HW Lecture #28: Fatty Acid Biosynthesis, Regulation of Fatty Acid Metabolism

Pg. 609 (Study Exercises 6,7,8)

6. Describe the shuttle systems for transporting fatty acids into the mitochondria and acetyl-CoA into the cytosol.

Fatty Acids into Mito: Fatty acids are activated in the cytosol (via ATP coupled ligation of fatty acid with CoA to form acyl CoA catalyzed by acyl Co synthase; pg 569). Once "activated" the fatty acyl CoA is transported from the cytosol into the mitochondria for fatty acid oxidation via the acyl-CoA transport system (Fig. 19-8; pg. 570). The acyl group is transferred from acyl-CoA to carnitine (catalyzed by carnitine palmitoyl transferase I). A carrier protein then transports acyl-carnitine into the mitochondrion while transporting free carnitine in the opposite direction (antiport). Once inside the mitochondrion, carnitine palmitoyl transferase II catalyzes transfer of the aceyl group from carnitine to Co-A. The product carnitine is returned to the cytosol.

Acetyl CoA into cytosol: During times of energy excess, acetyl CoA must be transported from the mitochondrion to the cytosol for fatty acid biosynthesis. In this case, the tricarboxylate transport system (Fig. 19-20; pg 583) transports Acetyl CoA from the mitochondrion into the cytosol. Because acetyl CoA can not cross the membrane it condenses with oxaloacetate to form citrate (catalyzed by citrate synthase; the first reaction of the Citric Acid Cycle)! Citrate is then carried into the cytosol via a carrier protein called the Tricarboxylate Transport System. Once in the mitochondrion, acetyl CoA and oxaloacetate are liberated by ATP-citrate lyase.

7. Summarize the similarities and differences between fatty acid oxidation and biosynthesis.

Opposing pathways of fatty acid oxidation and synthesis differ which permits them both to be thermodynamically favorable and indpendently regulated under similar physiological conditions. Differences include cellular localizations, redox coenzymes, manner in which C2 units are added or removed from the fatty acyl chain (see Fig 19-19; pg 582)

Note malonyl CoA is formed from acetyl CoA and HCO₃^-; catalyzed by acetyl CoA carboxylase. The carboxyl group, derived from bicarbonate is first transferred to biotin in an ATP-dependent reaction. The biotin group serves as a temporary carrier of CO2, transferring it to acetyl CoA in the second step to yield malonyl CoA.

6. Describe the major mechanisms of regulating fatty acid metabolism in humans.

The opposing pathways of fatty acid degradation and synthesis are hormonally regulated. Glucagon (released when blood glucose is low; i.e.,you are hungry) and epinephrine (fight/flight) activate hormone sensitive lipase in adipose tissue, thereby increasing the supply of fatty acids for oxidation in other tissues, and inactivate acyl-CoA carboxylase. (No need to synthesize fat when you want to oxidize it). Insulin (released when blood sugar is high; i.e., you just ate) has the opposite effects. Hormones also regulate levels of acetyl CoA carboxylase and fatty acid synthase by controlling their rates of synthesis.

Most amazingly, Malonyl CoA appears to inhibit appetite. Fatty acid synthase inhibitors may be the next (and perhaps the first effective) generation of diet pills!