What is citric acid cycle in respiration?

The citric acid cycle serves as the mitochondrial hub for the final steps in carbon skeleton oxidative catabolism for carbohydrates, amino acids, and fatty acids . Each oxidative step, in turn, reduces a coenzyme such as nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FADH2).

How does TCA cycle work?

Overview of the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). The TCA cycle starts when the two-carbon molecule acetyl-CoA combines with four-carbon oxaloacetate to form citrate, a reaction catalyzed by citrate synthase (CS). Citrate is then converted to isocitrate by aconitase 2 (ACO2).

What is cellular respiration Khan Academy?

Cellular respiration is a metabolic pathway that breaks down glucose and produces ATP . The stages of cellular respiration include glycolysis, pyruvate oxidation, the citric acid or Krebs cycle, and oxidative phosphorylation.

Which of the following is needed as a reactant for the first step of the citric acid cycle?

The pyruvate molecules undergo reactions that convert the three carbon pyruvate to a two carbon acetyl CoA and an one carbon carbon dioxide. The acetyl-CoA molecules are then used as the initial inputs for the citric acid cycle, as they are combined with oxaloacetate.

The citric acid cycle | Cellular respiration (article)

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Overview and steps of the citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle.

Introduction

How important is the citric acid cycle? So important that it has not one, not two, but three different names in common usage today!

The name we'll primarily use here, the citric acid cycle, refers to the first molecule that forms during the cycle's reactions—citrate, or, in its protonated form, citric acid. However, you may also hear this series of reactions called the tricarboxylic acid (TCA) cycle, for the three carboxyl groups on its first two intermediates, or the Krebs cycle, after its discoverer, Hans Krebs.

The first two intermediates of the citric acid cycle are shown below. Each has three carboxyl groups, marked with red boxes. When citrate gains three $H^{+}$ ‍ ions, so that it no longer has a negative charge, it is called citric acid.

Two chemical formulas diagramed. The diagram on the left is a chain of 5 carbons connected to each other by a single bond. The first carbon is COO with a negative charge, the second carbon is CH2, the third carbon has a single bond connecting it to an H and another line connecting it to a COO with a negative charge, the fourth carbon is CH2, and the fifth carbon is COO with a negative charge. There are red boxes around each COO with a negative charge. The diagram on the left is labeled Citrate. The diagram on the right is a chain of 5 carbons connected to each other by a single bond. The first carbon is COO with a negative charge, the second carbon is CH2, the third carbon is connected to an HC and the C is connected to COO with a negative charge by a single bond. The fourth carbon is CH and there is a single bond connecting the carbon to OH. The fifth carbon is COO with a negative charge. There are red boxes around each COO with a negative charge. The diagram on the right is labeled Isocitrate.

Whatever you prefer to call it, the citric cycle is a central driver of cellular respiration. It takes acetyl $CoA$ ‍—produced by the oxidation of pyruvate and originally derived from glucose—as its starting material and, in a series of redox reactions, harvests much of its bond energy in the form of $NADH$ ‍, ${FADH}_{2}$ ‍, and $ATP$ ‍ molecules. The reduced electron carriers— $NADH$ ‍ and ${FADH}_{2}$ ‍—generated in the TCA cycle will pass their electrons into the electron transport chain and, through oxidative phosphorylation, will generate most of the ATP produced in cellular respiration.

Below, we’ll look in more detail at how this remarkable cycle works.

Overview of the citric acid cycle

In eukaryotes, the citric acid cycle takes place in the matrix of the mitochondria, just like the conversion of pyruvate to acetyl $CoA$ ‍. In prokaryotes, these steps both take place in the cytoplasm. The citric acid cycle is a closed loop; the last part of the pathway reforms the molecule used in the first step. The cycle includes eight major steps.

Simplified diagram of the citric acid cycle. First, acetyl CoA combines with oxaloacetate, a four-carbon molecule, losing the CoA group and forming the six-carbon molecule citrate. After citrate undergoes a rearrangement step, it undergoes an oxidation reaction, transferring electrons to NAD+ to form NADH and releasing a molecule of carbon dioxide. The five-carbon molecule left behind then undergoes a second, similar reaction, transferring electrons to NAD+ to form NADH and releasing a carbon dioxide molecule. The four-carbon molecule remaining then undergoes a series of transformations, in the course of which GDP and inorganic phosphate are converted into GTP—or, in some organisms, ADP and inorganic phosphate are converted into ATP—an FAD molecule is reduced to FADH2, and another NAD+ is reduced to NADH. At the end of this series of reactions, the four-carbon starting molecule, oxaloacetate, is regenerated, allowing the cycle to begin again.

In the first step of the cycle, acetyl $CoA$ ‍ combines with a four-carbon acceptor molecule, oxaloacetate, to form a six-carbon molecule called citrate. After a quick rearrangement, this six-carbon molecule releases two of its carbons as carbon dioxide molecules in a pair of similar reactions, producing a molecule of $NADH$ ‍ each time $^{1}$ ‍. The enzymes that catalyze these reactions are key regulators of the citric acid cycle, speeding it up or slowing it down based on the cell’s energy needs $^{2}$ ‍.

The remaining four-carbon molecule undergoes a series of additional reactions, first making an $ATP$ ‍ molecule—or, in some cells, a similar molecule called $GTP$ ‍—then reducing the electron carrier $FAD$ ‍ to ${FADH}_{2}$ ‍, and finally generating another $NADH$ ‍. This set of reactions regenerates the starting molecule, oxaloacetate, so the cycle can repeat.

Overall, one turn of the citric acid cycle releases two carbon dioxide molecules and produces three $NADH$ ‍, one ${FADH}_{2}$ ‍, and one $ATP$ ‍ or $GTP$ ‍. The citric acid cycle goes around twice for each molecule of glucose that enters cellular respiration because there are two pyruvates—and thus, two acetyl $CoA$ ‍s—made per glucose.

Steps of the citric acid cycle

You've already gotten a preview of the molecules produced during the citric acid cycle. But how, exactly, are those molecules made? We’ll walk through the cycle step by step, seeing how $NADH$ ‍, ${FADH}_{2}$ ‍, and $ATP$ ‍/ $GTP$ ‍ are produced and where carbon dioxide molecules are released.

Step 1. In the first step of the citric acid cycle, acetyl $CoA$ ‍ joins with a four-carbon molecule, oxaloacetate, releasing the $CoA$ ‍ group and forming a six-carbon molecule called citrate.

Step 2. In the second step, citrate is converted into its isomer, isocitrate. This is actually a two-step process, involving first the removal and then the addition of a water molecule, which is why the citric acid cycle is sometimes described as having nine steps—rather than the eight listed here $^{3}$ ‍.

Step 3. In the third step, isocitrate is oxidized and releases a molecule of carbon dioxide, leaving behind a five-carbon molecule—α-ketoglutarate. During this step, ${NAD}^{+}$ ‍ is reduced to form $NADH$ ‍. The enzyme catalyzing this step, isocitrate dehydrogenase, is important in regulating the speed of the citric acid cycle.

Step 4. The fourth step is similar to the third. In this case, it’s α-ketoglutarate that’s oxidized, reducing ${NAD}^{+}$ ‍ to $NADH$ ‍ and releasing a molecule of carbon dioxide in the process. The remaining four-carbon molecule picks up Coenzyme A, forming the unstable compound succinyl $CoA$ ‍. The enzyme catalyzing this step, α-ketoglutarate dehydrogenase, is also important in regulation of the citric acid cycle.

Detailed diagram of the citric acid cycle, showing the structures of the various cycle intermediates and the enzymes catalyzing each step.

Step 1. Acetyl CoA combines with oxaloacetate in a reaction catalyzed by citrate synthase. This reaction also takes a water molecule as a reactant, and it releases a SH-CoA molecule as a product.

Step 2. Citrate is converted into isocitrate in a reaction catalyzed by aconitase.

Step 3. Isocitrate is converted into α-ketoglutarate in a reaction catalyzed by isocitrate dehydrogenase. An NAD+ molecule is reduced to NADH + H+ in this reaction, and a carbon dioxide molecule is released as a product.

Step 4. α-ketoglutarate is converted to succinyl CoA in a reaction catalyzed by α-ketoglutarate dehydrogenase. An NAD+ molecule is reduced to NADH + H+ in this reaction, which also takes a SH-CoA molecule as reactant. A carbon dioxide molecule is released as a product.

Step 5. Succinyl CoA is converted to succinate in a reaction catalyzed by the enzyme succinyl-CoA synthetase. This reaction converts inorganic phosphate, Pi, and GDP to GTP and also releases a SH-CoA group.

Step 6. Succinate is converted to fumarate in a reaction catalyzed by succinate dehydrogenase. FAD is reduced to FADH2 in this reaction.

Step 7. Fumarate is converted to malate in a reaction catalyzed by the enzyme fumarase. This reaction requires a water molecule as a reactant.

Step 8. Malate is converted to oxaloacetate in a reaction catalyzed by malate dehydrogenase. This reaction reduces an NAD+ molecule to NADH + H+.

Step 5. In step five, the $CoA$ ‍ of succinyl $CoA$ ‍ is replaced by a phosphate group, which is then transferred to $ADP$ ‍ to make $ATP$ ‍. In some cells, $GDP$ ‍—guanosine diphosphate—is used instead of $ADP$ ‍, forming $GTP$ ‍—guanosine triphosphate—as a product. The four-carbon molecule produced in this step is called succinate.

$GTP$ ‍ is similar to $ATP$ ‍: both serve as energy sources, and the two can be readily interconverted. Which of the two molecules is produced during the citric acid cycle depends on the organism and cell type. For example, $ATP$ ‍ is made in human heart cells, but $GTP$ ‍ is made in liver cells.

Step 6. In step six, succinate is oxidized, forming another four-carbon molecule called fumarate. In this reaction, two hydrogen atoms—with their electrons—are transferred to $FAD$ ‍, producing ${FADH}_{2}$ ‍. The enzyme that carries out this step is embedded in the inner membrane of the mitochondrion, so ${FADH}_{2}$ ‍ can transfer its electrons directly into the electron transport chain.

$FAD$ ‍ is a better electron acceptor than ${NAD}^{+}$ ‍, meaning that it has a higher affinity, or “hunger”, for electrons. Succinate is not a great electron donor, meaning that it has a fairly high affinity for electrons itself and is not eager to give them up. ${NAD}^{+}$ ‍ is not electron-hungry enough to pull electrons away from succinate, but $FAD$ ‍ is $^{4, 5}$ ‍.

Step 7. In step seven, water is added to the four-carbon molecule fumarate, converting it into another four-carbon molecule called malate.

Step 8. In the last step of the citric acid cycle, oxaloacetate—the starting four-carbon compound—is regenerated by oxidation of malate. Another molecule of ${NAD}^{+}$ ‍ is reduced to $NADH$ ‍ in the process.

Products of the citric acid cycle

Let’s take a step back and do some accounting, tracing the fate of the carbons that enter the citric acid cycle and counting the reduced electron carriers— $NADH$ ‍ and ${FADH}_{2}$ ‍—and $ATP$ ‍ produced.

In a single turn of the cycle,

two carbons enter from acetyl $CoA$ ‍, and two molecules of carbon dioxide are released;
three molecules of $NADH$ ‍ and one molecule of ${FADH}_{2}$ ‍ are generated; and
one molecule of $ATP$ ‍ or $GTP$ ‍ is produced.

These figures are for one turn of the cycle, corresponding to one molecule of acetyl $CoA$ ‍. Each glucose produces two acetyl $CoA$ ‍ molecules, so we need to multiply these numbers by $2$ ‍ if we want the per-glucose yield.

Two carbons—from acetyl $CoA$ ‍—enter the citric acid cycle in each turn, and two carbon dioxide molecules are released. However, the carbon dioxide molecules don’t actually contain carbon atoms from the acetyl $CoA$ ‍ that just entered the cycle. Instead, the carbons from acetyl $CoA$ ‍ are initially incorporated into the intermediates of the cycle and are released as carbon dioxide only during later turns. After enough turns, all the carbon atoms from the acetyl group of acetyl $CoA$ ‍ will be released as carbon dioxide.

Where’s all the $ATP$ ‍?

You may be thinking that the $ATP$ ‍ output of the citric acid cycle seems pretty unimpressive. All that work for just one $ATP$ ‍ or $GTP$ ‍?

It’s true that the citric acid cycle doesn’t produce much $ATP$ ‍ directly. However, it can make a lot of $ATP$ ‍ indirectly, by way of the $NADH$ ‍ and ${FADH}_{2}$ ‍ it generates. These electron carriers will connect with the last portion of cellular respiration, depositing their electrons into the electron transport chain to drive synthesis of ATP molecules through oxidative phosphorylation.

Attribution:

This article is adapted from “Oxidation of pyruvate and the citric acid cycle” by OpenStax Biology, CC BY 3.0.

Download the original article for free at http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@9.85:36/Oxidation-of-Pyruvate-and-the-.

Additional references

Berg, J. M., J. A. Tymoczko, and L. Stryer. "The Citric Acid Cycle." In Biochemistry, 475-501. 6th ed. New York, NY: W.H. Freeman and Company, 2007.

Caprette, D. R. "Hans Krebs (1900-1981)." Experimental Biosciences: Resources for Introductory & Intermediate Level Lab Courses. May 26, 2005. http://www.ruf.rice.edu/~bioslabs/studies/mitochondria/krebs.html.

"Citric Acid Cycle." Wikipedia. August 23, 2015. Accessed September 10, 2015. https://en.wikipedia.org/wiki/Citric_acid_cycle.

"Hans Adolf Krebs." Wikipedia. August 15, 2015. Accessed September 10, 2015. https://en.wikipedia.org/wiki/Hans_Adolf_Krebs.

Karp, Gerald. "The Role of Mitochondria in the Formation of ATP." In Cell and Molecular Biology: Concepts and Experiments, 182-91. 6th ed. Hoboken, NJ: Wiley, 2010.

Krantz, B. "Citric Acid Cycle." 2008. https://mcb.berkeley.edu/labs/krantz/mcb102/lect_S2008/MCB102-SPRING2008-LECTURE8-CITRIC_ACID_CYCLE.pdf.

Krebs, Hans Adolf, and Leonard Victor Eggleston. "The Oxidation of Pyruvate in Pigeon Breast Muscle." Biochem. J. Biochemical Journal 34, no. 3 (1940): 442-59. doi:10.1042/bj0340442.

Lehninger, A., D. Nelson, and M. Cox. "Regulation of the Citric Acid Cycle." In Principles of Biochemistry. 2nd ed. New York, NY: Worth Publishers, 1992.

Pasani, S. "Why Is FADH2 Made Instead of NADH in One of the Reaction of Krebs Cycle? [answer]." Biology Stack Exchange. September 7, 2013. http://biology.stackexchange.com/questions/10313/why-is-fadh2-made-instead-of-nadh-in-one-of-the-reaction-of-krebs-cycle.

Raven, P. H., G. B. Johnson, K. A. Mason, J. B. Losos, and S. R. Singer. "How Cells Harvest Energy." In Biology, 122-46. 10th AP ed. New York, NY: McGraw-Hill, 2014.

"Redox Reactions." Essential Biochemistry. 2004. http://www.wiley.com/college/pratt/0471393878/student/review/redox/4_reduction_potential.html.

Reece, J. B., L. A. Urry, M. L. Cain, S. A. Wasserman, P. V. Minorsky, and R. B. Jackson. "Cellular Respiration and Fermentation." In Campbell Biology, 162-84. 10th ed. San Francisco, CA: Pearson, 2011.

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PrincessDeen101
8 years agoPosted 8 years ago. Direct link to PrincessDeen101's post “Is there a difference bet...”
Is there a difference between ATP and GTP?
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(13 votes)
- William H
  8 years agoPosted 8 years ago. Direct link to William H's post “ATP is adenosine triphosp...”
  ATP is adenosine triphosphate, or adenine (the DNA base) with a ribose (the sugar) attached which makes it adenosine, then with three phosphate groups added. GTP is all the same stuff, except for Guanine substituted in for Adenine.
  Comment on William H's post “ATP is adenosine triphosp...”
  (61 votes)
VINI
8 years agoPosted 8 years ago. Direct link to VINI's post “Explain why citric acid c...”
Explain why citric acid cycle can't operate in the absence of oxygen?
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(16 votes)
- Ali Sasani
  7 years agoPosted 7 years ago. Direct link to Ali Sasani's post “Cooper is right...Once ...”
  Cooper is right...
  Once the ETC stops oxidizing NADH to NAD+ there is no longer any NAD+ available for the Krebs cycle to reduce back to NADH and the cycle comes to a halt. Therefore, the Krebs cycle is actually regulated by the availability of NAD+
  It is true that the Fermentation process an contribute to NAD+ regeneration but remember that under anaerobic condition most of the cell's pyruvate is being sent to the Fermentation pathway... and even when NAD+ is regenerated during Fermentation, there will be much less Pyruvate (I'm trying to avoid words like "none") entering the Kreb's Cycle.
  All this being said, yes technically it can but it would not be contributing to the overall goal (ETC) so the ATP production will be significantly less.
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  (23 votes)
  See Also
  2.28: Krebs Cycle
Mohammad mahdy yousefi
8 years agoPosted 8 years ago. Direct link to Mohammad mahdy yousefi's post “How kerebs found this cyc...”
How kerebs found this cycle?
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(5 votes)
- Darmon
  8 years agoPosted 8 years ago. Direct link to Darmon's post “Krebs was working on the ...”
  Krebs was working on the problem of finding the chemicals that act as intermediaries in cellular respiration. He discovered that when he added certain chemicals to pigeon breast muscle cells, their oxygen consumption would increase, thus indicating that more respiration reactions were taking place. These chemicals are the same ones we now identify as those making up the Kreb's Cycle. :)
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Devon Dryer
8 years agoPosted 8 years ago. Direct link to Devon Dryer's post “Which provides more energ...”
Which provides more energy output, 1 ATP molecule or 1 GTP molecule?
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(7 votes)
- Chunhku
  8 years agoPosted 8 years ago. Direct link to Chunhku's post “The difference between AT...”
  The difference between ATP and GTP is not on their energy output, but on their relative abundance in cells. There are far more ATP than GTP in cells to provide energy, because of evolution.
  Comment on Chunhku's post “The difference between AT...”
  (10 votes)
fiky95
8 years agoPosted 8 years ago. Direct link to fiky95's post “I was wondering whether i...”
I was wondering whether it's necessary to remember the formula of each compound? Thank you! :)
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(3 votes)
- William H
  8 years agoPosted 8 years ago. Direct link to William H's post “Most basic biology classe...”
  Most basic biology classes, even AP bio don't require you to know the exact structure, although you might want to know their basic structure such as oh this is glucose with a phosphate group attached, this is a molecule with an extra proton, since most questions in that topic will revolve around that.
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BSnailer
8 years agoPosted 8 years ago. Direct link to BSnailer's post “Going from Malate to Oxal...”
Going from Malate to Oxaloacetic Acid 2 hydrogen ions are hydrolyzed but only one NADH is formed. Where did the other Hydrogen Ion go?
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- Maxime
  8 years agoPosted 8 years ago. Direct link to Maxime's post “NAD+ needs 2 electrons en...”
  NAD+ needs 2 electrons en 1 proton to make NADH.
  The oxidation of malate transfers these products to NAD+. There is indeed a remaining H+ ion that is released in the matrix as a proton. That way the charge is kept on both ends of the reaction.
  This also happens with the other times that NADH is formed (releasing a proton) but there the proton was released beforehand when the carboxyl group was created.
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Martin
5 years agoPosted 5 years ago. Direct link to Martin's post “Can GTP serve the same fu...”
Can GTP serve the same functions as ATP?
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- tyersome
  5 years agoPosted 5 years ago. Direct link to tyersome's post “They are both energy carr...”
  They are both energy carriers and there are even enzymes that will exchange high-energy phosphates among ribonucleotides§.
  However, these molecules are not interchangeable at a molecular level — most enzymes can only use one or the other as a source of energy.
  For example, ribosomes use GTP (never ATP) to drive the correct decoding of the codons in mRNA — in contrast, aminoacyl-tRNA synthetases can only use ATP to couple amino acids to the correct tRNA‡.
  Does that help?
  §Note: Nucleoside-diphosphate kinases (NDKs) — for details see:
  https://en.wikipedia.org/wiki/Nucleoside-diphosphate_kinase
  ‡Note: Khan academy has more about these processes here:
  https://www.khanacademy.org/science/biology/gene-expression-central-dogma#translation-polypeptides
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Gale
a year agoPosted a year ago. Direct link to Gale's post “If using this for CLEP bi...”
If using this for CLEP bio should I memorize this cycle and equation?
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- FrozenPhoenix45
  a year agoPosted a year ago. Direct link to FrozenPhoenix45's post “Having taken the CLEP Bio...”
  Having taken the CLEP Biology exam, I would recommend it. You may not come across it, but it can't hurt. I had a few questions regarding this, but I can't remember whether I needed the equation memorized. I still memorized it though, because I would rather know it and not need it than not know it and need it.
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caominh11122000
8 years agoPosted 8 years ago. Direct link to caominh11122000's post “In the picture "Oxidation...”
In the picture "Oxidation of pyruvate and citric acid cycle", in step 3 and 4, I saw there are 2 H+ ions produced but I'm not sure where they came from. I think there should be no spare H+ ion in step 3 and 4.
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- Ivana - Science trainee
  5 years agoPosted 5 years ago. Direct link to Ivana - Science trainee's post “They are not spare, that'...”
  They are not spare, that's the way NAD+ is reduced. Those H+ ions are used in generating proton gradient later for ETC.
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Thatmysticchick
a year agoPosted a year ago. Direct link to Thatmysticchick's post “SOMEBODY PLEASE HELP IT’S...”
SOMEBODY PLEASE HELP IT’S DRIVING ME NUTS!
Synthethases are ligase enzymes and differ from synthases in that they use energy in the reaction derived from a nucleoside triphosphate. I’m aware the nomenclature has changed to using synthases for the same purpose but that’s recent. I REALLY WANT TO UNDERSTAND how the enzyme responsible for the PRODUCTION of GTP/ATP (the only one for that matter) is a SYNTHETASE given that they USE gtp/atp, NOT PRODUCE. Please and Thank you very much in advance!
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The citric acid cycle | Cellular respiration (article) | Khan Academy (2024)

Introduction

Overview of the citric acid cycle

Steps of the citric acid cycle

Products of the citric acid cycle

Where’s all the $ATP$ ‍?

Attribution:

Additional references

Want to join the conversation?

FAQs

What is citric acid cycle in respiration? ›

The citric acid cycle | Cellular respiration (article) | Khan Academy (2024)

Introduction

Overview of the citric acid cycle

Steps of the citric acid cycle

Products of the citric acid cycle

Where’s all the ATP‍?

Attribution:

Additional references

Want to join the conversation?

FAQs

What is citric acid cycle in respiration? ›

Where’s all the $ATP$ ‍?