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M.Prasad Naidu MSc Medical Biochemistry, Ph.D,. PHOSPHO LIPIDS
Definition • Phospholipids are polar , ionic compounds composed of an alcohol that is attached by a phosphodiester bridge to either diacylglycerol or to sphingosine
Introduction • Phospholipids are amphipathic in nature they have hydrophilic head ( the phosphate group & what ever attached to it–serine,ethanolamine,choline ,etc) & a long hydrophobic tail ( containing 2 fatty acid chains ). • Phospholipids are the major lipids of the cell membranes.
phospholipids • There are 2 classes of phospholipids 1 ) those that have glycerol as back bone (phosphoglycerides ) 2 ) those that contain sphingosine (sphingomyelins ) .
Phosphoglycerides • Phosphoglycerides constitutes the major class of phospholipids . • Phosphatidic acid is the simplest phosphoglyceride & is the precursor of the other phophoglycerides & triacylglycerol synthesis . • Phospholipids are formed from phosphatidic acid & an alcohol .
PHOSPHOLIPIDS are synthesized in the smooth endoplasmic reticulum. • From there they are transported to the golgi apparatus & then to membranes of organelles or the plasma membrane or are secreted by the cell by exocytosis.
Uses of Cephalin • Cephalin is found in all living cells, although in human physiology it is found particularly in nervous tissue such as the white matter of brain, nerves, neural tissue, and in spinal cord. Whereas lecithin is the principal phospholipid in animals, cephalin is the principal one in bacteria. • As a polar head group phosphatidylethanolamine creates a more fluid lipid membrane compared to phosphatidylcholine
Phosphatidyl choline • Phosphatidyl choilne is also called as lecithin . • Dipalmityl phosphotidyl choline is lung surfactant . • Choline is reutilized in the body . • Phosphatidylcholine is a major constituent of cell membranes, and also plays a role in membrane-mediated cell signalling.
Phosphotidyl Inositiol • PI is synthesized from the free myoinosiotol & CDP- Diacyl glycerol . • PI is an unusual phospholipid it contains Stearic acid in C-1 position & arachidonic acid on C- 2 of glycerol . • PI has role in signal transmission across membrane . • PI has role in membrane protein anchoring.
1.Role of PI in signal transmission across membranes: • phosphorylation of PI occur in response to binding of neurotransmitter,hormones ,growthfactors to receptors on cell membrane. • The degradation of this PI result in mobilization of intra cellular calcium & activation of protein kinase c. • Both act synergistically & promote cellular responses,resulting in signal transmission across the membrane.
2.Role of PI in membrane protein anchoring: • Specific proteins are covalently attached by a carbohydrate bridge to membrane bound PI. eg:alkaline phosphatase:digestive enzyme attacks organic phosphates. acetyl choline esterase:degrades neuro- transmitter acetylcholine. • Some proteins are found in parasitic protozoans
Eg:toxoplasma,leishmania etc. • These proteins allow PI glycan anchored protein rapid mobility on surface of plasma membrane. • These proteins can be cleaved from anchor by phospholipase-C releasing DAG that activate protein kinase-c.
Cardiolipin • Cardiolipin is formed when two molecules of phosphatidic acid esterified through their phosphate groups to an additional molecule of glycerol . • This is the only human phospholipid that is antigenic . • Cardiolipin is an important component of the inner mitochondrial membrane .
Uses Because of cardiolipin’s unique bicyclic structure, a change in pH and the presence of divalent cations can induce a structural change. CL shows a great variety of forms of aggregates. It is found that in the presence of Ca2+ or other divalent cations, CL can be induced to have a lamellar-to-hexagonal phase transition. And it is believed to have a close connection with membrane fusion.
Helps to build quaternary structure • The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion. • It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the mitochondrial (or bacterial) membrane. • It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. • Complex IV has been shown to require two associated CL molecules in order to maintain it’s full enzymatic function. Cytochrome bc1(Complex III) also needs cardiolipin to maintain its quaternary structure and to maintains its functional role. • Complex V of the oxidative phosphorylation machinery also displays high binding affinity for CL, binding four molecules of CL per molecule of complex V.
Triggers apoptosis • During apoptosis, cytochrome c (cyt c) is released from the intermembrane spaces of mitochondria into the cytosol. • Cyt c can then bind to the IP3 receptor on ER, stimulating calcium release, which then reacts back to cause the release of cytochrome c. When the calcium concentration reaches a toxic level, this causes cell death. Cytochrome c is thought to play a role in apoptosis via the release of apoptotic factors from the mitochondria . • A cardiolipin-specific oxygenase produces CL hydroperoxides which can result the conformation change of the lipid. Then, the oxidized CL first transfers from inner membrane to the outer membrane and then helps to form a permeable pore which releases cyt c.
Serves as proton trap for oxidative phosphorylation • During the oxidative phosphorylation process catalyzed by Complex IV, large quantities of protons are transfered from one side of the membrane to another side causing a large pH change. • CL is suggested to function as a proton trap within the mitochondrial membranes, thereby strictly localizing the proton pool and minimizing the changes in pH in the mitochondrial intermembrane space. • This function is due to CL’s unique structure. As stated above, CL can trap a proton within the bicyclic structure while carrying a negative charge. Thus, this bicyclic structure can serve as an electron buffer pool to release or absorb protons to maintain the pH near the membranes.
Plasmalogens • When unsaturated fatty acid attached by an ether rather than by ester linkage at carbon 1 of the core glycerol molecule a plasmalogen is produced . • 1 – alkenyl, 2 – acetyl phosphatidalcholine is platelet activating factor , this is a plasmalogen .
Effects of PAF include • Increasing airway & pulmonary edema in lungs. • It serve as mediator of hypersensitivity,acute inflammatory reactions & anaphylactic shock, causing neutrophils,alveolar macrophages to generate superoxide radicals. • PAF causes these responses by binding to receptor on cell membrane & activating transmembrane signaling mechanisms.
uses • In many tissues plasmalogens are minor constituents, but in heart tissue nearly 50% of phosphatidylcholine contains the alkenyl ether at carbon 1. • Nervous tissues, contains large amounts of ethynolamine plasmalogen . • Testes and kidneys also contain significant amounts of plasmalogens. • Alkenyl ether-containing phospholipids can protect cells against the damaging effects of singlet oxygen, which at high concentrations can kill cells.
Sphingomyelin • The back bone of sphingomyelin is the amino alcohol sphingosine rather than glycerol . • A fatty acid is attached to the amino group of sphingosine by an amide linkage , producing ceramide this is present in all sphingolipids. • The fatty acids found most frequently in sphingomyelin are palmitic , stearic , lignoceric ,& nervonic acids . • The alcohol group at carbon 1 of sphingosine is esterified to phosphoryl choline producing sphingomyelin , an important constituent of the myelin of nerve fibers .
USES • Sphingomyelin of the myelin sheath ( a structure that insulates & protects neuronal fibers of C.N.S ) contains predominantly longer chain fatty acids such lignoceric & nervonic acid . • Grey matter of brain has sphingomyelin that contains primarily stearic acid.
PhosphilipidsroleinMembranes • The favoured structure for most phospholipids in aqueous media is bimolecular sheet rather han a micelle . • The reason for this is two fatty acyl chains of a phospholipid are too bulky to fit into the interior of the micelle . • Formation of bilayers instead of micelles is of critical biological importance .
contd • Formation of bilayers is a self assembly process . • Hydrostatic forces are the major driving forces for the formation of lipid bilayers. • Water molecules are released from the hydrocarbon tails as these tails become sequestered in the non polar interior of the membrane . • Vanderwalls forces between hydrocarbon tails favours close packing of tails .
contd • There are electrostatic & hydrogen bonding attractions between polar head groups & water molecules . • Liposomes are aqueous compartments enclosed by a lipid bilayer . • Liposomes are useful for delivery of drugs & enzymes to the targeted organs .
Functions of Phospholipids • Phospholipids play a role in blood coagulation ( activation of clotting factors prothrombin & factor 8 requires PL ). • Role in lipid absorption : lecithin lowers surface tension of water & aids in emulsification of lipid & water mixtures . • Role in transport of lipids from intestine : exogenous TAG is carried as lipoprotein complex , chylomicrons in which PL takes an active part.
contd • PL exist as component of VLDL particle helps in transport of lipids from liver . • As most important storage of choline helps in lipotropic action of choline . • L/S ratio in amniotic fluid prior to 34 weeks of gestation is useful in assesing fetal lung maturity . • L/S ratio more than 2 – 5 indicates adequate lung maturity . • L/S ratio less than 1 indicates lung immaturity.
Degradationofphospholipids: • By phospholipases found in all tissues & pancreatic juice. • Toxins & venoms have phospholipase activity. • Pathogenic bacteria produce phospholipases that dissolve cell membrane & spread infection. A.Degradation of phosphoglycerides: • They hydrolyse esters of phosphodiester bonds at specific site.
Normal plasma levels of phospholipids • 125-275mg / dL • METHOD OF MEASUREMENT • THIN LAYER CHROMATOGRAPHY METHODS TO MEASURE PULMONARY SURFACTANT • LECITHIN/SPHINGOMYELIN (L/S) RATIO • DPPC MEASUREMENT BY TLC • PHOSPHATIDYLGLYCEROL • FOAM STABILITY INDEX • FLUORESCENCE POLARIZATION • LAMELLAR BODY COUNTS
