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Lecture 23

BIOC13H3 Lecture 23: BIOC13 Lecture 23

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Biological Sciences
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Jason Brown

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BIOC13 Lecture 23  Skip a few slides and accept that fatty acids can get from the blood off of the albumin and get into the cytosol of the cell  In first step, the fatty acid will get activated, similar to glucose activation during glycogen synthesis  You have fatty acyl-coa synthetase, in the first step the fatty acid is going to react with the proximal most phosphate of atp causing it to break down and release free energy and use that energy to attach fatty acid to amp part of the molecule  That creates a fatty acyl adenylate, it remains enzyme bound so the enzyme doesn’t release the intermediate  In the second step, catalyzed by the same enzyme, we have a coa group which is going to react with the carbon on the fatty acyl adenylate and lead to a new bond forming, which is going to be a thioester (high energy structure)  The energy to drive the synthesis of the thioester comes from the simultaneous breaking of the bond between amp and the fatty acid part of the molecule  We end up with a fatty acyl coa, the amp goes free, at the end of this we have activated a fatty acid, we have taken a fatty acid and turned it into a more energetic compound, a fatty acyl coa, energetic because it has a thioester within its structure  Delta g for this process is near equilibrium, this confirms that the fatty acyl coa is energetically equivalent to that atp  Similar to glucose activation, where we turned glucose to udp glucose  When we have a bond break in the first part of the reaction, there’s a pyrophosphate that is liberated at that time and pyrophosphatase breaks the bond between the 2 phosphates and that liberates a large amount of free energy  This free energy released from the degradation of the pyrophosphate is what serves to drive the entire process towards the synthesis of fatty acyl coa  2 fates for Fatty acyl coa, one is that it can be used for triacylglycerol  Other fate for this fatty acyl coa would be for it to enter into the mitochondrial matrix and there it can be oxidized  The imm is completely impermeable to any coa containing molecule, like acetyl coa, free coa, similar to how oxaloacetate cant, nadh cant  To get it into matrix we need a shuttling system, such as carnitine shuttle  Carnitine shuttle has 3 proteins together  On the outer face of the outer mm you find cpt1 reacts carnitine with acyl coa to produce acyl carnitine and a free coa, swapping coa for a carnitine  We remove the coa and attach a carnitine in its place to get it across membrane  This is now able to diffuse into the inter membrane space  The translocase will carry the acyl carnitine across the imm into the matrix  Once inside the matrix, cpt2 comes in, sitting on the inner face of the imm, and it will carry out the reverse of the reaction that cpt1 did  So it will move the carnitine from the acyl group and put a coa in its place  We have regenerated a free carnitine which can be shuttles back out through the translocase so it can participate in this cpt1 reaction and the acyl coa can be oxidized  Imm is impermeable to coa because theres reactions in the cytosol which require coa and multiple reactions in the matrix that require coa, so we are worried that if we allow fatty acyl coa to enter into the matrix and that coa eventually gets taken off, then is it just going to go back out or is it going to get caught up in whats going on in the matrix (similar to what we saw with NADH before)  So we just make it impermeable to coa so that it will always be out in the cytosol and wont accidently get sucked into the matrix  Since we are breaking acyl coa apart and making acyl carnitine with that energy, then acyl carnitine must be a highly energetic molecule  Carnitine is a zwitterion, meaning it has a positive and negative charge in its structure  These are stable molecules as long as they are water soluble  Carnitine is water soluble, but as soon as you attach a big fatty acyl group on it, it’s no longer water soluble  As we convert carnitine into fatty acyl carnitine, that’s going to be an endergonic process because we are converting a low energy, stable molecule into a something unstable  The free energy from breaking thioester in acyl coa is used to turn carnitine into a much less stable and more energetic molecule  In the mitochondria we break that acyl carnitine and free that carnitine, it becomes very stable so there’s a huge free energy release and use that to stick coa back onto acyl group  How do we oxidize it?  Basic mechanism for oxidation for fatty acyl coa was known from 100 years ago  Experiment was he fed dogs fatty acids that were modified so they had a benzene ring attached onto their omega carbon, and we cant oxidize benzene rings, so creating a fatty acid with a non-oxidizable tag on it  Fed both odd chain and even chain fatty acids with benzene, one or the other  Then collected the urine to see what was excreted  The excretion product differed depending on whether he gave them an even or odd chain  Why does excretion product depend on odd, even?  Because benzene rings are not soluble, the liver will tag onto them this more water soluble glycine  When we oxidize fatty acids, we don’t oxidize every individual carbon, instead we oxidize every other carbon of the fatty acid  Proposed a process called beta oxidation, beta carbon gets oxidized  If we oxidized every individual carbon we get to the benzene ring which we cant oxidize and we stop there and excrete the product  If we were oxidizing all carbons then in even and odd we should get the same benzene ring, but that’s not what happens we get 2 different end products  This tells us that it can only be like that if we oxidize every other carbon  There are 4 steps to beta oxidation pathway  This only applies to even number chain, saturated fatty acids  As soon as you go to odd chain or unsaturated, you have to use additional steps to assist  First reaction is an oxidation reaction, carried out by acylcoa dehydrogenase, uses fad as its electron acceptor, instead of NAD, create trans enol coa  Then the double bond created gets hydrated, creates beta hydroxyacyl coa  Then oxidize it with HOAD, uses NAD as electron acceptor, creating a molecule called ketoacyl coa, and the last step is to break the bond between the alpha and beta carbon and that is done by an enzyme called thiolase  It is called thiolase because it will use a sulfur based molecule a coa to carry out the breakage of the bond  When you break the bond between the alpha and beta carbon you will have a 2 carbon molecule with a thioester and a coa and that molecule is an acetyl coa  So the oxidation of fatty acids produces acetyl coa, which then goes to citric acids cycle  After you still have the rest of the molecule, which is just a fatty acyl coa, but its been shortened by 2 carbons because of the 2 carbons we just cut off  Now this fatty acyl coa will just go through the cycle again getting oxidized and cleaved, keep going until the last step produces 2 acetyl coa and at that point
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