professor biochemistry phospholipid metabolism. learning objectives at the end of the session the...
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Professor BiochemistryPhospholipid Metabolism
Learning Objectives At the end of the session the student shall
be able to:1. Define phospholipids and explain the
pathways for synthesis and degradation.2. Enumerates the functions of PL specifically
in relation to CNS.3. Interprets the biochemical basis of lipid
storage disorders.
Diseases associated with phospholipid metabolism 1. RDS (Respiratory distress syndrome)
2. Niemann-pick diseas
3. Farbers disease
4. Gauchers disease
5. Krabbes disease
6. Tay-sachs disease
Phospholipids-Relation to CNSLecithin (Phosphatidyl
choline) : plays important role in the neural transmission.
Plasmalogens: Constitutes 10% of the lipid component of the brain.
Phosphitidyl Inositol : signal transmission as second messenger.
Glycosphingolipids : widely distributed in brain.
Gangliosides: abundantly present in the nervous system.
Sphingomyelin: chief constituent of myelin sheath.
How do phospholipids differ from triacylglycerides (TAGs)?
TAGs have three fatty acids hooked to a glycerol molecule.
GLYCEROL
Phospholipids
Phospholipids have two fatty acids hooked to either a glycerol or Sphingosine backbone.
A phosphate (polar group) group has replaced one fatty acid of the TAG this is attached by a Phosphodiester bond.
Structure of a phospholipidsDistribution of phospholipids in the membranes
Distribution is asymmetric.PC and Sphingomyelin in the outer layerPS and PE and PI in the inner layer
Phospholipids
These are triglycerides in which one fatty acid has been replaced by a phosphate group.
Phosphate group is soluble in water, while the fatty acid tails are not.
Phospholipids are thus hydrophilic at one end and hydrophobic at the other end.
Nitrogenous base.
Classification Phospholipids:
1. Glycerophospholipids
2. Sphingophospholipids
Phospholipids
Glycerophospholipids
Sphingophospholipids
Synthesis of GlycerophospholipidsSite: smooth endoplasmic reticulum
Synthesized from Phosphatidic acid and 1,2 DAG, intermediates in the production of TAG Metabolism.
Formation of Lecithin and Cephalin
Choline and Ethanolamine first gets Phosphorylated and then combine with CTP to form, CDP-Choline and CDP-ethanolamine respectively.
CDP-Choline and CDP-ethanolamine combine with 1,2DAG to form Phosphotidyl Choline (lecithin) Phosphotidyl Ethanolamine (Cephalin).
Significance of LecithinIt is phosphatidylcholine these are most abundant in
cell membranes.Dipalmitoyl lecithin is found in lungs acts as a
surfactant and prevents the adherence of inner surface of the lungs.
Mechanism of RDS
Respiratory distress syndrome
Is synthesized shortly before parturition in full-term infants.
Preterm new-borns have this syndrome due to deficiency of lung surfactant.
Respiratory distress syndrome (RDS) in infants is due to absence of phosphatidylcholine. It is
Administration of either natural or artificial surfactant has been useful.
Significance of CephalinPhosphotidyl ethanolamine it differs in the base
from lecithin.Take part in blood clotting.
Formation of Phosphotidyl Serine
Phosphotidyl ethanolamine can exchange its ethanolamine group with free serine to produce Phosphotidyl serine.
Formation of Phosphotidyl Inositol
CDP-DAG produced from Phosphatidic acid combines with Inositol to form PI.
PI is important for signal transmission across membranes.
Synthesis of Cardiolipin
CDP-DAG combines with glycerol-3-phosphate to form Phosphotidyl glycerol, which in turn combines with another molecule of CDP-DAG to produce Cardiolipin.
This is the only PL possessing antigenic properties.
Formation of PlasmalogensThese are PL with fatty acid at carbon 1 bound
by an ether linkage instead of ester linkage.An important Plasmalogen, is 1-alkenyl 2 acetyl
glycerol 3- Phospho Choline causes platelet aggregation and is referred to as platelet-activating factor.
Sphingophospholipids
Ganglioside
Sphingomyelin synthesisSynthesis: these contain
a complex amino alcohol, sphingosine, instead of glycerol.
Palmitoyl CoA and Serine combine and undergo a series of reactions to produce sphingosine.
which is then acetylated to produce Ceramide.
This reacts with CDP-Choline to form Sphingomyelin.
Degradation of Sphingomyelin
Ceramidase
Sphingomyelinase
Def: Niemann-pick disease
Def: Faber’s disease
Niemann-pick disease
It is an inherited disorder due to defect in Sphingomyelinase.
Clinical symptoms: accumulation of Sphingomyelins in liver and spleen, resulting in enlargement of these organs,
mental retardation.Cherry red spot in macula.Death usually occurs by 2 years.
Farber’s diseaseDefect in Ceramidase.
Clinical symptoms: Skeletal deformities, Subcutaneous nodules, Dermatitis and Mental retardation.
Biosynthesis of Glycolipids(Cerebrosides)
• These are derivatives of Ceramide (sphingosine bound to fatty acid)) most appropriately known as cerebrosides.
• Galactocerebroside and glucocerebroside are the common glycosphingolipids.
• These are the major component of membrane lipids in the nervous system.
Degradation of Glycolipids(Cerebrosides)
β-glucosidase
Def: Gaucher's disease
Gaucher's diseaseThis is due to the enzyme β-Glucosidase
deficiency .As a result glucocerebroside levels increase.
Degradation of Glycolipids(Cerebrosides)
β-galactosidase
Def: Krabbe’s disease
Krabbe’s diseaseEnzyme defect is β-Galactosidase results in
accumulation of Galactocerebroside.Clinical features: Total absence of myelin in the nervous tissue is
a common feature, severe mental retardation, convulsions, Blindness and deafness.
GlucocerebrosideGalactocerebroside.SphingomyelinCeramide
Degradation of Phospholipids These are degraded by Phospholipases which
will cleave the Phospho di ester bonds.1. Phospholipase A1: specifically cleaves the
fatty acid at C1 position of phospholipids.2. Phospholipase A2: hydrolyses the fatty acid at
C2 position of phospholipids.3. Phospholipase C (A3): specifically cleaves the
bond between phosphate and glycerol of phospholipids.
4. Phospholipase D(A4): hydrolyses and removes the nitrogenous base from the phospholipids.
Phospholipases
Lecithin-cholesterol acyl transferase LCAT is a plasma enzyme, synthesized in
the liver.It is associated with apo A1 of HDL.This enzyme esterifies cholesterol by
transferring acyl group from the second position of lecithin.
Lecithin + Cholesterol LCAT Lysolecithin + Cholesterol ester.
This reaction is responsible for reverse cholesterol transport mediated by HDL.
Synthesis of gangliosides
Synthesis of gangliosidesGroup of glycolipids contain one or more sialic
acid residues.Present in high concentrations in CNS and on
surface of the membranes.The major gangliosides of brain are GM1, GM2
GM3.For ganglioside synthesis the active form is
NANA (N-acetyl neuraminic acid).NANA is attached by the hydroxyl group of its 2nd
carbon to the 3rd hydroxyl group of sugars.
Degradation of Gangliosides
Hexosaminidase A
Def: Tay-sachs disease
Tay-sachs diseaseIncidence 1 in 6000 births.Deficiency of Hexosaminidase A Mental retardationCherry red spot in macula.Prognosis is bad.
Lysosomal storage diseases
Lysosomal storage diseases
1. These are also called sphingolipidosis.
2. Normally catabolised by a series of bond specific lysosomal hydrolases.
3. Diseases results from failure of breakdown of a particular spingolipid due to deficiency of a single enzyme (gene mutation).
4. Children are affected.
5. These diseases can be diagnosed prenatally by amniocentesis.
Phospholipids and Sphingolipids are involved in Multiple Sclerosis (M.S.)
MS is a demyelinating disease, caused due to degeneration of myelin sheath.
Interfering the nerve conduction. Oligodendroglial cells synthesize the myelin sheath.Clinical symptoms:Presents with tingling and numbness in her fingers and toes.Loss of balance Blurred vision.
.
Guillain-Barre syndromeIt is an inflammatory autoimmune neuritis
wherein T-cells formed in response to a viral illness mistakenly attack the myelin sheath of peripheral nerves.
The myelin sheaths are composed of sphingolipids and phospholipids.
They present with progressive weakness of low extremities, loss of deep tendon reflexes, respiratory distress and flu like symptoms.
Foods rich in sphingolipids are soy and dairy products.
Antiphopsholipid syndrome (Hughes syndrome)Body produces antibodies against its own
phospholipids.The major one being anticardiolipin antibody.These antibodies will bind to proteins involved in
coagulation and increase the risk of blood clots (thrombosis)
Clinical symptoms: repeated miscarriagesThrombocytopeniaDeep vein thrombosis.