Biochemistry 401 lecture 20 Today we re going to talk about the TCA cycle This is a cycle that involves eight enzymes and its purpose is the oxidation of fuel and the formation of anabolic precursors This cycle also produces one GTP three NADH and one FADH2 We re going to discuss key reactions of this cycle and its regulation These notes are color coded to make things easier for you The enzymes are colored in blue and are italicized inhibitors are red positive effectors are green and important anabolic products are pink Some key thoughts regarding regulation are shown below There are primarily three modes of regulation in the cycle The first is the availability of substrate As metabolites build up in the cell this increase in substrate will drive reactions forward When these substrates are scarce the reactions will slow down Some enzymes are also inhibited by their products And finally there is negative feedback by downstream intermediates This is the TCA cycle TCA stands for tri carboxylic acid This is another name for citrate which appears at the top of the cycle If this were a clock citrate would be at twelve o clock Citrate s three carboxylic acid groups are highlighted in red This cycle is also called the citric acid cycle and the Krebs cycle for Hans Krebs who elucidated much of this cycle Now in looking at this it is important that you know the names of the enzymes and the metabolites that they important that you know the names of the enzymes and the metabolites that they form It is also important that you know where NADH FADH2 carbon dioxide and GTP are made As we go further on into this lecture you re going to see that many of the intermediates in this cycle can be used for other things besides just the production of energy and it s important that you know those as well One thing that I d like to tell you is that in the next exam you will not be asked to discriminate between real names and fake names If you see an enzyme on the exam it will be an actual enzyme So you re not going to have to distinguish between isocitrate dehydrogenase for instance and isocitrate synthetase or something like that Please note that there are two enzymes in this cycle that sound pretty similar succinyl CoA synthetase and succinate dehydrogenase Now the citric acid cycle is the hub of metabolism This is where fuels go to be oxidized A lot of the intermediates are also very important for other pathways Alpha ketoglutarate and oxaloacetate are important both for the synthesis of nucleotides and amino acids Succinyl CoA in the production of porphyrins and so truly the TCA cycle lies at the center of metabolism So let s look at this as an overview to really figure out what s going on here We re going to start and end with a four carbon molecule oxaloacetate We re going to bring in two carbons in the form of an acetyl group to yield a six carbon molecule Then there are going to be two oxidative decarboxylations in succession Each one will yield NADH and CO2 After the first one we ll have five carbons After the second one we ll have four carbons Following this we are going to form GTP or ATP depending on the tissue FADH2 and the last NADH to end up with oxaloacetate And so in this process there are three molecules of NADH that are produced Two molecules of carbon dioxide a molecule of either GTP or ATP depending on the tissue and one molecule of FADH2 and this is for every complete turn of the cycle going from oxaloacetate at the start and ending at oxaloacetate Let s look at this a little more closely before we go into the individual reactions And so oxaloacetate is going to combine with two carbons from acetyl CoA This is going to occur through a condensation reaction which produces the six carbon molecule citrate Then citrate is going to undergo an isomerization Water is going to leave and then water is going to come back again to form isocitrate and again this is an isomerization reaction that involves a dehydration and rehydration The next thing that s going to happen is the first oxidative decarboxylation to produce alpha ketoglutarate and since this is a redox reaction we have to have an electron carrier The electron carrier is NAD NAD accepts electrons two at a time as a hydride ion and the extra proton is released into solution And so at the end of this reaction we have five carbon alpha ketoglutarate carbon dioxide and NADH plus a proton The next thing that s going to happen is we re going to have a second oxidative decarboxylation This happens in reactions that are a lot like what happens in the pyruvate dehydrogenase complex Very similar enzyme complex conducting very similar reactions and what we re left with at the end is succinyl CoA carbon dioxide NADH and a proton Again this is a second oxidative decarboxylation and we ve now produced two molecules of NADH We ve released two molecules of carbon dioxide and now we re left with a four carbon intermediate succinyl CoA Now this is an activated intermediate The next thing that s going to happen is pretty big We re going to make ATP And this occurs through a substrate level phosphorylation and so we re going to use GDP or ADP it depends on the tissue which one is used and inorganic phosphate to make GTP or ATP And what we re left with is succinate This is a four carbon molecule and we ve produced also of course the GTP or the ATP and coenzyme A is also released And again this happens through substrate level phosphorylation the next thing that s going to happen is we re going to take this succinate and we re going to get all the energy that we can out of this So we re going to make sure that this is oxidized as much as it can be The next thing that s going to happen is we re going to in fact oxidize this with FAD as the electron carrier and we re going to end up with FADH2 and fumarate which is a four carbon molecule Now the next thing we re going to do is we re going to hydrate this fumarate We re going to add water in order to form malate Now we ve seen malate before and in order to get from malate to the starting material oxaloacetate so we can start all over again we re going to oxidize malate to form oxaloacetate And the electron carrier is going to be NAD and we re going to end up with NADH and a proton and oxaloacetate the four carbon molecule And so now we are back at the beginning and the reducing equivalents the NADH or the FADH2 are going to be used in the electron transport chain in order to make …
View Full Document
Unlocking...