Krebs cycle Definition

The Krebs cycle, also known as the citric acid cycle or the TCA cycle, is a chain of chemical reactions that takes place in the mitochondria and results in the oxidation of acetyl CoA, which releases carbon dioxide and hydrogen atoms, which then results in the creation of water.

• It is called the citric acid cycle because the initial metabolic intermediate that is produced throughout this cycle is citric acid.
• This cycle is sometimes known as the tricarboxylic acid (TCA) cycle since it wasn’t obvious at the time if citric acid or another tricarboxylic acid (such as isocitric acid) made up the cycle’s first product. Since it is now known that the original product was really citric acid, the use of this word has been discouraged.
• This cycle only occurs under aerobic circumstances because energy-dense molecules like NAD+ and FAD can only be retrieved from their reduced state when they donate electrons to molecular oxygen.
• The citric acid cycle is the most fundamental process for the oxidation of all biomolecules, including proteins, fatty acids, and carbohydrates. Molecules from several pathways and cycles reach this cycle through acetyl CoA.
• The citric acid cycle is a series of eight enzyme-mediated processes that occur repeatedly.
• This cycle is also crucial for producing ATPs and water because it feeds the electron transport chain with high-energy molecules and electrons.
• At the conclusion of glycolysis, pyruvate is converted into acetyl CoA and subsequently enters the citric acid cycle.

Krebs cycle Location

In prokaryotes, the citric acid cycle happens in the cytoplasm, while in eukaryotes it occurs in the mitochondria.

The cytoplasmic pyruvate produced during glycolysis is moved into the mitochondria, where additional procedures happen.

The several enzymes participating in the citric acid cycle are situated in the matrix space or the inner membrane of the mitochondria.

Krebs cycle Equation/ Reaction

The citric acid cycle’s general reaction/equation is:

Acetyl CoA + 3 NAD+ + 1 FAD + 1 ADP + 1 Pi    →   2 CO2 + 3 NADH + 3 H+ + 1 FADH2 + 1 ATP

The equation reads as follows:

Acetyl CoA + Nicotinamide adenine dinucleotide + Flavin adenine dinucleotide + Adenosine diphosphate + Phosphate   →   Pyruvate + Water + Adenosine triphosphate + Nicotinamide adenine dinucleotide + Hydrogen ions

Krebs cycle Enzymes

The enzymes that catalyze the steps of the citric acid cycle are located in the mitochondrial matrix, with the exception of succinate dehydrogenase and aconitase, which are present in the inner mitochondrial membrane of eukaryotic cells.

Nearly all the enzymes involved in the citric acid cycle have the property that they almost all need Mg2+.

The enzymes that catalyze various stages in the citric acid cycle include the ones listed below:

1. Citrate synthase
2. Aconitase
3. Isocitrate dehydrogenase
4. α-ketoglutarate
5. Succinyl-CoA synthetase
6. Succinate dehydrogenase
7. Fumarase
8. Malate dehydrogenase

Krebs cycle Steps

• In aerobic species, the pyruvate molecules undergo carboxylation following glycolysis to produce acetyl CoA and CO2.
• Pyruvate’s oxidative decarboxylation to produce acetyl CoA
• Pyruvate undergoes oxidative decarboxylation. This links the citric acid cycle to glycolysis.
• In this process, the pyruvate dehydrogenase complex in the mitochondrial matrix of eukaryotes and the cytoplasm of prokaryotes oxidatively decarboxylates the pyruvate generated from glycolysis to acetyl CoA and CO2.
• From one molecule of glucose, two molecules of pyruvate are produced, and after the process of pyruvate oxidation is complete, each of these two molecules produces one acetyl CoA and one NADH.
• The citric acid cycle is where the acetyl CoA produced by pyruvate oxidation, fatty acid metabolism, and the amino acid route enters.
• The eight enzyme-catalyzed processes or phases in the aerobic oxidation of glucose via the citric acid cycle are as follows:

Step 1: Condensation of acetyl CoA with oxaloacetate

• Combining the four-carbon chemical oxaloacetate (OAA) with the two-carbon compound acetyl CoA is the first stage of the citric acid cycle.
• Oxaloacetate binds with water and the acetyl group of acetyl CoA to produce citric acid, CoA, a molecule having six carbons.
• Then, in order to create Citryl-CoA, which is subsequently broken down to liberate coenzyme A and form citrate, the enzyme citrate synthase combines the methyl group of acetyl CoA with the carbonyl group of oxaloacetate.

Step 2: Isomerization of citrate into isocitrate

• As a result of the synthesis of the intermediate enzyme cis-aconitase, citrate is now converted to isocitrate for subsequent metabolism.
• The enzyme is in charge of catalyzing this reversible reaction (aconitase).
• The two steps in this reaction are the dehydration of citrate to cis-aconitase in the first step and cis-aconitase rehydration to isocitrate in the second.

Step 3: Oxidative decarboxylations of isocitrate

• The first of the cycle’s four oxidation-reduction processes occurs in the third stage of the citric acid cycle.
• Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to produce the five-carbon molecule ketoglutarate.
• This reaction is a two-step reaction, much like the second reaction.
• Isocitrate is dehydrogenated to oxalosuccinate in the first phase, and oxalosuccinate is decarboxylated to ketoglutarate in the second.
• The same enzyme is used to catalyze both irreversible processes.
• However, the first stage causes the creation of NADH, whereas the second step causes the release of CO2.

Step 4: Oxidative decarboxylation of α-ketoglutarate

• In this procedure, -ketoglutarate is oxidatively decarboxylated to produce succinyl-CoA, a four-carbon molecule, and CO2 in another oxidation-reduction process.
• The enzyme complex known as ketoglutarate dehydrogenase is located in the mitochondrial space and is responsible for the irreversible process.
• This process, which is equivalent to the oxidative decarboxylation of pyruvate, converts NAD+ into NADH.

Step 5: Conversion of succinyl-CoA into succinate

• Next, succinyl-CoA passes through an energy-saving process in which it is cleaved to create succinate.
• Guanosine diphosphate (GDP) is phosphorylated to guanosine triphosphate in conjunction with this process (GTP).
• The resulting GTP easily joins ADP with its terminal phosphate group to create an ATP molecule.
• The enzyme succinyl-CoA synthase is responsible for catalyzing the reaction.

Step 6: Dehydration of succinate to fumarate

• Here, the intramitochondrial space enzyme complex succinate dehydrogenase catalyzes the dehydrogenation of succinate derived from succinyl-CoA to fumarate.
• The citric acid cycle contains just one further dehydrogenation stage, in which NAD+ is not involved.
• Flavin adenine dinucleotide (FAD), a different high-energy electron carrier, serves as the hydrogen acceptor and creates FADH2 as a result.
• After delivering the electrons to ubiquinone through complex II, FADH2 eventually forms 2ATPs by entering the electron transport chain.

Step 7: Hydration of fumarate to malate.

Fumarate is reversibly hydrated to produce L-malate when the enzyme fumarate hydratase is present.

Due to the reversibility of the reaction, hydration is necessary for the synthesis of L-malate, while dehydration is necessary for the synthesis of fumarate.

Step 8: Dehydrogenation of L-malate to oxaloacetate

• In the presence of L-malate dehydrogenase, which is located in the mitochondrial matrix, L-malate is dehydrogenated to oxaloacetate during the final phase of the citric acid cycle, which is also an oxidation-reduction process.
• In this reversible process, L-malate is oxidized, and NAD+ is reduced to NADH.
• The subsequent production of oxaloacetate allows the cycle to be continued, and the NADH produced participates in oxidative phosphorylation.
• The cycle is finished with this response.

Product of the Krebs cycle

This process is cyclical; thus the oxaloacetate that is produced at the end condenses with acetyl CoA in the subsequent cycle.

Every time the cycle turns,

3 NADH,

1 FADH2,

1 GTP (or ATP),

2 CO2

When pyruvate is converted to acetyl CoA by oxidative decarboxylation, one NADH is produced from each pyruvate molecule.

Frequently Asked Questions (FAQs) / Practice Questions

What is the purpose of the Krebs cycle?

The purpose of the Krebs’ cycle is the complete oxidation of glucose, resulting in energy-rich molecules that later produce ATPs in the electron transport chain.

Where does the Krebs cycle take place?

Krebs cycle takes place in the mitochondria of eukaryotes and in the cytoplasm of prokaryotes.

How much ATP is produced in the citric acid cycle?

One ATP is formed in a single citric acid cycle while two ATPs are formed from a single molecule of glucose (two molecules of pyruvate are formed from one molecule of glucose).

Does the citric acid cycle require oxygen?

Yes, the citric acid requires oxygen as the cycle operates only under aerobic conditions as NAD+ and FAD can be regenerated from their reduced form in the mitochondria only by electron transfer to molecular oxygen.

Where do the reactions of the citric acid cycle occur in prokaryotic cells?

The citric acid cycle reactions occur in the cytoplasm in prokaryotic cells.

Where do the reactions of the citric acid cycle occur in eukaryotic cells?

The citric acid cycle reactions occur in the mitochondria in eukaryotic cells.

What inhibits the citric acid cycle?

Various factors like the absence of oxygen, low levels of oxaloacetate or pyruvate, necessary enzymes and coenzymes, high levels of ATP and NADH, and the accumulation of ketone bodies.

References

• Jain JL, Jain S, and Jain N (2005). Fundamentals of Biochemistry. S. Chand and Company.
• Nelson DL and Cox MM. Lehninger Principles of Biochemistry. Fourth Edition.
• Berg JM et al. (2012) Biochemistry. Seventh Edition. W. H Freeman and Company.
• Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 17.2, Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22347/

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