Biochemistry 401 Lecture 27 Today we re going to talk about some additional topics in fatty acid oxidation These include the catabolism of odd numbered fatty acids and the catabolism that occurs in peroxisomes We re then going to turn to the glyoxylate cycle and then fatty acid synthesis This is going to include both the synthesis of saturated fatty acids and unsaturated fatty acids We re then going to turn to fatty acid synthesis This includes the synthesis of saturated and unsaturated fatty acids And finally were going to talk about the regulation of fatty acid metabolism both the regulation of fatty acid degradation and fatty acid synthesis So let s get started What about fatty acids with odd numbers of carbons Well fatty acid catabolism will proceed as normal releasing two carbons at a time until the very last round of beta oxidation leaves a three carbon fatty acid proprionyl CoA This proprionyl CoA will be used to synthesize succinyl CoA in three steps The first step is a carboxylation We re going to add carbon in an ATP dependent carboxylation using biotin We end up with D methylmalonyl CoA and we re going to racimize that from D to L methylmalonyl CoA and then finally we re going to rearrange this molecule to make succinyl CoA Now this step involves an intramolecular reconfiguration and this is a big job and so we re going to use a big cofactor cobalamin B12 Now this is a process that involves some radical chemistry and finally we re going to end up with succinyl CoA that can enter the TCA cycle So let s look at each of these individual steps one by one and we ll start with an overview of what cobalamin is Cobalamin is a large complex ring structure prosthetic group that contains a central cobalt This cobalt is organized in the center of a corrin ring that is a lot like the porphyrin rings that we saw previously in that it is comprised of four pyrrole rings However these pyrrole rings have different degrees of saturation and different substituents than the porphyrin ring Additionally it has another functional group called a benzimidazole ring that helps suppress that a group to function properly There is a variable region shown here by x This x can involve different functional groups one of which is a 5 deoxyadenosyl group that is shown here Now this prosthetic group is used in reactions that involve difficult rearrangements of configuration and the one that we re going do to convert methylmalonyl CoA to succinyl CoA is pretty radical 1 This mutase reaction results in intramolecular rearrangement of methylmalonyl CoA Cobalt allows formation of a free radical that s necessary for this reaction and the reason that this can occur is that the bond between CH 2 and cobalt is very tenuous and can be broken easily to yield a radical This happens through something called a homolytic bond cleavage and what this means is that one electron stays with the cobalt to reduce it to Co 2 and the other one goes with CH2 to form a 5 deoxyadenosyl radical This is not the normal heterolytic cleavage in which both electrons go with one or the other bonding partner but rather it is a homolytic bond cleavage in which one electron goes with one bonding partner and the other one stays with the other binding partner In this case we re left with 5 deoxyadenosyl radical and cobalt that is reduced to 2 It is the ability of cobalamin to form radicals that allows it to function in this mutase reaction So now that we have a free radical at the 5 deoxyadenosyl group what we going to do with it and how is this going to affect the formation of succinyl CoA Well the first thing that s going to happen is the radical is going to abstract a hydrogen atom from the methyl group of L methylmalonyl CoA to form a CH 2 radical there This is going to spontaneously rearrange such that the carboxyl CoA is going to migrate to the site where the radical is and the electron is going to migrate to where the carboxylate coenzyme A was This is the intramolecular rearrangement and it happens spontaneously after radical formation Finally this radical will abstract a hydrogen atom from 5 deoxyadenosine to form a 5 deoxyadenosine radical again To reconstitute the functional enzyme this radical will form a covalent bond to cobalt in the corrin ring and so from an Lmethylmalonyl CoA we get succinyl CoA Cobalamin vitamin B12 is necessary for this reaction and it involves radical chemistry Now we talked about catabolism of fatty acids occurring in the mitochondrial matrix but it also can occur in peroxisomes in mammals and it occurs exclusively in peroxisomes in plants and in yeast rather than the mitochondria Now the peroxisome is bounded by a single membrane and this organelle is thought to arise from the endoplasmic reticulum There are many enzymes that are found here that catalyze reactions that result in the production of peroxides H2O2 In mammals long chain fatty acids are catabolized here to form shorter octanoyl fatty acid chains that can then go to the mitochondrion for further degradation 2 In this side we see the first cycle of fatty acid breakdown as it occurs in peroxisomes It s different from what we see in mitochondria In this pathway acyl CoA dehydrogenase uses FAD to oxidize the acyl group to yield a double bond In the process FADH2 is generated This FADH2 passes its electrons off to molecular oxygen to form peroxide and then an enzyme called catalase can actually break down this peroxide to form water and one half O 2 The fatty acyl intermediate can then go on through further oxidations that are very similar to those that we see in the beta oxidation that occurs in mitochondria Now in plants and yeast acetyl CoA units can enter something called the glyoxylate cycle This is similar to the citric acid cycle in some ways as it involves similar enzymes However there s one main difference We re not going to do any decarboxylations We re going to start with acetyl CoA and oxaloacetate using the enzyme citrate synthase to form citrate We re then going to do the molecular rearrangement using aconitase that we saw in the TCA cycle But this is where the steps differ Once we get to isocitrate we re going to use an enzyme called isocitrate lyase that breaks apart isocitrate to form succinate and glyoxylate Now succinate as you ll recall is a four carbon molecule Glyoxylate is a two carbon molecule The succinate that s generated can go on to make glucose and so in plants and in yeast we can use acetyl CoA to form succinate
View Full Document
Unlocking...