form
-Beta-galactosidase not working
22
Q

Gaucher Disease

A
  • accumulation of glucocerebrosides
  • most common lysosomal storage disease
  • hepatosplenomegaly
  • osteoporosis of long bones
  • CNS involvement in rare infantile and juvenile forms
  • enzyme replacement therapy
  • Beta-glucosidase not working
23
Q

Sandhoff Disease

A
  • accumulation of GM2 and globosides
  • same neurologic symptoms as Tay- Sachs (including red macula) but visceral involvement as well
  • Beta-hexosaminidase A (Beta subunit) not working
24
Q

Fabry Disease

A
  • accumulation of globosides
  • red purple skin rash
  • kidney and heart failure
  • burning pain in lower extremities
  • enzyme replacement therapy
  • alpha galactosidase not working
25
Q

Niemann-Pick Disease

A
  • accumulation of sphingomyeline
  • hepatosplenomegaly
  • neurodegenerative course (Type A)
  • cherry red macula
  • sphingomyelinase not working
26
Q

Farber Disease

A
  • accumulation of ceramide
  • painful and progressive joint deformity
  • subcutaneous nodules of lipid- laden cells
  • hoarse cry
  • tissues show granulomas
  • ceraminidase not working
27
Q

Metachromatic Leukodystropy

A
  • accumulation of sulfatides
  • cognitive deterioration
  • demyelination
  • progressive paralysis and dementia in infantile form
  • nerve stain yellow-brown with cresyl violet
  • deficiency of activator protein (saposin B) in some cases
  • deficient Arylsulfatase A
28
Q

Krabbe Disease (Globoid Cell Leukodystrophy)

A
  • accumulation of galactocerebrosides
  • mental and motor deterioration
  • blindness and deafness
  • near-total loss of myelin
  • globoid bodies (glycolipid-laden macrophages) in white matter of brain

MS 1 Unit VI MCP (12 decks)

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