Phospholipid Degredation

• Phospholipases


  Digestive enzymes that generate highly active intracellular signal molecules
• Phospholipid degradation


  1. Membrane-bound PLs are continually being formed and degraded by living cells

  2. Hydrolysis of membrane-bound PL by PLC yields DAG and IP3
• 1. stimulatory (G) and G-inhibitory (G) proteins


  • Function through GTP/GDP or ATP/ADP to couple certain hormone receptors to PLC
• Part of the antiinflammatory action of the glucocorticoids is accounted for by their ability to inhibit PLA₂
• Some bacterial toxins act through stimulating the activity of PLC
• Some tumor promoters are potent activators of PKC
• Cytoplasmic Ca2+


  Can be derived from extracellular fluid, or from mitochondria and the endoplasmic reticulum from within cells
• IP3


  A water-soluble inducer of Ca2+ release from the endoplasmic reticulum
• Ca2+ binds intracellularly to calmodulin (CAM)


  This complex activates specific and multifunctional CAM kinases
• Phospholipid degradation


  1. Enzymes called phospholipases (PLases) catalyze the hydrolysis of ester bonds in glycerophospholipid substrates

  2. PLases show catalytic specificity for ester bonds and have two general functions: act as digestive enzymes and generate highly active signal molecules
• Although PLs are actively degraded in plasma membranes, each portion of the molecule turns over at a different rate due to the presence of enzymes that allow partial degradation followed by resynthesis
• PLA2


  Catalyzes hydrolysis of the ester bond in position 2 of membrane-bound glycerophospholipids to form a polyunsaturated (free) fatty acid and lysophospholipid
• Lysolecithin


  May also be formed by the enzymatic action of lecithin:cholesterol acyltransferase (LCAT), which catalyzes transfer of a FA residue from the 2-position of lecithin to cholesterol, forming a cholesterol ester
• Incorporation of FAs into lecithin

  Can occur through complete synthesis of the PL, by transacylation between CE and lysolecithin, or by direct acylation of lysolecithin by acyl-CoA
• Lysophosphatidylcholine (lysolecithin)


  May be additionally attacked by lysophospholipase A₁ (PLA₁), removing the remaining 1-acyl group and forming glycerophosphocholine
• Phospholipase C (PLC)


  Attacks the ester bond in position 3, liberating 1,2-diacylglycerol (DAG) plus a phosphoryl base
• Phospholipase D (PLD)


  Hydrolyzes the nitrogenous base or inositol from PLs
• Phospholipase B (PLB)


  Appears to possess both PLA₁ and PLA₂ activity
• Ca2+ signaling


  1. Ca2+ can enter from outside the cell through Ca2+-specific voltage- or ligand-gated channels, or be released from internal stores in mitochondria and the endoplasmic reticulum

  2. Localized Ca2+ signals can activate highly localized cellular processes or coordinate to create global Ca2+ signals that activate processes at a more global level
• Ca2+ messenger system


  1. Certain hormones or neurotransmitters interact with their plasma membrane receptors, setting up a chain of events through the Ca2+ messenger system

  2. This involves hydrolysis of membrane-bound phosphatidylinositol 4,5-bisphosphate, releasing IP3 which induces Ca2+ release from the endoplasmic reticulum
• Ligands


  e.g. hormones and neurotransmitters
• Cell-surface receptors


  • Ligands bind to them
  • Can cause elevation in cytosolic calcium (Ca++) concentration even when Ca++ is absent from extracellular medium
• Calcium release into cytosol

  1. Initial stages of stimulation

  2. From endoplasmic reticulum (ER) or other intracellular vesicles (e.g. mitochondria)

  3. Not from extracellular medium
• Phosphatidylinositol 4,5-bisphosphate


  One of several inositol phospholipids found in cytoplasmic leaflet of plasma membrane
• Hydrolysis of phosphatidylinositol 4,5-bisphosphate

  1. By plasma membrane-bound phospholipase C (PLC)

  2. Yields two products: DAG (remains in membrane) and IP3 (released into cytosol)
• 1. stimulatory (Gs) protein


  • Couples hormone receptors to PLC
  • Pertussis toxin inactivates Gs and abolishes PLC activation
• Subtypes of mammalian PLC

  • α
  • β
  • γ
  • δ
• 1. inhibitory (Gi) protein


  Inhibits membrane-associated enzyme activities
• G proteins


  Function through GTP/GDP or ATP/ADP
• IP3 release and action

  1. Diffuses to ER surface

  2. Binds to IP3 receptor (IP3-R)

  3. Induces opening of Ca++ channel proteins

  4. Allows Ca++ exit from ER lumen into cytosol
• Calmodulin (CAM)


  Ca++-dependent regulatory protein that binds to Ca++ in cytosol
• Only IP3 has been found to cause Ca++ release by binding to ER receptor protein
• IP3 hydrolysis


  1. To inositol 1,4-bisphosphate (inactive)

  2. Usually terminates Ca++ release unless more IP3 is formed
• Diacylglycerol (DAG)


  Stays within plasma membrane
• Protein kinase C (PKC)


  • Activated by DAG and Ca++
  • Phosphorylates serine and threonine residues in target enzymes
• Tumor promoters


  • Lipid-soluble chemicals that activate PKC
  • Play a part in transforming normal cells into malignant ones
• Phorbol esters


  A class of tumor promoters that act as PKC "receptors"
• Phosphorylation of EGF receptor by PKC

  Decreases its affinity for EGF
• Overproduction of PKC in normal fibroblasts causes them to grow unattached to extracellular matrix, like tumor cells
• Appropriate degradation of phosphatidylinositol 4,5-bisphosphate to DAG and IP3, and subsequent stimulation of PKC by DAG, is fundamental in controlling cell growth