PHOSPHOLIPIDS METABOLISM BY Dr. Walid Said Zaki Dr. Marwa Ali LECTURER OF BIOCHEMISTRY AND MOLECULAR BIOLOGY
1. State the definition and classification of Phospholipids. 2. Describe the general structure and characters of Phospholipids. 3. Explain the physiological importance of Glycero-phospholipids 4. Illustrate and explain steps of Glycero-phospholipids synthesis 5. Describe structure and importance of lung surfactant and Respiratory distress syndrome resulting from defect in its synthesis 6. Know different phospholipases responsible for Glycerophospholipids degradation
Polar compounds composed of an alcohol backbone bound to fatty acids by phosphodiester bridge: This alcohol may be: Phospholipids Glycerol OR Sphingosine 3
Phospholipids Amphipathic in nature Predominant lipids of cell membranes Components of lung surfactant Essential components of bile 4
Phospholipids Sphingo-lipids Glycero-phospholipids Sphingomyelin Glyco-sphingolipids
Glycero-phospholipids It contain glycerol + 2 fatty acids attached to C1,2 + phosphate group attached to C3 + base or alcohol Usually saturated fatty acid Usually unsaturated fatty acid Ethanolamine, choline, serine, inositol, glycerol
Types of phospholipids (1) (2) (3) Choline Phosphatidyl choline ( lecithin) Dipalmityl lecithin =lung surfactant Serine or ethanolamine Phosphatidyl serine/ ethanolamine (cephalins) They have role in blood coagulation
Types of phospholipids (4) (5) Stearic acid Arachidonic acid inositol Phosphatidyl inositol Phosphatidyl inositol 4,5 bisphosphate has a role in signaling transduction Plasmalogens They resemble phospholipids, except: -Have ether link in C1 -Alcohol in C1 -Ethanolamine plasmalogen present in brain
Types of phospholipids (6) (7) Cardiolipin glycerol Phosphatidyl- glycerol - Present in mitochondrial membrane. (Diphosphatidyl glycerol) Present in mitochondrial memb.
Types of phospholipids (8) lysolecithin Lysophospholipid (lysophosphatidyl choline) - is phospholipid with free OH in C2
Functions of phospholipids ) 1( Structural component of membranes (2) Enter in lipoprotein structure, which help in lipid transport in body -Transport of TAG from liver to body, any defect lead to fatty liver (3) Solubilize cholesterol in bile, any defect lead to cholesterol stones
PHOSPHOLIPIDS SYNTHESIS Most phospholipids are synthesized in the smooth endoplasmic reticulum From there, they are transported to the Golgi apparatus and then: to membranes of organelles, or the plasma membrane, or secreted from the cell by exocytosis.
A. Phosphatidic acid PA is the precursor of many other phosphoglycerides
B. Phosphatidylcholine and phosphatidylethanolamine PC and PE are the most abundant phospholipids in most eukaryotic cells. Their synthesis uses choline and ethanolamine obtained from: Diet or, Turnover of the body s phospholipids.
Steps 1- Phosphorylation of choline or ethanolamine by kinases 2- Conversion to the activated form, CDP-choline or CDP-ethanolamine 3- Choline-phosphate or ethanolamine-phosphate is transferred from the Nucleotide (leaving CMP) to a molecule of DAG
Dipalmityl Phosphatidyl choline = Dipalmityl lecithin = Lung surfactant - It contains palmitic acid at C1,2 - It decrease the surface tension in the lung alveoli. - So, it prevent adherence of the inner surfaces of the lung. - At, birth if decrease----- >it leads to RDS respiratory distress syndrome
1. Dipalmitoyl-ecithin (Lung surfactant) Synthesis and secretion: by granular pneumocytes Major lipid component (65%) of lung surfactant (Remaining 35%: Other phospholipids, cholesterol & proteins) Surfactant decreases surface tension of fluid layer lining of alveoli, reducing the pressure needed for their inflation by air, and preventing alveolar collapse (atelectasis) Congenital Respiratory distress syndrome (RDS): Insufficient production of lung surfactant (especially in pre-term babies) neonatal death
Congenital Respiratory distress syndrome (RDS) Pre-natal diagnosis by: Lecithin/sphingomyelin (L/S) ratio in amniotic fluid Ratio of 2 or above indicates lung maturity and no RDS (i.e., shift from sphingomyelin to lecithin synthesis by pneumocytes that normally occurs by 32 weeks of gestation) Prevention: Glucocorticoids to the pregnant mother with low L/S ratio shortly before delivery Treatment: Intra-tracheal administration of surfactant to pre-term infants with RDS
C. Phosphatidylserine Ethanolamine of PE is exchanged for free serine
Synthesized from free inositol and CDPdiacylglycerol D. Phosphatidylinositol
Phosphatidyl inositol 4,5 bisphosphate: Act as second messenger in signal transduction Signal: Hormones or neurotransmitters e.g., Acetylcholine, antidiuretic hormone (V1- receptor) and catecholamines (α 1 actions) Receptor: G-protein coupled receptor Effects: *Activation of phospholipase C Hydrolysis of phosphatidylinositol 4,5-bisphosphate Production of IP3 ( Ca 2+ ) and DAG Activation of protein kinase C Phosphorylation of cellular proteins Response: Biological responses to hormones
E.Phosphatidylglycerol and cardiolipin Phosphatidylglycerol is a precursor of cardiolipin
DEGRADATION OF PHOSPHOLIPIDS By phospholipases found in all tissues and pancreatic juice For glycerophospholipids: Phospholipases A1, A2, C and D Present in snake venoms and bacterial toxins
Glycero-phospholipases
Functions of Phospholipases (1) Degradation of phospholipids Production of second messengers Digestion of phospholipids by pancreatic juice Pathogenic bacteria degrade phospholipids of membranes and causing spread of infection (2) Remodeling of phospholipids: Specific phospholipase removes fatty acid from phospholipid Replacement of fatty acid by alternative fatty acid using fatty acyl CoA transferase e.g., Binding of 2 palmitic acids in: Dipalmitoylphosphatidylcholine (DPPC) Binding of arachidonic to carbon 2 of PI or PC