31 - Monday, November 8, 2010 Lecture 31 1. Reading and...

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Monday, November 8, 2010 Lecture 31 1. Reading and problems for this week as in LG. PYMOL assignment #9, ATP Synthase 2. Have a final exam conflict? Meet immediately after class on 11/10 to set the day and time for the make-up final exam. Friday’s class: CAC: . complete ox of acetyl group. . Control at the three steps where enzyme is not fully active, as recognized by large negative G of the rxn. Also, rxn rate in PDH Complex is under control. . CAC intermediates are directly connected to AA biosyn, fatty acid and steroid biosyn, porphyrin biosyn. . Fatty acid uptake from the diet Today's lecture: Where are the reactions going on? All enzymes for fatty acid oxidation are in the mitochondrial matrix. But FA start out in the cytosol. In the outer mitochondrial membrane is the enzyme fatty acyl-CoA synthetase (since the outer membrane is so permeable, this enzyme is accessible to any small molecules in the cytosol). This enzyme uses a two-step reaction in its active site: 1. (top of p. 215) the fatty acyl O - attacks the α -P of ATP, releasing pyrophosphate. The pyrophosphate is very important, and we will return to it in a moment. 2. This FA with AMP now attached is said to be "activated", since hydrolysis of the bond would release a lot of energy. In the second reaction, still in the active site of FA-CoA synthetase, there is a nucleophilic attack of the S: of CoA on the activated carbon. AMP is released and Co-A is now attached via a thioester bond. Since this is a high-energy bond, the molecule is still "activated." The creation of this fatty acyl-CoA thioester is made more favorable because the pyrophosphate that was formed in the first step of the reaction is hydrolyzed , catalyzed by the enzyme inorganic pyrophosphatase, a very favorable step, which helps drive the overall reaction of FA activation. r p. 216 New principle of metabolism: Here we come to an important general way that cells regulate metabolism in an overall sense. Metabolism involves several 1000s of rxns. At all costs, these rxns must never be allowed to go out of control. One way that cells prevent rxns from "taking off" is to limit availability of a key substrate. One such key molecule is CoA. Cells keep tight control over the concentration of CoA in each compartment (we have noticed that the cytosol and
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the mitochondrial matrix are two membrane-separated compartments). In that way, chemical rxns of metabolism can never go far out of control, as could happen, for example, if too much fuel in the form of fatty acyl-CoA were to enter the mitochondrion. In the case of fatty acyl-CoA, the CoA that is part of the cytosolic pool of CoA does not enter the mitochondrion. Carnitine is substituted for CoA in a reaction catalyzed by carnitine acyltransferase I on the outside of the inner mitochondrial membrane (this is called the intermembrane space). Although an ester is formed in the carnitine- FA, the bond is still "high energy" because of steric hindrance of the ester with the quaternary ammonium of carnitine. The resulting fatty acyl carnitine passes through the inner mitochondrial
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This note was uploaded on 12/10/2011 for the course BCHEM 3350 taught by Professor Feig during the Fall '09 term at Cornell University (Engineering School).

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31 - Monday, November 8, 2010 Lecture 31 1. Reading and...

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