membrane enzymes and receptors

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
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. • Epithelial growth factor (EGF) domains (red), membrane
binding domains (yellow), and catalytic domains (blue and gray).

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. 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. Eicosapentaenoic acid (20:5ω-3)
Omega-3 Fatty Acids

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. 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. 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. 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

12. 12
• 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