C OO -

1. COO- COO- AcCoA O O O O CH2 CH2 H H COO- COO- OC OC COO- COO- COO- COO- COO- CH2 CH2 C C C CH2 C COO- CH2 CH2 CH2 CH2 CH2 COO- COO- COO- COO- COO- O O O COO- COO- CH3C-SCoA CH3C-SCoA CH3C-SCoA OH HC C O CH2 CH3 COO- CO2 or CO2 + + COO-

2. COO- COO- O O O O CH2 CH2 H H COO- COO- OC OC COO- COO- COO- COO- COO- CH2 CH2 COO- COO- C C C CH2 C CH2 CH2 CH2 CH2 CH2 COO- COO- COO- COO- COO- O O O COO- COO- CH3C-SCoA CH3C-SCoA CH3C-SCoA OH HC C O CH2 CH3 COO- AcCoA CO2 or CO2 + +

3. prostaglandins Prostaglandin H2 Synthase

4. NSAIDS: nonsteroidal anti inflamatory drugs inhibit formation of prostaglandins involved in fever, pain and inflammation

5. Synthesis of prostaglandins from arachidonic acid: the cyclic pathway What: Prostaglandins and related compounds are "local hormones" that are synthesized from the polyunsaturated fatty acid arachidonate. They have specific effects on target cells close to their site of formation. They are rapidly degraded, so they are not transported to distal sites within the body. Prostaglandins and related compounds are collectively known as eicosanoids.They are produced from arachidonic acid, a 20-carbon polyunsaturated fatty acid  (5,8,11,14-eicosatetraenoic acid). How: Prostaglandin receptors: Prostaglandins and related compounds are transported out of the cells that synthesize them. Most affect other cells by interacting with plasma membrane G-protein coupled receptors. Depending on the cell type, the activated G protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release. Effects: They have roles in inflammation, fever, regulation of blood pressure, blood clotting, control of reproductive processes and tissue growth, and regulation of the sleep/wake cycle.

6. Synthesis of prostaglandins Prostaglandin H2 Synthase is a heme-containing dioxygenase, bound to endoplasmic reticulum membranes. (A dioxygenase incorporates O2 into a substrate.) PGH2 Synthase exhibits two catalytic activities, Cyclooxygenase and Peroxidase. The enzyme expressing both activities is sometimes referred to as Cyclooxygenase, abbreviated COX.

7. COX-1 vs COX-2 • COX-1 is constitutively expressed at low levels in many cell types. COX-1 is essential for maintaining the integrity of the gastrointestinal epithelium. • COX-2 expression is stimulated by growth factors, cytokines, and endotoxins. Inflammation is associated with up-regulation of COX-2 and increased formation of prostaglandins. COX-2 levels increase in inflammatory disease states such as arthritis. Increased expression of COX-2 is seen in some cancer cells. Angiogenesis (blood vessel development) essential to tumor growth requires COX-2. Overexpression of COX-2 leads to increased expression of VEGF (vascular endothelial growth factor).

8. NSAIDS: nonsteroidal anti inflamatory drugs inhibit formation of prostaglandins involved in fever, pain and inflammation • Ibuprofen and related compounds act by blocking the hydrophobic channel by which arachidonate enters the Cyclooxygenase active site. • Aspirin acetylates a serine residue, near the • Cyclooxygenase active site. This prevents binding • of arachidonate. The inhibition by aspirin is • irreversible. 

9. More selective COX-2 inhibitors have been developed, e.g., Celebrex and Vioxx. COX-2 inhibitors are anti-inflammatory and block pain, but are less likely to cause the gastric toxicity that often accompanies chronic use of less specific NSAIDs.  

10. OH -OOC CH2C- O O O O O O O O O O O O O CH3 CH2C-O- CH2C-SCoA CH3C- CH2C-SCoA CH3C- CH2C-O- CH3C-SCoA CH3C- CH3C-SCoA CH3C- CH2C-SCoA CH3C-SCoA CH3C-SCoA CH3 O 2 CH3C-SCoA + Synthesis of ketone bodies CoASH HMGCoA synthase bhydroxy bmethyl glutaryl CoA HMGCoA Succinyl CoA acetoacetate Succinate OH CH3C- acetone H CoA Acetoacetyl CoA bhydroxy butyrate

11. Liver blood tissue 2 AcCoA FFA Acetone AcAcCoA AcAc AcAc AcAc b-hydroxybutyrate b-hydroxybutyrate b-hydroxybutyrate

12. Effect of activity of circulating ketone bodies 2 X X non-athelete [KB] (mM) 1 running X athelete X X X X before activity X X X X X 1 2 3 Time (hours)