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Ch.9 12

membrane enzymes, membrane receptors

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Ch.9 12

  1. 1. • Also called cyclooxygenase (COX), main catalytic function is the conversion of arachidonic acid to prostaglandin H2 (PGH2) •Monotopic integral membrane proteins: bind to luminal leaflet of ER membrane and nuclear membrane •Implications in thrombosis, inflammation, neurological disorders,and cancer. •Great deal of attention as the target of non- steroidal anti-inflammatory drugs (NSAIDs) Prostaglandin H2 synthase
  2. 2. 2 Eicosanoids: paracrine hormones • Derived from the 20 carbon polyunsaturated fatty acid (arachidonic acid) • Involved in reproduction, inflammation, fever and pain • 3 classes: Prostaglandins, thromboxanes, leukotrienes Regulate synthesis of cAMP production  fever, pain, blood flow, and uterine contraction Produced by platelets, important in clotting and blood flow Inflammation, asthma, allergy
  3. 3. • Epithelial growth factor (EGF) domains (red), membrane binding domains (yellow), and catalytic domains (blue and gray).
  4. 4. Figure 9.4 Structure of a PGHS monomer, showing POX and COX active sites • Each monomer has 3 domains: catalytic domain (blue) has two active sites the POX (top of heme) and the COX (bottom) •Arachindonic acid (yellow space fill) is bound between these •Membrane binding domain (orange) below arachindonic acid •Epidermal growth factor (green) is on the side that becomes the subunit interface in the dimer.
  5. 5. NSAIDS •Many NSAIDS act as competitive inhibitors •They prevent substrate binding by occupying the upper part of the COX channel •Interactions between the drugs and the enzyme are hydrophobic •Exceptions being the interaction of the acidic NSAIDs with Arg120 and potential of a hydrogen bond with Ser530
  6. 6. Eicosapentaenoic acid (20:5ω-3) Omega-3 Fatty Acids
  7. 7. Phospholipid membrane Phospholipase A2 Cyclooxygenases (COX) Prostaglandins (PG) & Thromboxanes (TX) Lipoxygenases (LOX) Leukotrienes O HO O HO Arachidonic acidEicosapentaenoic acid -poor substrate for cyclooxygenases -gives rise to series 5 leukotrienes
  8. 8. G protein-coupled receptors • GPCRs respond to chemicals, light or odor and activate G proteins to initiate signal cascades – Prototype rhodopsin – Share a common structure of seven TM helices • Mechanosensitive (MS) channels transduce physical perturbations of the membrane into chemical and electrical signals
  9. 9. Generalize function of GPCR •Respond to a variety of stimuli including : light, odorants, calcium ions, small molecules and proteins •Trigger activation of the αβγ complex which stimulates the release of second messengers
  10. 10. Rhodopsin • located in rod cells of the eye •Rhodopsin consists of an apoprotein called opsin and a chromophore, 11-cis retinal •Bovine rhodopsin spans the membrane with seven α-helices with its C- terminus in the cytosol and its N-terminus on the exo-cytoplasmic surface •The seven helices have highly conserved residues at key positions
  11. 11. • The eye has two types of light sensitive neurons, rod cells and cone cells •Rod cells responsible for high resolution and night vision while cone cells are responsible for discerning color • Hyperpolarization of rod cells in response to light •In the absence of light cGMP- dependant ion channels in the outer segmant of the rod are open. •Decreases the Na+ gradient being pumped out by the Na+K+-ATPase. •Light absorption by rhodopsin causes the degradation of cGMP and the channels close and the cell becomes hyperpolarized.
  12. 12. 13 • Converted to active form • Regulates response of rod and cone cells in the retina to light • Regulates gene expression of development of epithelial tissue • Used to treat severe acne, wrinkled skin