Module 6 - Citric Acid Cycle Flashcards
Anaplerotic Reactions
Chemical reactions that form intermediates of a metabolic pathway in order to replenish them.
Glyoxylate Cycle
A pathway present in plants and some microorganisms that allow the conversion of fats to carbohydrates.
Oxidative Decarboxylation
An oxidation reaction in which a carboxylate group is removed, forming carbon dioxide.
citric acid cycle
This is the metabolic pathway where the complete oxidation of fuels to CO2 occurs, and where the high-energy electrons that result from this oxidation are generated.
What else can the citric acid cycle be called?
the tricarboxylic acid cycle - named for the presence of intermediates that have three carboxylate groups
the Krebs cycle - named after the scientist Sir Hans Kreb who proposed the existence of this cycle
What is the starting molecule of the citric acid cycle?
Acetyl CoA
Where does citric acid occur in the cell?
in the mitochondria
How does pyruvate become Acetyl CoA?
pyruvate is converted to acetyl Coenzyme A (acetyl CoA) by the enzyme complex called the pyruvate dehydrogenase complex
Pyruvate + CoA + NAD+ → acetyl CoA + CO2 + NADH + H+
Note that this is a redox reaction (loss of electrons from pyruvate which are gained by NAD+ to form NADH) and a decarboxylation reaction (pyruvate is a 3-carbon molecule while acetyl CoA has 2 carbons).
For this reason, it is called an oxidative decarboxylation
This reaction, like most decarboxylation reactions, is irreversible.
What are the other sources of Acetyl CoA?
acetyl CoA produced by any means is able to enter the citric acid cycle and thus used to generate ATP.
In fact, we will see in future modules that the breakdown of fats and some amino acids result in the production of acetyl CoA, which is why they both are useful fuels
acetyl CoA has other possible metabolic fates; for example, it can be used to synthesize cholesterol, fatty acids, and ketone bodies.
The Pyruvate Dehydrogenase Complex
There is an oxidation-reduction;
a decarboxylation;
and a transfer of CoA to the acetyl group
this reaction is catalyzed by a large enzyme complex that contains three different enzymes and five coenzymes
What are the 3 enzymes that make up the Pyruvate dehydrogenase complex?
Note that three of the coenzymes; TPP, lipoamide, and FAD, are prosthetic groups which means they are covalently attached to their corresponding enzyme. The other two coenzymes, NAD and CoA, function as substrates in this reaction.
why do these enzymes exist in a complex?
the three enzymes (depicted by the yellow, green and red circles) work together
By having the three enzymes close in proximity to each other, the overall reaction rate is increased by keeping the intermediates bound to the complex throughout the reaction. Moreover, the intermediates are not lost to side reactions that could significantly reduce the flux through this step.
How is The Pyruvate Dehydrogenase Complex regulated
it is regulated in two ways
First, and most important of the two, it is regulated by covalent modification, specifically phosphorylation
There is a specific kinase, called pyruvate dehydrogenase kinase, which phosphorylates the E1 component which results in the inactivation of the complex
The pyruvate dehydrogenase complex is also regulated allosterically by molecules which reflect high or low energy charge in the cell
How do the allosteric modifiers change the activity of PDH?
by promoting phosphorylation or dephosphorylation of the complex
What is a simple overview of the citric acid cycle?
Acetyl CoA, a C2 (2-carbon) molecule, condenses with a C4 molecule to form a C6 molecule
The C6 molecule undergoes two oxidative decarboxylations to release two CO2 and high energy electrons in the form of NADH
The resulting C4 molecule is further oxidized to capture more high-energy electrons in the form of NADH and FADH2 in stage 2
The resulting C4 molecule, oxaloacetate, is able to condense with another acetyl CoA to produce another C6 molecule, allowing the cycle to continue on
What is the basic summary of the citric acid cycle?
a two-carbon molecule enters the cycle (acetyl CoA), and two carbons are lost during the cycle as CO2
there isn’t much ATP produced in this cycle, just one ATP for every acetyl CoA
the high-energy electrons captured in the form of NADH and FADH2 will be used to generate ATP in a process called oxidative phosphorylation
glucose, fatty acids, and some amino acids can all be metabolized to acetyl CoA and therefore enter into the citric acid cycle.
What is the detailed summary of the citric acid cycle?
it consists of 8 reactions
it produces 3 NADH, 1 FADH2, 1 ATP, and 2 CO2
it is a true cycle since oxaloacetate, which condenses with acetyl CoA, is reformed during the cycle which allows the cycle to continue
The first reaction in the cycle cycle
Acetyl CoA enters the citric acid cycle by condensing with oxaloacetate to form a 6-carbon molecule called citrate, with the release of CoA.
This reaction is catalyzed by citrate synthase. Note that citrate has three carboxylate groups; two of these will eventually be lost as CO2 molecules.
the energy required for the condensation is obtained from the hydrolysis of the thioester between CoA and the acetyl group.
The second step of the cycle
citrate is converted to isocitrate through an isomerization reaction catalyzed by aconitase
This reaction changes the position of the hydroxyl group.
By repositioning the hydroxyl group, the subsequent reactions are facilitated
The third step of the cycle
Isocitrate dehydrogenase converts isocitrate to α-ketoglutarate
This is an oxidative decarboxylation reaction, where high-energy electrons are captured in NADH, and CO2 is released.
The fourth step of the cycle
In another oxidative decarboxylation reaction, α-ketoglutarate is converted to succinyl CoA
this reaction is catalyzed by
α-ketoglutarate dehydrogenase.
NADH is produced from the captured electrons, and another CO2 is released.
For the cycle to continue, succinyl CoA has to be converted to oxaloacetate so it can condense with another acetyl CoA
The fifth step of the cycle (start of stage 2)
succinyl CoA is converted to succinate by succinyl CoA synthetase
The thioester bond between CoA is cleaved, and the energy released is used to generate a molecule of ATP
The sixth to eighth step of the cycle
Once succinate is formed, there are three more reactions that occur that regenerate oxaloacetate.
They are catalyzed by succinate dehydrogenase, fumarase, and malate dehydrogenase
The high-energy electrons that are generated from the additional oxidations that occur in two of these reactions are captured in the form of FADH2 and NADH
What are the key enzymes that regulate the citric acid cycle?
The two key enzymes regulated are isocitrate dehydrogenase and
α-ketoglutarate dehydrogenase, and both are regulated by allosteric mechanisms
Since the major goal of the cycle is to produce energy, not surprisingly molecules such as NADH and ATP which reflect a positive energy charge in the cell inhibits isocitrate dehydrogenase, while ADP, which reflects a low energy charge, activates the enzyme.
Similarly, α-ketoglutarate dehydrogenase is inhibited by ATP and NADH, as well as the product of its reaction, succinyl CoA.
While the major role of the citric acid cycle is to oxidize acetyl CoA for ATP generation what is its other role?
to provide intermediates for the biosynthesis of a number of other biomolecules
The Citric Acid Cycle Can Be Replenished When Intermediates Are Drawn Off for Biosynthetic Processes
One of the most important anaplerotic reaction is the synthesis of oxaloacetate from pyruvate and CO2 by pyruvate carboxylase
The oxaloacetate produced by this enzyme can be used for glucose synthesis in liver when a higher energy state exists, but it can also be used to replenish the citric acid cycle when the energy charge is low
The Glyoxylate Cycle Enables Plants and Bacteria to Convert Fats into Carbohydrates
This pathway is similar to the citric acid cycle, but differs in that two molecules of acetyl CoA enter the pathway at different points in the cycle rather than just one
there are no decarboxylation steps and thus no carbons are lost
Succinate can be used to form glucose using reactions in the citric acid cycle and gluconeogenesis
