The Krebs cycle, also sometimes called the citric acid cycle, is a series of metabolic oxidation reactions that extracts energy the molecule acetyl-CoA to create ATP. ATP is the primary energy currency of the living cells, so the Krebs cycle is necessary for generating the energy that drives biochemical processes. The Krebs cycle is part of the larger process of cellular respiration, the process by which organic molecules are processed and converted into energy. The Krebs cycle creates important chemicals like NADH that assist in the electron transport chain that is used to create ATP. It also produces a number of secondary products that are used in other biochemical reactions.
All aerobic (oxygen-breathing) organisms use the citric acid cycle to generate their energy. In eukaryotic cells, the Krebs cycle occurs in the intracellular matrix of the mitochondria. In prokaryotes like bacteria or archaea that do not have mitochondria, the Krebs cycle occurs in the cytosol.
“Aside from the reams of paperwork involved with the refinance, none of this stuff has been all that difficult. Certainly it was nowhere near as difficult as memorizing the Kreb’s cycle or being on call in the ICU for 30 hours straight.” — Geoff Hubbell, M.D.
In a nutshell, the Krebs cycle takes acetyl-CoA—produced from the oxidation of pyruvate which is derived from glucose—and converts its bond energy into the products NADH, FADH2, and GTP (guanosine triphosphate). The electron carriers NADH and FADH2 play a crucial role in the electron transport chain that creates the majority of ATP during oxidative phosphorylation.
Overview Of the Krebs Cycle
The Krebs cycle is composed of about 8 distinct oxidation reactions. The cycle forms a closed loop, where the last reaction of the cycle reforms the molecule that it started with. In the first step, acetyl-CoA gives away its acetyl functional group to a compound called oxaloacetate to form a 6 carbon molecule called citrate. After some modifications, the citrate sheds two of its carboxyl groups in the form of carbon dioxide, each reaction producing 1 molecule of reduced NAD+ (NADH).
The remaining 4 carbon atoms left go through a handful more reactions first producing either a molecule of ATP or GTP, then reducing the electron carrier FAD to FADH2. Lastly, the carbon molecule goes through a handful more reactions, producing one more molecule of NADH, and regenerating the oxaloacetate molecule so the cycle can start again. In all, one full loop of the Krebs cycle produces 4 carbon dioxides, 1 ATP/GTP, 3 NADH, and 1 FADH2. For each molecule of glucose, the Krebs cycle does two complete loops because for each molecule of glucose, there are 2 pyruvates and so 2 acetyl-CoAs. Thus, for one molecule of glucose, the Krebs cycle produces a grand total of 4 molecules of carbon dioxide, 2 molecules of ATP/GTP, 6 NADH, and 2 FADH2
Steps Of The Krebs Cycle
Now that we have an overview of the cycle, let’s look a bit more in depth so that we can account for the reactant/products are each major step on the loop.
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During the first step, one molecule of acetyl-CoA binds to a four-carbon oxaloacetate molecule. The molecule sheds the CoA group and forms a 6 carbon molecule called citrate. This citrate molecule becomes the core of the subsequent chemical reactions. Each step in the cycle modifies this base, creating intermediate reactants. The energy from these intermediate reactions go towards making the other products of the Krebs cycle.
Next, the citrate molecule gets converted into an isomer called isocitrane. This is technically a two-step process that involves The addition and subsequent removal of a water molecule. Isocitrate has the same chemical formula as citrate, just a different molecular organization.
In the next step of the cycle, the newly formed 6-carbon isocitrate is oxidized, releasing one of its carboxyl groups in the form of a single carbon dioxide molecule. The resulting 5-carbon molecule left is called α-ketoglutarate. The energy from this oxidation reaction is used to add a single electron to NAD+, creating one molecule of the reduced electron carrier NADH.
The α-ketoglutarate molecule formed in the previous step is once again oxidized, jettisoning another carboxyl group in the form of carbon dioxide. The energy from this redox reaction is used to form another NADH molecule. The remaining 4-carbon molecule binds to Coenzyme A, creating a compound called succinyl-CoA.
The succinyl-CoA sheds its CoA group, replacing it with a phosphate group. This phosphate group is then transferred to a molecule of ADP, creating one molecule of ATP. In some cells, the phosphate group is added to a molecule of GDP, creating one molecule of GTP. The product of step 5 is a 4-carbon molecule is called succinate.
During the 6th step, the new succinate molecule is once again oxidized to make a 4-carbon compound called fumarate. Two hydrogen atoms from succinate are transferred to a molecule of FAD into FADH2. The FADH2 formed during this step plays an important role in the electron transport chain during the terminal phase of cellular respiration, oxidative phosphorylation.
Step 7 is a small one, consisting solely of a single reaction that adds one water molecule to fumarate, turning it into another 4 carbon molecule called malate.
During the last step of the Krebs cycle, the malate molecule is oxidized once again, which recreates our starting compound oxaloacetate. The energy from this reaction is used to reduce one more molecule of NAD+ into NADH.
What Are The Products Of The Krebs Cycle?
Taking a step back and looking at all the steps, we can see the ultimate fate of our carbon molecule and the relevant products of the Krebs cycle. Counting all the carbon dioxide, NADH, FADH2 and ATP/GTP, we get:
- 2 carbons atoms are put into oxaloacetate to create citrate, which are later released via oxidization the form of two carbon dioxides
- 3 molecule of NADH and one molecule of FADH2 are formed from the oxidation of various intermediary carbon molecules
- 1 molecule of ATP or GTP is made via the addition of a phosphate group to ADP or GDP
These values correspond to the products of one full iteration of the cycle for one molecule of acetyl-CoA. As each glucose molecule makes 2 molecules of acetyl-CoA, multiplying these values by 2 gives us the grand total of products per single molecule of glucose: 4 carbon dioxide, 6 NADH, 2 FADH2, and 2 molecules of either ATP or GTP.
Although cells mostly use ATP for energy, theoretically, GTP would make suitable energy substrate. It is unclear exactly why all aerobic organisms use ATP instead of GTP, considering how chemically similar the two are. GTP can be used to produce energy like ATP, however, the majority of GTP produced instead get used as a signaling molecule.
What About The ATP?
The Krebs cycle is extremely important for the production of ATP, but it does not directly produce ATP. Instead, it produces a lot of NADH molecules (6 per molecule of glucose) which perform the bulk of the work in forming the electron transport chain that creates ATP.
In eukaryotic cells, NADH produced from the Krebs cycle will embed themselves in the mitochondrial membrane and each give an electron to proteins and enzyme embedded in the membrane. The electrons get passed down this chain, moving from the less to more electronegative sites until it reduces an oxygen in the terminal reaction. The movement of the electrons down this chain creates an electrochemical potential that pumps lone protons across the mitochondrial membrane into the intermembrane space. The thermodynamic work generated during this process is used to add a phosphate group onto ADP to create ATP.
“Energy cannot be created or destroyed. It can only be changed from one form to another.” — Albert Einstein
So here we see the pay off of the lengthy Krebs cycle. The Krebs cycle creates a large amount of NADH and FADH2, the two main electron donors that drive the transport chain that generates ATP. Each molecule of NADH has a theoretical yield of 3 ATP while each FADH2 can make 2. In practice, slippage of the membrane enzymes or inefficiencies in the proton pump reduce the actual yield to approximately 2.5 ATP per NADH and 1.5 ATP per molecule of FADH2. Overall, the Krebs cycle is responsible for the main mechanism that produces the lion’s share of ATP during cellular respiration.
Citric Acid Cycle In Prokaryotes
In eukaryotes, the citric acid cycle takes place primarily in the mitochondria. Prokaryotes, on the other hand, lack mitochondria entirely, so the Krebs cycle occurs mainly in the intracellular cytosol. Bacteria still require a scaffolding though for their electron transport chain. Many bacteria have evolved to use their outer cell membrane as the scaffolding for the protein pump.
In addition, many bacteria have developed modified forms of the citric acid cycle. Most of these variations involve differing enzymes that catalyze the intermediate reactions. A handful of bacteria have developed citric acid cycles that use lithium-based compounds as reducers. These lithotrophs are considered anaerobic, as they do not rely on oxygen for their metabolic processes.
In summary, the Krebs cycle is one of the main sequences in the process of cellular respiration. The Krebs cycle takes acetyl-CoA produced from the oxidation of pyruvate and creates the electron carrier molecules NADH and FADH2. The products of the Krebs cycle are the main mechanisms that drive the electron transport chain that produces ATP.