| Chem 431 |
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Fall 2007 |
| Lecture Notes: 28 November |
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| PREVIOUS |
Fat Metabolism
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 
-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 are bound to Fatty acid binding protein for transport within the cytosol. They 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:
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, crosses the membrane via facilitated diffusion catalysed by the Carnitine transporter, 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 -oxidation of long chain fatty acids. This step is limited by the acylation by Carnitine acyl transferase enyme. This enzyme is also the control step, as it is inhibited by Malony-CoA, the product of the first step of fatty acid biosynthesis. Thus simultaneous fatty acid biosynthesis and breakdown is prevented.
Note that this system also maintains separate pools of CoASH in the cytosol vs. the matrix.
Once inside the mitochodrial matrix fatty acyl CoA can be broken down in the matrix by the fatty acid -oxidation cycle [overhead] as shown in Figure 16.19, and the -oxidation scheme in your Biochemistry Packets. [overhead] Note that the first three reactions of -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 in the cleavage reaction.
 Pathway Diagrams |
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Last modified 28 November 2007
