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Citric acid cycle : Central metabolic cycle and its SignificanceCitric acid cycle is also called Krebs Cycle and Tricarboxylic acid cycle. The citric acid cycle is a aerobicuniversal Acetyl~coA catabolic cycle. It is a central metabolic cycle. The cycle was first elucidated by scientistSir Hans Adolf Krebs (LT, 1900 to 1981). He shared the Nobel Prize for physiology and Medicine in 1953 withFritz Albert Lipmann , the father of ATP cycle. For their work in intermediary Metabolism.

TCA cycle mainly takes place in Mitochondrial Matrix.The product is Citric acid (tricarboxylic acid), so the name is given as Tricarboxylix acid (or) citric acidcycle.The eight enzymes of the citric acid cycle catalyze a series of well-known organic reactions thatcumulatively oxidize an acetyl group to two CO2 molecules with the concomitant generation of threeNADH and one FADH2, and one GTP.

Reactions of the Citric acid Cycle:1.Condensation:The acetyl CoA is condensed with Oxaloacetic acid (OAA) it gives Tricarboxylic acid Citric acid. This reaction iscatalyzed by Citrate synthase.

Oxaloacetic acid + Acetyl ~ CoA > Citric acid + HS~CoA

2. Dehydration:Citric acid self dehydrates into Cis-Aconitate. This reaction is catalyzed by Aconitase.

Citric acid> Cis-Aconitate + H2O

3. Hydration:The cis-Aconitate is converted into IsoCitrate by using one water molecule. This reaction is catalyzed byAconitase.

Cis-Aconitate + H2O > IsoCitrate

4. Dehydrogenation:IsoCitrate is converted into Oxalosuccinate. Here two protons (or) two hydrogen atoms are extracted from theIsocitrate by NAD+. This reaction is catalyzed by Isocitrate dehydrogenase.

Isocitrate + NAD+ > Oxalo succinate + NADH + H+

5. Decarboxylation:Oxalosuccinate is decarboxylated into -ketoglutarate. This reaction is catalyzed by Isocitrate dehydrogenase.

Oxalosuccinate > -ketoglutarate + CO2

Citric acid cycle or krebs cycle diagram

6. Dehydrogenation:

-ketoglutarate is converted into Succinyl~coA by taking one Acetyl~CoA and one molecule of NAD +. Thisreaction is catalyzed by -ketoglutarate dehydrogenase.

-ketoglutarate + Acetyl~CoA + NAD + > Succinyl~coA + NADH + H+

7. Substrate-level-Phosphorylation:Succinyl~coA is converted into Succinate. In this reaction one High energy compound is synthesized. Here GDP(or ADP) is converted into GTP (or ATP) by utilizing one phosphoric acid (inorganic acid) molecule. In animalsGTP is produced, in case of plants it is ATP. This reaction is catalyzed by Succinyl~coA synthatase.

Succinyl~coA + GDP + Pi > Succinate + GTP

8. Dehydrogenation:Succinate is dehydrogenated into Fumarate by using FAD is a Proton acceptor. This reaction is catalysed bySuccinate dehydrogenase.

Summary equation for Krebs cycle and krebs cycle equation

Succinate + FAD > Fumarate + FADH2

9. Hydration:Fumarate is hydrated into Malate by taking one water molecule. This reaction is catalyzed by Fumarse.

Fumarate + H2O > Malate

10. Dehydrogenation:Malate is dehydrogenated into Oxaloacetic acid by using NAD as a proton acceptor. This reaction is catalyzed byMalate dehydrogenase.

Malate + NAD+ > Oxaloacetic acid + NADH + H+

Krebs Cycle Equation:

Regulation of Citric AcidCycle:The capacity of TCA cycle to generateenergy for cellular needs is closelyregulated by the availability ofSubstrate and the need of TCA cycleintermediates and demand for ATP.

1. The formation of citrate fromoxaloacetate and acetyl coA is animportant part of control (Step 1).ATP acts as an allosteric inhibitoro f citrate synthase. Citrateallosterically inhibits PFK, the keyenzyme of glycolysis; stimulates Fructose-1,6-bisPhosphatase, a key enzyme of Gluconeogenesis andactivates Acetyl CoA carboxylase , key enzyme of Fatty acid synthesis.

2. Another control point is Isocitrate dehydrogenase reaction (step 3). ADP acts as a positive modifierenhancing the binding of substrate. the substrate binding also has a positive cooperative effect. NADH isan inhibitor and displaces NAD+ from its binding.

3. -ketoglutarate dehydrogenase is inhibited by succinyl~coA and NADH.4. The regulation of the cycle is by cellular needs of ATP. When the energy charge of the cell is low, as

indicated by high level of NAD+ and FAD, the cycle operates at a faster rate. The cycle is tightly coupled tothe respiratory chain providing ATP.

Net ATP Calculation of Citric acid cycle:

Step number Reactions Coenzyme ATP generatedStep 4 & 5 Isocitrate -> -ketoglutarate NADH 3Step 6 -ketoglutarate -> Succinyl~coA NADH 3Step 7 Succinyl ~ coA -> Succinate GTP or ATP 1Step 8 Succinate -> Fumarate FADH2 2

Step 10 Malate -> Oxaloacetate NADH 3

Inhibitors of TCA cycle:1. Aconitase is inhibited by Flouro Acetate. This is a non-competitive inhibition.2. -ketoglutarate dehydrogenase is inhibited by Arsinite. This again is a non-competitive inhibition.3. Succinate dehydrogenase is inhibited by Malonate. This is a competitive inhibition.

Significance of TCA cycle:1. Citric acid cycle is the final common oxidative pathway. Carbohydrates are entering this cycle as Pyruvate

and Acetyl~coA. Fatty acids are Broken down into Acetyl~coA which then enters in this cycle. All aminoacids after transamination enter into some or other point in this cycle.

2. In the body oxidation of fat need the help of oxaloacetate. One passage of cycle oxidizes acetyl~coA intotwo CO2 molecules. Here oxaloacetate acts as true catalyst; it enters into the cycle but is regenerated inthe end. The major source of OAA is Pyruvate.

3. Excess carbohydrates are converted as neutral fat and deposited in adipose tissue. The pathway isGlucose -> Pyruvate -> Acetyl~coA -> Fatty acid. However, fat cant be converted to Glucose becausePyruvate dehydrogenase reaction is an absolutely irreversible.

4. Fat is completely broken down in the cycle, and there is no net synthesis of carbohydrates from Fat.5. Many amino acids after transamination enter into the citric acid cycle.E.g: Glutamic acid enter at the level

of alpha-ketoglutarate, and aspartate enters at OAA level. Those amino acids which are converted asmembers of TCA cycle can enter the Gluconeogenesis pathway through OAA.

6. Some amino acids such as Leucine catabolized to Acetyl~coA or not converted to Glucose becausePyruvate to Acetyl~coA reaction is Irreversible. The acetyl~coA molecule either enter the TCA cycle andare completely oxidized, or are channeled into Ketone body formation. Hence, they are called as ketogenicamino acids.

7. All other pathways such as beta-oxidation of fat (or) glycogen synthesis are either catabolic or anabolic.But TCA cycle is truly amphibolic. It is also called amphiphatic in nature.(Greek word amphi=both,pathos=feeling).

8. Citric acid cycle acts as a source of precursor of biosynthetic pathways. Example is HEME is synthesizedfrom succinyl~coA and Aspartate from OAA. There is a continuous efflux of four carbon units from thecycle. To counter balance this loss, and to keep the concentrations of the four carbon unit in the cell,anaplerotic reactions are essential. This is called Anaplerotic role of TCA cycle. (Greek work ana=up;plerotikos=to fill). Anaplerotic reactions are filling up reactions or influx reactions, which supply 4 carbonunits to the TCA cycle.

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Citric acid cycle : Central metabolic cycle and its SignificanceReactions of the Citric acid Cycle:1.Condensation:2. Dehydration:3. Hydration:4. Dehydrogenation:5. Decarboxylation:7. Substrate-level-Phosphorylation:8. Dehydrogenation:9. Hydration:10. Dehydrogenation:

Krebs Cycle Equation:Regulation of Citric Acid Cycle:Inhibitors of TCA cycle:

Significance of TCA cycle: