Hello friends, today's topic of discussion is tricarboxylic acid cycle. It is a very very important question for university examination. It is a long answer question frequently asked in university or college examination.
Coming to the introduction, this cycle was completely described by Sir Hans Green. in 1937 and got Nobel Nobel Prize in 1953. That's why the another name of this cycle is Krebs cycle. This tricyclic acid tricarboxylic acid was later known by the name citric acid.
It is due to the discoverer that is Oxtone. Later in 1948, Oxton described that the tricarboxylic acid described by the hand scrapes is citric acid. That's why the another name for this cycle is citric acid cycle.
PCA cycle, citric acid cycle, scrapes cycle or metabolic traffic circle. As number of pathways or number of intermediates from this scrapes cycle are important. metabolic intermediate in other pathways that was that's why it is also known as metabolic traffic circle now coming to the significance of this pathway this pathway occurs in the mitochondria mitochondria i'm coming to the significance it is a final common oxidative pathway oxidative pathway for conversion into carbon dioxide. It is a final common oxidative pathway for oxidation of all foodstuffs, carbohydrate, protein, fat. Okay.
Second important point, it gives reducing equivalence that is NADH FADH2. There is synthesis of ATP one substrate level phosphorylation reaction GTP which ultimately converted into ATP. Oxaloacetate act as a catalyst in this pathway. It is condenses with citrate then this acetyl CoA it condenses with acetyl CoA converted into citrate and again through all reaction it is again regenerated. That's why it is known as catalyst and one sentence is there that is fat is burn on the weak of carbohydrate is fat is burn on weak of carbohydrate here weak is oxaloacetate which is generated from carbohydrate from pyruvate by pyruvate carboxylase reaction so fat is burn on the weak of carbohydrate for burning of fat fat is ultimately converted into acetyl coenzyme a and for oxidation of acetyl coenzyme a oxaloacetate is required That's why it is known as fat is born on the weak of carbohydrate and excess of fat.
This excess of carbohydrate, this carbohydrate is converted into fat, but reversal is not possible because of irreversible reaction catalyzed by pyruvate dehydrogenase complex irreversible reaction catalyzed by pyruvate dehydrogenase complex. This is important, this pathway is important in synthesis of non-essential amino acids. It is important in the synthesis of heme, porphyrins. It is important in the synthesis of purines and pyrimidines. Heme, sub-synil coenzyme A plus glycine is an initial substrate for heme synthesis.
It is important in the synthesis of aspartate from oxaloacetate which is important in purine and pyrimidine synthesis. It provides the intermediates of number of metabolic pathways and the intermediates of this TCA cycle also act as a regulatory factors in number of pathways. So this is significance of this TCA cycle.
a great cycle. Now coming to the steps, it has eight important steps in the mitochondrial matrix. How many steps? Eight important steps catalyzed by eight important enzymes. This is the first reaction in which this acetyl coenzyme A condenses with oxaloacetate.
This is a four carbon compound. This is two carbon compound. to give a 6 carbon compound that is tricarboxylic acid citrate with the help of enzyme citrate synthase. In the next reaction this citrate is isomerized into isocitrate. It is a two-step reaction in which citrate is converted into cis aconitrate and this cis aconitrate is converted into isocitrate by the process of dehydration and rehydration.
dehydration, removal of water molecule and addition of water molecule. It is converted into isocytes. There is shifting of OH group from one carbon to another. That's why it is known as isomerization reaction. Citrate is converted into isocytes.
Then isocytrate is converted into oxalo subsinate. It is a two-step reaction in which isocytrate is converted into oxalo subsinate which is converted it into alpha-ketoglutar. There is production of NADH here from NAD and from oxalanoxoxonate by spontaneous decarboxylation there is formation of alpha-ketoglutarate. So this is oxidative decarboxylation conversion of isocitrate to alpha-ketoglutarate with the help of isocitrate dehydrogenase oxidative decarboxylation. alpha-ketoglutarate again undergoes oxidative decarboxylation to give NADH.
There is liberation of one molecule of CO2. Coenzyme A is added here. Okay.
So, 2CO2, they are removed. 2 carbon from acetyl coenzyme A removed as CO2. One in the state catalyzed by isocytrate dehydrogenase and another in the state catalyzed by alpha-ketoglutarate dehydrogenase. This is the first site for NADH production. This is the second site for NADH production.
This is a multi enzyme complex. It is a multi enzyme complex. It is composed of this alpha-ketoglutarate dehydrogenase composed of three enzymes and five coenzymes.
It is an important MCQ. Three enzymes and five coenzymes. Five coenzymes are PPP, FAD, NAD, lipoic acid and coenzyme A. These are the five coenzymes.
It is an important MCQ. It is similar to that of pyruvate dehydrogenase complex. This alpha-ketoglutarate is converted into succinyl coenzyme A by oxidative decarboxylation catalyzed by alpha-ketoglutarate dehydrogenase. then succinyl coenzyme a is converted into succinate with the help in this reaction this gdp is converted into gtp which ultimately gives atp this is a high energy compound the coenzyme this succinyl coenzyme a it is a high energy compound and from this compound there is direct production of atp that's why it is known as substrate level phosphorylation by succinate thiocyanate substrate level phosphorylation synthesis of ATP without undergoing electron transport chain is known as substrate level phosphorylation.
Then here succinate is converted into fumarate by succinate dehydrogenase. FAD is converted into FADH2. Then fumarase by addition of water molecule it is converted into malate and again malate is converted into oxaloacetate by malate dehydrogenase in this NAD is converted into NADH and oxaloacetate is regenerated so oxaloacetate is known as catalyst in the grape cycle because it enters in the reaction and remains as it is at the end that's why it is known as catalyst oxaloacetate it is a weak of carbohydrate which is required for burning of fat burning of acetyl coenzyme a to carbon from acetyl coa Liberated as CO2, one in the isocytrate dehydrogenase reaction and another in alpha-ketoglutarate dehydrogenase reaction.
Three sites for NADH production. First, this is isocytrate dehydrogenase. First, second alpha-ketoglutarate dehydrogenase.
Third one is the malate dehydrogenase. Three NADH production. One FADH2 production by succinate dehydrogenase. And one ATP production by substrate level phosphorylation.
Okay. So, coming to the energetics of this pathway. 3 NADH production will give 2.5 is equal to 7.5 ATP. 1 FADH2 will give 1.5 ATP and 1 substrate level phosphorylation will give 1 ATP.
Total is 10. Per turn of acetyl coenzyme A you will get 10 ATP. For glucose you will get 20 ATPs from glucose you will get two pyruvate then two acetone coenzyme A and 20 ATPs from one molecule of glucose by TCA cycle but per turn of acetone coenzyme A will give 10 ATPs this is the energetic of TCA cycle then some inhibitors are there inhibitors of TCA cycle it is a very very important MCQ inhibitors of TCA cycle the pneumonic There is one important and easy mnemonic to remember this TCA cycle that is citrate is Krebs starting substrate for making oxaloacetate. This is a mnemonic to remember intermediates of TCA cycle citrate, isocitrate.
Ketoglutarate, succinyl coenzyme A, succinate, fumarate, malate, oxaloacetate. It is a pneumonic to remember intermediates of TCA cycle. Now inhibitors of TCA cycle, one important pneumonic is there to remember the inhibitors of TCA cycle. That is FAMAKS. FAMAKS.
FAMAKS. Okay. This is aconitase. Ketoglutarate dehydrogenase, succinate dehydrogenase.
These are the enzymes. These are inhibitor. Aconitase, it is inhibited by fluoroacetate. Then alpha-ketoglutarate dehydrogenase inhibited by arsenide.
And succinate dehydrogenase inhibited by malonate. This is an important MCQ, malonate, important, very, very important MCQ. succinate dehydrogenase is inhibited by malonate these are the inhibitor this is pneumonic to remember tca cycle this is pneumonic to remember inhibitors of tca cycle now coming to the regulation regulation is important and it is dependent on availability of the substrate regulation of tca cycle is important in the important it is first by the availability of substrate availability of substrate. Okay. ADP is important regulator.
Availability of ADP is important. ADP will stimulate the pathway. It is regulated by citrate synthase, isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. These are the three important enzymes which are allosterically regulated by different inhibitors. The important role of this pathway is the production of ATP.
So, if ATP is available, ATP will inhibit this pathway. If NADH is available, NADH will inhibit this pathway. If ADP is available, it will stimulate the pathway. And the substrates, for example, succinyl coenzyme A will inhibit alpha-ketoglutarate dehydrogen.
the acetyl coenzyme a will inhibit pyruvate dehydrogenase in this way this pathway is regulated this is the regulation of tca cycle now coming to the amphibolic role of tca cycle it is important amphibolic amphibolic role of tca cycle means this cycle is anabolic as well as catabolic that is known as amphibolic role of tca cycle anabolic as well as catabolic okay So catabolic role of TCA cycle we already seen. This acetyl coenzyme A is converted catabolic. Catabolic means this acetyl coenzyme A will give you two molecule of CO2.
This is a catabolic role. All foodstuffs they are oxidized into CO2 by this pathway. In anabolic role this pathway for example this oxaloacetate in anabolism Amphibolic role means catabolic as well as anabolic. This oxaloacetate it is converted into aspartate and this aspartate is imported into synthesis of purines and pyrimidines. This is the anabolic role.
then this citrate it is an important source of acetyl coenzyme a in cytosol in cytosol the citrate citrate is important source of acetyl coenzyme A which is required for fatty acid synthesis, cholesterol synthesis. This is the second. Then this alpha-ketoglutarate, it will give you glutamate, it will give you GABA, gamma-aminobutyric acid, glutamate and GABA.
In succinyl coenzyme A it is important In the synthesis of heme, it is important in the synthesis of porphyrin heme, succinyl coenzyme. Also, it is important in ketolysis, heme synthesis, ketolysis. So, this is important anabolic role of this TCA cycle. Synthesis of aspartate, synthesis of purines, pyrimidines, synthesis of non-essential amino acids. synthesis of fatty acid and cholesterol from acetyl coenzyme A in the cytosol via the citrate.
Then it will give you glutamate, gamma amyl butyric acid, succinyl coenzyme A will give you heme. It is important in fetalysis. So this is anabolic role of TCA cycle. Now coming to the important short note that is anaplerotic reactions of the TCA cycle. What do you mean by anaplerotic reaction of the TCA cycle.
Anaflurosis means The reaction which replenishes the intermediates of TCA cycle is known as anaplerotic reaction. Anaplerotic reaction it is an important short note. Okay, the first anaplerotic reaction is formation of oxaloacetate from pyruvate by pyruvate carboxylase. Carboxylase, Carboxylase required A, B, C, ATP, biotin and CO2 is required.
Pyruvate is converted into oxaloacetate by pyruvate carboxylase. The reaction which replenishes the stores are the intermediates of TCA cycle are known as anaplerotic reaction. So this is oxaloacetate. It is the intermediate of TCA cycle. Second important is This glutamate is converted into alpha-ketoglutarate by transamination and deamination.
Glutamate is converted into alpha-ketoglutarate. Then important amino acids, for example, this glutamate, then arginine, proline, arginine, proline, histidine. These amino acids will give you alpha-ketoglutarate. Then third succinyl coenzyme A, propionyl coenzyme A will give you succinyl coenzyme A and it is also from valine, methionine, isoleucine and threonine. Threonine you will get succinyl coenzyme A.
then Tyrosine phenylalanine will give you fumarate. Urea cycle also gives you fumarate. Then synthesis of malate from pyruvate by the malic enzyme is an example of.
anaplerotic reaction pyruvate is converted into malate by malic enzyme this is a NADPH dependent reaction And sixth one is the conversion of aspartate to oxaloacetate. This is important by transamination reaction aspartate is converted into oxaloacetate. So these are the six important anaplerotic reaction which fills up the intermediates of TCA cycle. Pyruvate is converted into oxaloacetate, glutamate and these amino acids are converted into alpha-ketoglutarate.
Propinyl coenzyme, valine, methionine, isoleucine, threonine will give succinyl coenzyme. Glucogenic amino acid urea cycle will give you fumarate. This pyruvate is converted into malate by malic enzymes and aspartate is converted into oxaloacetate by transaminase reaction.
This is important short note. Anapluritic reactions of TCA cycle. Summarizing the TCA cycle, it is an important metabolic pathway.
It is common oxidative pathway for all foodstuff. Oxaloacetate in this pathway act as a catalyst it is regenerated. Oxaloacetate is required for the burning of acetyl coenzyme A that's why sentence is there fat is burned on the beak of carbohydrate.
There are three inhibitors of TCA cycle that is a malonate, arsenide, fluoroacetate arsenite and malonate these are the three inhibitors of tca cycle So this is all about TCA cycle. Keep watching. Stay home. Stay safe.
Thank you.