Initiation of Fatty Acid Synthesis

in order to build fatty acid chains we have to begin with acetyl coenzyme a molecules because ultimately when we're synthesizing fatty acid chains were combined many acetyl coenzyme a molecules together now where do we get our supply of acetyl coenzyme a molecules well we obtain it in the matrix of the mitochondria via processes such as the beta oxidation of fatty acids we also generate acetyl coenzyme a molecules v the decarboxylation of pyruvate the catabolism of certain amino acids as well as the breakdown of ketone bodies but ultimately this acetyl coenzyme a molecule is found in a matrix of the mitochondria and that pose is a problem because fatty acid synthesis takes place in the cytoplasm of the cell but the existing coenzyme a molecules are located in the matrix of the mitochondria so we have to be able to move these as AZ of coenzyme a molecules from the matrix into the cytoplasm cell to actually initiate the process of fatty acid synthesis now there's a problem with moving acetyl coenzyme a molecules across the membrane of the mitochondrion the problem is its water soluble so if we look at the ctul coenzyme a molecule the coenzyme a component of the acetyl coenzyme a molecule prevents that acetyl group from actually moving across the inner mitochondrial membrane and so to ultimately allow the movement of that acetyl coenzyme a molecule across we have to remove that coenzyme a and so what happens is we transfer this cetyl group onto oxaloacetate in the process that is catalyzed by citrate synthase to form the citrate molecule and now we can move that citrate across the inner and then the outer membrane of the mitochondria and so this if we recall is simply the step step number one in the citric acid cycle now before we move on to the next steps of this is actually moving it across the membrane of the mitochondria and then seeing what happens inside the cytoplasm let's discuss which conditions actually lead to the synthesis of fatty acid so what conditions do we have to have in the matrix of the mitochondria to actually promote the process of fatty acid synthesis so in the matrix of the mitochondria by the way this is our matrix our cytoplasm the inner and the outer membrane of the mitochondria so we know that in the matrix we have the citric acid cycle and electron transport chain basically generating ATP molecules and so when we have high levels of ATP inside the matrix of the mitochondria we don't want to actually produce any more ATP molecules we want to stop the process of ATP synthesis and so what happens is when there are high levels of ATP in the matrix the mitochondria that ATP act as an allosteric inhibitor of one of the enzymes of the citric acid cycle so which enzyme isocitrate dehydrogenase isocitrate dehydrogenase basically transforms Isis citrate into alpha ketoglutarate and when we have high levels of ATP it blocks the activity of this enzyme and that leads to a buildup of Isis citrate in the matrix of the mitochondria now Isis citrate if we call back to the citric acid cycle can be interconverted in says citrate so it basically converts back and forth but if we have high levels of Isis citrate we're also going to see an accumulation of citrate molecules and this will promote fatty acid synthesis so high levels of ATP and high levels of citrate molecules basically stimulates the process of fatty acid synthesis and that makes sense because we need ATP and we need citrate to actually begin the process of fatty acid synthesis so once again what actually promotes what stimulates fatty acid synthesis well when the level of the matrix is high this means that we no longer need to actually synthesize any more ATP and therefore the ATP will create a negative feedback loop that will inhibit isocitrate dehydrogenase and this causes a buildup by the citrate which in turn causes a buildup of state-trait molecules and once we actually form citrate which involves transferring acetyl the acetyl group from acetyl coenzyme a onto oxaloacetate then that citrate can actually move across the inner and the outer membrane of the mitochondria and into the cytoplasm of that cell so in step 3 we have citrate is then transport across the membrane and the cytoplasm of that cell now the citrate itself is not actually used in the fatty acid synthesis process we have to actually obtain that acetyl coenzyme a back and so what happens is we have a process in which we take that citrate and we form back that oxalá oxaloacetate that we begin with and we also generate an acetyl coenzyme a molecule and this is carried out by the enzyme we call ATP citrate lyase so in order to regenerate the acetyl coenzyme a in cytoplasm the enzyme ATP citrate lyase uses an ATP and a coenzyme to reform the acetyl coenzyme a and that oxaloacetate as the byproduct so this is the reaction shown here so we have the citrate that is now on the cytoplasmic side we have a coenzyme a that is different than the coenzyme a that we had here because remember in this process the coenzyme a was essentially kicked off we combine these two by hydrolyzing ATP and we form an acetyl coenzyme a and the oxaloacetate so ultimately what actually moved across the membranes of the mitochondria are the oxaloacetate and the cetyl group that was attached onto oxaloacetate and it's the cetyl group that will ultimately be used to synthesize those fatty acids so it's this acetyl coenzyme a that will now go on to help synthesize fatty acid molecules as we'll discuss in the next several lectures now what about this oxaloacetate what is the fate of this oxaloacetate well now we actually have to transform the oxaloacetate into a molecule that can move across the membrane back into the matrix of the mitochondria so that we can recycle and reuse that oxaloacetate the problem is oxalá acetate cannot simply diffuse across the membrane of the mitochondria and we have to transform that oxaloacetate in a two-step process into pyruvate so let's see how this actually takes place so we have oxaloacetate we basically reduce oxaloacetate by using the reduction power of NADH to form a malate and this is step number five so the oxaloacetate cannot cross the mitochondrial membrane therefore to return back to the matrix it is first transformed into malate by malate dehydrogenase and this requires NADH and so we produce nad plus in this process now once we form mallilie an important process takes place that allows us not only to form the pyruvate that can now move across the matrix across the membrane of the mitochondria but we also generate NADPH and NADPH and this is important as we'll see in just a moment because this is the NADPH that we're going to use in the fatty acid synthesis process so next the malate undergoes an oxidative decarboxylation step that is catalyzed by the enzyme nadp+ linked malate enzyme also known as Mallik enzyme and this reaction is important because not only does it give us a way to actually move that molecule across the membrane of the mitochondria it also generates that nadph that will be used in fatty acid synthesis so malate in the presence of nadp+ and this enzyme nadp+ linked malate enzyme is transformed into pyruvate we essentially release a carbon dioxide and we form the NADPH and it's this NADPH that will be used by fatty acid synthesis in fact this is the major pathway that produces the highest number of NADPH molecules that will be used by the fatty acid synthesis process the remaining NADPH is will be produced via the pentose phosphate pathway now once we form pyruvate it moves across the membranes of the mitochondria into the matrix and inside the matrix we use pyruvate carboxylase to transform the pyruvate into oxaloacetate so the pyruvate can now move across the membrane into the matrix where it is transformed into oxaloacetate so this is the process by which we ultimately move that acetyl group from the matrix of the mitochondria into the cytoplasm so that now we can use that acetyl group to actually elongate and form those fatty acid chains and just like I said in the beginning what stimulates or promotes the process of fatty acid synthesis are high levels of ATP and citrate in the matrix of the mitochondria

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Keywords: inititation of fatty acid synthesis, fatty acid synthesis, oxaloacetate, acetyl-CoA transport, ATP citrate lyase, biochemistry, synthesis of fatty acids

Id: 6W5dntsodvo

Length: 10min 25sec (625 seconds)

Published: Sat Apr 09 2016