The Citric Acid Cycle is a major metabolic pathway found in both plants and animals. The cycle produces ATP, the body’s cellular energy currency, and other small molecules that are either used for biosynthesis or to regulate metabolism. This article will describe what the Citric Acid Cycle is, how it works, its reactants and products. However, in case you wish to skip this guide to reasons such as a busy schedule, our top writers are ready to have you covered by acing that assignment for you. All you need to do is place an order.
The citric acid cycle is a series of reactions in which four molecules of acetyl CoA are converted into two molecules of carbon dioxide. This is not a complicated process; it’s just a simple oxidation pathway that involves the transfer and oxidation of several groups until all that remains are carbon dioxide and water. The name specifically refers to the citric acid molecule because it is involved in one of the reaction steps.
Here are the main reactions of the citric acid cycle, in simple language:
Citrate synthase adds CoA to Oxaloacetate, creating citrate. Acetyl coenzyme A synthetase transfers acetyl group from ATP to a molecule called acetic acid (or acetate). This produces a molecule of acetyl-CoA. Acetyl-CoA travels from the cytosol to the mitochondria. Acetyl-CoA is converted by another chemical reaction in a process called beta-oxidation.
During this process, three acetate molecules are oxidized into carbon dioxide and glycerol3. Substrate-level phosphorylation converts one molecule of phosphate to ATP. Pyruvate is oxidized into an intermediate molecule called Oxaloacetate, which can be recycled back into citrate via the citrate synthase reaction.
The Citric Acid Cycle is a complex pathway that converts pyruvate and other organic compounds into usable forms of bioenergy like ATP and NADH.
The Citric Acid Cycle occurs in the mitochondria, where these compounds are broken down through a series of steps catalyzed by enzymes. The Citric Acid Cycle is also known as the Krebs Cycle, which is named after Hans Adolf Krebs, who was the first to investigate this cycle in detail.
The Citric Acid Cycle only occurs in eukaryotic cells, which are those cells that have nuclei and other organelles. These structures occur in the cytoplasm of the cell. In contrast, bacteria lack these membrane-bound components and thus cannot perform this cycle.
The Citric Acid Cycle begins with two molecules of pyruvate, which are broken down into smaller molecules via a series of steps catalyzed by enzymes.
The Citric Acid Cycle produces TCA (tricarboxylic acid) cycle intermediates that can be converted back into pyruvate in the form of Oxaloacetate or further metabolized to carbon dioxide and water. The Citric Acid Cycle/Krebs cycle is the only pathway that produces carbon dioxide, a significant contributor to the greenhouse effect.
To summarize, the complete Citric Acid Cycle consists of three stages: a) irreversible decarboxylation; b) synthesis; c) regenerations.
Stage 1: In stage one, pyruvate carboxylase catalyzes an irreversible decarboxylation of pyruvate to form Oxaloacetate. Pyruvate is then released into the cytoplasm. The carboxyl group from pyruvate then binds with a molecule of CO2 to form an intermediate called citrate, catalyzed by citric acid synthase.
Stage 2: Citrate is then cleaved into two separate molecules, producing coenzyme A and acetyl CoA. The coenzyme A then travels to the mitochondria, where it participates in an ATP generating reaction through substrate-level phosphorylation.
Stage 3: The tricarboxylic acid cycle enzyme succinyl-CoA synthetase regenerates Oxaloacetate from the acetyl CoA, completing cycle one.
Enzymes catalyzed this reversible decarboxylation reaction of pyruvate into Oxaloacetate by treating both molecules as substrates to form an intermediate known as citrate.
Citrate was cleaved into its two separate components, coenzyme A and acetyl CoA, via an enzyme-catalyzed reaction.
The coenzyme A is then returned to the mitochondria as a substrate for ATP production through substrate-level phosphorylation.
To produce acetyl groups, pyruvate is taken up by the cell through the help of pyruvate transporters and gets converted into acetyl-CoA in the mitochondria. The intermediate products formed during this reaction are also used as substrates for other reactions, such as fatty acid biosynthesis.
Citrate is a tricarboxylic acid (TCA) cycle intermediate, which is later cleaved via ATP to regenerate Oxaloacetate. This process is known as the citric acid cycle or Krebs cycle. Pyruvate and lactate are produced when glucose enters glycolysis, by-products of this metabolic pathway that are later used to regenerate other products. The by-products of glycolysis are shuttled to the different metabolic pathways via a protein known as lactate dehydrogenase, which is found in the mitochondria and catalyzes the interconversion between pyruvate and lactate.
Pyruvate is transported to the mitochondria through pyruvate transporters. The transporter proteins are classified under three classes: monocarboxylate transporters, dicarboxylate transporters, and inorganic phosphate transporters.
Pyruvate transporter proteins are categorized into three types: monocarboxylate, dicarboxylate, and inorganic phosphate (Pi). The monocarboxylate transporter proteins include MCT1 and MCT4. MCT1 is found on the surface of cells such as red blood cells. MCT1 transports lactate and pyruvate, although at a higher affinity for lactate than pyruvate.
In contrast, MCT4 is found on the surface of epithelial cells lining the gastrointestinal tract and transports the only pyruvate across epithelial cell membranes into capillaries within the lumen. The dicarboxylate transporters include SLC13A1 and 2; they have a higher affinity for pyruvate but a lower affinity for lactate.
Furthermore, SLC13A2 only transports pyruvate across the epithelial cells lining the renal tubule into capillaries within the lumen. The inorganic phosphate (Pi) transporters include SLC25A1 and 2; they are found on the surface of cells such as hepatocytes and transport pyruvate across cell membranes.
The pyruvate transported through the mitochondrial membrane gets converted into acetyl-CoA by the enzymes involved in the citric acid cycle.
A ketone is a type of organic compound that has one or more carbonyl (C=O) groups. In contrast, an acetyl group is formed when the hydroxyl (-OH) group in alcohol reacts with a hydrogen atom from a carboxylic acid.
This reaction produces HCO3- and HOCH2CH3 (or CH3CO2H). Acetyl groups are also the building blocks of more complex molecules, such as amino acids. They are an essential energy source in cells and can be converted into ketone bodies when there is a low oxygen level or a high demand for energy production.
There are two main reasons why the Citric Acid Cycle/Krebs cycle is essential for aerobic respiration. First, aerobic respiration depends on the production of energy throughout the Citric Acid Cycle. Secondly, by-products from aerobic respiration in eukaryotic cells provide the Oxaloacetate necessary to begin another cycle.
The Citric Acid Cycle produces the majority of the ATP during aerobic respiration through substrate-level phosphorylation. Glycolysis, a substrate-level phosphorylation occurs when ATP is produced by adding a phosphate to ADP using energy from the breakdown products (step 1) of glycolysis:
Pyruvate + NAD+ —> 2 CH3COOH + NADH + H+
When pyruvate is carboxylated, a phosphate group from ATP is transferred to the carboxyl group of pyruvate, producing one molecule of phosphoenolpyruvate (PEP) and one molecule of CO2.
By employing the remaining carbon atoms in pyruvate, one molecule of Oxaloacetate is produced per cycle from the decarboxylation of pyruvate. This process is summarized below:
Pyruvate + ADP —> PEP + CO2 + ATP
Citric Acid Cycle —> NADH + H+ + FADH2
Oxaloacetate (from pyruvate) —> Citrate (via citric acid synthase)
Citrate —> Acetyl CoA (via aconitase & isocitrate dehydrogenase)
Acetyl CoA —> Succinyl CoA (via succinate thiokinase)
Succinyl CoA —> Oxaloacetate (via Succinyl-CoA synthetase)
This process can be summarized as:
Pyruvate + ATP —> Oxaloacetate + ADP + PEP
The Citric Acid Cycle also contributes to energy production during aerobic respiration by providing the Oxaloacetate essential at the beginning of another cycle. Oxaloacetate is produced from pyruvate and then cleaved into three separate molecules: coenzyme A, acetyl CoA, and NADH + H+.
The coenzyme A then undergoes the citric acid cycle again to produce additional molecules of acetyl CoA through acetyl-Coenzyme A synthetase.
The acetyl CoA is then converted to energy, driving ATP production through the process of oxidative phosphorylation. NADH + H+ are also produced from the Citric Acid Cycle.
These molecules are recycled to their electron transport chain equivalents and then transferred back to the matrix of the mitochondria to produce ATP through oxidative phosphorylation. Oxaloacetate is recycled by completing another cycle in glycolysis, producing pyruvate and NADH for further use in aerobic respiration.
The Citric Acid Cycle produces energy during aerobic respiration through substrate-level phosphorylation and provides Oxaloacetate for recycling after each cycle, contributing to the overall energy production of aerobic respiration.
The Citric Acid Cycle reactants include pyruvic acid, oxaloacetic acid, succinic acid, fumarate and malate.
In the first stage, pyruvic acid is oxidized into a molecule called acetyl-coenzyme A. This reaction takes place in the mitochondria and requires oxygen and several enzymes, which are NADH dehydrogenases, acyl carrier protein, malate dehydrogenase, lysine decarboxylase, oxaloacetate decarboxylase, and phosphoenolpyruvate carboxykinase.
The second stage of the citric acid cycle involves six enzymes: succinate dehydrogenase, fumarate reductase, malate dehydrogenase, NAD-malic enzyme, NADP-malic enzyme, and isocitrate dehydrogenase, which convert Fumarate into Malate.
A third step takes place in the mitochondria and involves reactions such as malic enzyme converting Malate back to Oxaloacetate; oxidative decarboxylation of Isocitrate by NAD-dependent isocitric dehydrogenase alpha-ketoglutarate; and oxidative decarboxylation of alpha-ketoglutarate by the mitochondrial malic enzyme to succinyl CoA.
In the last step, Acetyl-CoA is converted to CO2 by ATP synthase using energy from a proton gradient across a membrane.
The end products of this process are carbon dioxide, water-free ATP and ionized hydrogen ions that can feed into other metabolic pathways such as gluconeogenesis or form part of respiratory electron transport chain reactions.
Your body runs on an intricate cycle called the Citric Acid Cycle (Krebs cycle). This basic process converts food and oxygen into energy your cells can use to function. It acts as a generator – converting what you eat and what you breathe into environmental compounds that can be used immediately by your cells for fuel. The end products of this process are Co2, H20, and ATP – with ATP being the most important in generating cellular chemical reactions that make muscles contract!
The role of ATP in the citric acid cycle is to provide energy for the reactions that drive it. When ATP is broken down into two ADP (adenosine diphosphate) molecules, it can supply a total of 32-35 chemical bonds worth of energy needed to sustain life processes. This means that in just one “speeding ticket” worth of ATP, your body can create a vast amount of energy in the form of ADP.
The mitochondrial membrane transports ATP from the mitochondria out to various sites within the cell where they can be utilized. It is this ATP that serves as a fuel molecule in the Krebs cycle. Early studies of the Citric Acid Cycle confirmed how important it was to include mitochondria in experiments due to how critical mitochondria are to its process.
The Citric Acid Cycle/Krebs cycle is a series of chemical reactions within the cells’ mitochondria and relies on two essential molecules: ATP and NADH (Nicotinamide adenine dinucleotide). The latter is created by passing electrons onto it via the electron transport chain.
In the absence of oxygen, pyruvic acid is decarboxylated by a non-enzymatic process to yield CO2 and an intermediate compound known as Acetyl CoA.
The reaction takes place in the presence of Enzyme Pyruvate Dehydrogenase (PDH). The coenzyme NAD(P) is reduced to NAD(P), while the coenzyme acetyl CoA combines with CO2 (released from pyruvate in the process) to produce two molecules of Acetyl-COA.
In human cells, usually, this reaction takes place in the matrix of mitochondria, where there are large amounts of oxygen and proteins specific for the process that take place within its membrane.
Pyruvate dehydrogenase catalyzes the oxidative decarboxylation of pyruvic acid to acetyl-CoA, mediated by a series of proton transfers between two bicarbonate anions that are bound to the enzyme. The overall reaction can be written as: Pyruvate + ATP + H2O → Acetyl-CoA + NADH + H+
The specific orientation of the whole process is that pyruvic acid in the cytosol is converted into acetyl coenzyme A, which then moves into the mitochondria for use in the Citric Acid Cycle or other Krebs Cycle reactions. Without this unique ability of the enzyme and its location within the cell, cells would not be able to proceed with aerobic respiration.
In addition, since ATP is formed during this reaction when pyruvic acid combines with ADP (adenosine diphosphate), energy is stored. The end product of pyruvic acid in the cytosol is citric acid, which can be used for further metabolic reactions or be broken down to carbon dioxide and water through decarboxylation.
The Citric Acid Cycle Produces NADH, Which Is Important!
The Krebs cycle (AKA citric acid cycle) is one of the most fundamental metabolic pathways found in all living cells. The purpose of this cycle in cellular respiration is to produce energy-rich molecules that can be used to power other biochemical reactions, like glycolysis and fatty acid oxidation. This pathway allows for the breakdown of carbohydrates (sugars), fats, and protein in the cell.
This Krebs cycle represents the last link in a sizeable oxidative phosphorylation system that uses ATP for energy production. This pathway generates two products: NADH (nicotinamide adenine dinucleotide) and FADH2 (flavin adenine dinucleotide). NADH and FADH2 are two essential chemicals produced by aerobic cellular respiration that are then utilized for subsequent metabolic reactions.
The Citric Acid Cycle also produces carbon dioxide, which is then released into the air during exhalation! Carbon dioxide needs to be expelled from cells to keep a proper balance of gases within the human body. Hence, this cycle is also responsible for the regulation of pH in blood plasma. A high level of carbon dioxide within cells causes metabolic acidosis; while low levels cause metabolic alkalosis.
Cellular respiration is when cells produce energy and valuable molecules, such as proteins, using nutrients. Cellular respiration involves many chemical reactions used to break down molecules present in food and oxygen the body consumes.
Cellular respiration is a sequence of reactions that includes glycolysis, the Citric Acid Cycle and oxidative phosphorylation. Glycolysis produces two ATP molecules that can be used for cellular function. The Citric Acid Cycle also generates energy – specifically 2 ATPs for each molecule of glucose.
Oxidative phosphorylation produces the remaining 2 ATPs needed to make 4 per molecule of glucose oxidized in cellular respiration. Another important product of the Citric Acid Cycle is NADPH, which plays an essential role in biosynthesis and aids in regulation.
The Citric Acid Cycle aims to convert compounds into usable forms of bioenergy like ATP or NADH. It also converts small amounts of ATP into ADP (adenosine diphosphate).
Critical Components of the Citric Acid Cycle
There are several steps in the Citric Acid Cycle, each converting pyruvate or another compound into different forms that eventually end up as either ATP or NADH. These reactions are catalyzed by enzymes that activate the process.
1) Oxaloacetate (OAA) is converted into citrate via an enzyme called ATP-citrate lyase. ATP is involved in this reaction because it provides energy to convert OAA into citrate. High levels of ADP have been shown to decrease mitochondrial activity, and therefore the Citric Acid Cycle.
2) Citrate is converted into isocitrate via an enzyme called aconitase. This enzyme contains iron and magnesium as cofactors, which serve to regulate the activity of this reaction, according to Sahlin and Westerblad’s model. If there aren’t enough iron or magnesium ions in the mitochondrion, the activity of this reaction is decreased.
3) Isocitrate is converted into alpha-ketoglutarate via an enzyme called isocitrate dehydrogenase. This enzyme interacts with a coenzyme A (CoA) molecule, which acts as both a substrate and essential signaling molecule for the Citric Acid Cycle.
CoA’s interaction with isocitrate dehydrogenase is regulated by the product of this reaction, alpha-ketoglutarate. High levels of alpha-ketoglutarate inhibit its production during the Citric Acid Cycle via negative feedback inhibition.
4) Alpha-ketoglutarate undergoes an oxidative decarboxylation to form succinyl coenzyme A (CoA) via an enzyme called alpha-ketoglutarate dehydrogenase. This reaction also produces NADH in the electron transport chain.
5) Succinyl CoA is converted into succinate by an enzyme called succinyl CoA synthase.
6) Succinate is converted into fumarate by an enzyme called succinate dehydrogenase.
7) Fumarate is converted into malate via an enzyme called fumarase.
8) Malate is converted into pyruvate (also known as carboxyl groups or COOH-groups) via an enzyme called a malic enzyme. This reaction produces ATP through substrate-level phosphorylation. This means that the phosphate group is added directly to one of the compounds involved in the reaction, which ISN’T ADP or AMP.
The Citric Acid Cycle occurs in steps that convert compounds into usable forms of bioenergy like ATP or NADH. However, this cycle doesn’t produce much energy by itself.
Most of the energy produced by the Citric Acid Cycle/Krebs cycle comes from other reactions within the mitochondria, most notably oxidative phosphorylation and electron transport chain.
In other words, the Citric Acid Cycle is a component of a more significant pathway that produces most of the cell’s energy.
These steps can be summarized as follows:
- Pyruvate reacts with coenzyme A to be converted into Oxaloacetate
- Oxaloacetate (OAA) is converted into citrate via ATP-citrate lyase
- Pyruvate is converted into isocitrate and then alpha-ketoglutarate by the Citric Acid Cycle enzyme isocitrate dehydrogenase
- Alpha-ketoglutarate is converted into succinate
- Succinate undergoes an oxidative decarboxylation to form fumarate by the citric acid cycle enzyme, alpha-ketoglutarate dehydrogenase
- Succinate is converted into malate via the Citric Acid Cycle enzyme, succinyl CoA synthase
- Malate is converted back into pyruvate by the Citric Acid Cycle enzyme, malic acid dehydrogenase.
Malic Acid Dehydrogenase (Mitochondrial):
The process that converts malate into pyruvate is called substrate-level phosphorylation. This term refers to the addition of a phosphate group to a compound that ISN’T ADP or AMP. In the case of malate, the substrate is Oxaloacetate (OAA). OAA donates its carboxyl group to pyruvate in the form of an intermediate called phosphoenolpyruvate. The reaction is catalyzed by an enzyme called malic acid dehydrogenase, a component of the Citric Acid Cycle.
Malate + OAA–> pyruvate + CO2
Malic Acid Dehydrogenase Reaction:
OAA donates its carboxyl group to pyruvate in the form of an intermediate called phosphoenolpyruvate via a reaction catalyzed by the enzyme malic acid dehydrogenase.
Mitochondria take atmospheric oxygen and water and use them to produce ATP. This process is termed oxidative phosphorylation.
During oxidative phosphorylation, the hydrogen electron is removed from a molecule of water. This produces a free proton (and corresponding positive charge) on the oxygen atom and two electrons.
The free proton must be taken to the matrix section of the mitochondria, where it will be used during oxidative phosphorylation to provide a proton gradient, which will generate ATP.
This process is done via a series of electron transport chains. The electrons from the water molecule are transferred successively to other molecules in the mitochondrial matrix. These molecules participate in an electron transport chain, resulting in the loss of hydrogen ions (protons). The protons are moved from the matrix to the intermembrane space of the mitochondria by a protein called ATP synthase.
The protons released from this process flow back across the inner membrane of the mitochondria through a pH gradient, which creates an electrochemical potential. This, in turn, is used to make ATP via ATP synthase.
It is interesting to note that most ATP produced during aerobic respiration is made in this fashion. The process, which has about 30 molecules of ATP per molecule of glucose consumed, is responsible for 65% of overall energy production during aerobic respiration.
The electron transport chains and ATP synthase are embedded in the inner mitochondrial membrane. This sets up the proton-electron exchange discussed above, which produces ATP in a synthase reaction.
The F0 complex, also called NADH dehydrogenase, is embedded in the inner mitochondrial membrane and pulls electrons from NADH + H+ to produce NAD+. This process is reversible, and it oxidizes NADH + H+ and creating oxidized forms of the electron transport chain molecules.
The F1 complex, which contains CoQ (ubiquinone), is embedded in the inner mitochondrial membrane and accepts electrons from ubiquinone or cytochrome c. Finally, a series of hydrogens are added to NAPDH by the F0 complex, then transferred to the F1 complex. This process continues until electrons reach oxygen and hydrogen ions are released into the inner compartment of the mitochondrion.
The O 2 is then used in the third enzyme complex called cytochrome oxidase. This enzyme produces water by combining hydrogen ions from NADH + H+, oxygen, and hydrogen ions from the matrix.
The combination of hydrogen ions with oxygen results in water production along with a molecule called H2O2. The H 2 O 2 is an essential signaling molecule that activates some pathways involved in cell death or survival.
The brain’s need for constant energy production has resulted in developing a metabolically flexible tissue that can easily switch from glucose-based respiration to protein-based respiration.
When blood flow to the brain is limited, or there are no carbohydrates available, proteins are broken down into amino acids and subsequently used as an alternative source for ATP. This type of metabolism is called gluconeogenesis. It was previously thought that brain cells use ketone bodies as a secondary source of energy, but more recent studies have found that proteins are an equally important energy source for the brain.
These protein-based processes require the presence of a chemical known as coenzyme Q10 (CoQ10). CoQ10 is an essential component of the electron transport chain and serves to move hydrogen atoms through the chain, resulting in ATP production. This process, coupled with mitochondrial respiration, produces over 30 ATPs per 6 amino acids.
Another interesting finding regarding brain tissue is that it uses two different types of protein metabolism: aerobic glycolysis and fermentation. Aerobic glycolysis is only possible when there is a high level of oxygen present, whereas fermentation can occur with or without the presence of oxygen.
It has been demonstrated that the brain uses aerobic glycolysis for most of its energy needs and switches to fermentation in times of low oxygen availability. The brain can also switch between aerobic glycolysis and fermentation based on the available level of NADH, a coenzyme found within the mitochondria. This switch between pathways is regulated by the enzyme lactate dehydrogenase (LDH).
What Are Some of the Carbon Dioxide Molecules in the Citric Acid Cycle?
The carbon dioxide molecules produced by the citric acid cycle are:
-2 carbon atoms —> carbon dioxide (one molecule is removed as carbonic anhydrase splits carbonic acid, CO2 + H20).
The citric acid cycle’s products are carbon dioxide, carbonic acid, and carbonic anhydrase.
Each turn of the citric acid cycle produces 3 ATP molecules; each turn of glycolysis yields 2 (two) pyruvate (in the cytoplasm) and 1 NADH molecule for a total of 3 ATP produced. Therefore, each turn of glycolysis has 3 (three) total ATP. Glycolysis is carried out in the cytoplasm of cells. This is a significant difference between glycolysis and the citric acid cycle; one occurs in mitochondria and produces pyruvate-ATP, whereas the other occurs in the cytoplasm and yields NADH + H+ (hydrogen ion).
The main purpose of the citric acid cycle is to provide energy for aerobic cellular respiration via carbon dioxide molecules and ATP production, as well as carbon molecules for the biosynthesis of amino acids, fatty acids, and nucleic acids.
Essentially, one molecule of glucose gets broken down into two molecules, pyruvate (in the cytoplasm of the cell) and NADH. These two molecules are then oxidized into two CO2 molecules in electron transport to supply ATP to drive most cellular processes, including biosynthesis via reactions catalyzed by enzymes. The citric acid cycle ends with oxidation reactions that result in carbon dioxide molecules being released or derivatives of carbon dioxide (such as fumarate or succinic acid).
The Citric Acid Cycle is an essential process in cellular respiration, and its part of the Krebs cycle. It produces ATP and breaks down carbohydrates inside our body, but not without help from oxygen, which is why we need to breathe fresh air every day!
In this article, you learned how the citric acid cycle works, with its end products being carbon dioxide gas (CO2) and water (H2O).
I hope you enjoyed learning about the Citric Acid Cycle!