| Chem 431 |
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Fall 2001 |
| Lecture Notes:: 5 December |
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| PREVIOUS |
Fats come from two main sources: stored body fat and dietary fat. Dietary fat must first be emulsified to increase its surface area for contact with the water soluble lipases. This occurs largely in the duodenum after mixing with the bile acids, a family of cholesterol derived detergents. Triacylglycerols can then be hydrolyzed by pancreatic lipase to free fatty acids and 2-monoacylglycerol:
The fatty acids and monoacylglycerol are absorbed by the intestinal cells, converted to fatty acyl CoA and reassembled into triacylglycerols. The triacyl glycerols then assemble with phospholipids and lipoproteins to form chylomicrons for transport through the lymph and blood to the tissues.
When the chylomicrons reach tissue cells the triacylglycerols are again hydrolyzed by lipoprotein lipase to fatty acids which can be taken up by the peripheral tissue cells. In adipose cells the fatty acids are then converted into fatty acyl CoA's and combined into triacylglycerols for storage. Alternatively the fatty acids can be broken down for energy using the beta-oxidation pathway.
Free fatty acids are introduced into the cytosol, but b-oxidation occurs in the mitosol. Two situations occur.
Short to medium length fatty acids are permeable to the mitochondrial membrane. They are activated to fatty acyl CoA derivatives in the mitochondrial matrix by Butyryl-CoA Synthetase:
Note that two ATP equivalents are required: the phosphoanhydride and thioester bonds are of similar free energies, so a second phosphoanhydride bond is also hydrolyzed to drive the reaction to completion.
Long chain fatty acids are impermeable to the inner mitochondrial membrane (they are also toxic to the mito!). They are thus esterified in the cytosol by microsomal Fatty acyl CoA synthetase in a reaction identical to the one shown above. Again the reaction is driven by the hydrolysis of pyrophosphate. The enzyme involves an acyl AMP intermediate:
with Ping Pong Bi Uni-Uni Bi kinetics:
We now need to move the FA-CoA derivatives to the mitosol for breakdown by the b-oxidation pathway.
Carnitine Carrier: The resulting acyl CoA ester is still not permeable to the mitochondrial membrane so a carrier system is needed. In this system the fatty acyl group is transferred from CoA-S to carnitine, diffuses across the membrane, and then transferred back to another CoA-S within the matrix:
The carnitine transport step across the inner membrane is the slow step and flux generating step for b-oxidation of long chain fatty acids. Note that this system maintains separate pools of CoASH in the cytosol vs. the matrix.
The resulting fatty acyl CoA derivative can be broken down in the matrix by the fatty acid b-oxidation cycle [overhead] as shown in Figure 19.9, p 571, and the b-oxidation scheme in your Biochemistry Packets. [overhead] Note that the first three reactions of b-oxidation are the "mainline sequence" reactions we've already seen in the TCA Cycle. So you already know nearly all the reactions! The last reaction of the cycle releases an acetyl-CoA via a Claisen cleavage reaction (like an aldol cleavage but for esters instead of aldehydes). Note the similarity to the Claisen condensation from organic chemistry, but of course run in reverse, and with CoAS- substituting for the alkoxide ion:
Energy Yield: If we calculate the energy production for the complete oxidation of palmitate (16 C 's) we get:
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If we look at ATP/C we get 106/16= 6.63, while for glucose we get 32/6= 5.33, and for hexanoate: 36/6= 6. Thus, as expected, the fatty acids, being more reduced on average, give more energy per carbon and per gram. Along with the fact that they can also be stored without water of hydration, unlike carbohydrates, we can see their advantage as energy storage molecules for mobile organisms.
Another measure of fuel use is the P/O ratio, the number of ATP's generated for each oxygen atom consumed. For palmitate P/O = 106/46 = 2.3. As a comparison the P/O for glucose = 32/12 = 2.67. Notice by this measure glucose is the better fuel in situation where oxygen is limiting, since glucose will give more ATP's per mL of oxygen.
Most biological fatty acids are of even-numbered carbon chains. However, some organisms, particularly in the arctic marine environment, have a relatively high odd-chain component. Thus in organisms such as traditional Eskimos and polar bears eating lots of seal blubber and fish, odd-chain fatty acids can constitute a significant dietary component. These fatty acids are handled normally through beta-oxidation until the last turn, where pentyl-CoA is cleaved into acetyl-CoA and propionyl-CoA. The propionyl-CoA is converted, via some reactions we may look at with amino acid metabolism, through a number of steps to succinyl-CoA. These steps involve addition of carbon dioxide (with ATP energy) and an isomerization requiring cobalamin derived from vitamin B12. The succinyl-CoA can then be metabolized normally via the TCA cycle to malate, then to PEP and then to either 2-PGA for gluconeogenesis or to Pyruvate for energy production. (Propionate metabolism is also important to ruminants, since it is produced as a fermentation product by their symbiotic bacteria from plant matter.)
 Pathway Diagrams |
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