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بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيم. Phospatidylinositol and Phospholipases. By. Reem Sallam, MD, MSc, PhD. Phosphatidylinositol (PI) Structure Functions Plospholipases : Phospholipases A1, A2, C and D Lysosomal phospholipase : Sphingomyelinase. Objectives. Background: Phospholipids.

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بسم الله الرحمن الرحيم

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  1. بسم الله الرحمن الرحيم

  2. Phospatidylinositol and Phospholipases By Reem Sallam, MD, MSc, PhD

  3. Phosphatidylinositol (PI) • Structure • Functions • Plospholipases: • Phospholipases A1, A2, C and D • Lysosomalphospholipase:Sphingomyelinase Objectives

  4. Background: Phospholipids A. Glycerophospholipids Glycerol-containing phospholipids e.g., Phosphatidylinositol B. Sphingo-phospholipids: Sphingosine-containing phospholipids e.g., Sphingolmyelin

  5. Phosphatidylinositol (PI) Diacylglycerol (DAG) Saturated FA Parent Phospholipid Unsaturated FA OH - Inositol Phosphatidylinositol (PI)

  6. Phosphatidylinositol (PI): Functions • Protein anchoring to plasma membranes • Reservoir of arachidonic acid in membranesArachidonic acid is the precursor of prostaglandins • Signal transmission across membranes via production of second messengers:Inositol 1,4,5-trisphosphate (IP3) Diacylglycerol (DAG)

  7. PI- Protein Anchoring Anchoring of proteins to membranes via Carbohydrate-Phosphatidylinositol Bridge • Examples of anchored proteins: • 1. Alkaline phosphatase • (to the surface of small intestine) • 2. Acetylcholine esterase(to postsynaptic membrane) • These proteins can be cleaved from • their attachment to the membranes • byphospholipase C

  8. Phosphatidylinositol 4,5 bisphosphate

  9. Calcium/Phosphatidylinositol System Diacylglycerol (DAG) Inositol 1,4,5-Trisphosphate (IP3) Phospholipase C

  10. GTP-Dependant Regulatory Proteins (G-Proteins) Gq-Proteins: Trimeric membrane proteins (αβγ) Binds to GTP/GDP Forms of G-Proteins Active form α-GTP bound (α/GTP) Inactive form Trimeric –GDP bound (αβγ/GDP) The α-subunit has intrinsic GTP-ase activity, resulting in: Hydrolysis of GTP into GDP  Inactivation of G-proteins

  11. Phosphatidylinositol System What is the initial Signal? Hormones or neurotransmitters e.g., Acetylcholine, antidiuretic hormone (V1-receptor) & catecholamines(α1 actions)What is the Receptor? G-protein coupled receptor What are the downstream Effects? Activation of phospholipase C  Hydrolysis of phosphatidylinositol 4,5-bisphosphate Production of : IP3 ( release of Ca2+ from intracellular stores) and DAG Activation of protein kinase C What is the Response? Phosphorylation of cellular proteins response to hormones

  12. Gq * Gq protein with Gq protein * Acetylcholine Antidiuretic hormone (ADH)Catecholamines Intracellular Signaling by Inositol 1,4,5-trisphosphate (IP3)

  13. Phospholipases • (1) For glycerophospholipids: • PhospholipasesA1, A2, C andD • Present in all tissues and pancreatic juice • Present in snake venoms and bacterial toxins • (2) For sphingophospholipids: • Lysosomalphospholipase:Sphingomyelinase

  14. Functions of Phospholipases • (1) Degradation of phospholipids • Production of second messengers • Digestion of phospholipids by pancreatic juice • Pathogenic bacteria degrade phospholipids of membranes  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; lung surfactant) • Binding of arachidonic to carbon # 2 of PI or PC

  15. (1) Glycero-phospholipases

  16. Sphingosine-containing phospholipids: Sphingomyelin CH3 (CH2)12 CH CH CH CH CH2O Phosphorylcholine OH NH C (CH2)n CH3 O Long Chain Fatty acid

  17. Sphingosine CH3 (CH2)12 CH CH CH CH CH2OH OH NH2 Long chain, unsaturated amino alcohol

  18. Ceramide: Parent Sphingolipid Compound Ceramide = Sphingosine + Fatty acid CH3 (CH2)12 CH CH CH CH CH2OH OH NH C (CH2)n CH3 O Long Chain Fatty acid

  19. Sphingomyelin Sphingomyelin = Ceramide + phosphorylcholine CH3 (CH2)12 CH CH CH CH CH2O Phosphorylcholine OH NH C (CH2)n CH3 O Long Chain Fatty acid

  20. (2) Lysosomal Phospholipase: Sphingomyelinase Degradation of sphingomyelin by sphingomyelinase and ceramidase produce intracellular messengers: Ceramide and sphingosine

  21. Take Home Message • Phosphatidylinositol (PI) is present in membranes • Functions of PI: Anchoring for proteins to membrane Production of second messengers Reservoir of arachidonic acid, a PG precursor • Phospholipases: Phospholipases A1, A2, C andDLysosomal Phospholipase: Sphingomyelinase

  22. Take Home Message CONT’D Function of phospholipases: • Degradation of phospholipids e.g., production of second messengers • Remodeling of phospholipids • e.g., production of DPPC (lung surfactant)

  23. THANK YOU 

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