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Citric Acid Cycle

The reactions of the citric acid cycle
by

Jay Silveira

on 28 October 2013

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Transcript of Citric Acid Cycle

Citric Acid Cycle - Objectives
Understand the overall aspects of the citric acid cycle.
Learn the structures of the metabolites found in the cycle.
Know the enzymes involved in the pathway.
List the locations of the high-energy products (NADH, FADH2, GTP) and fully-oxidized carbon atoms (CO2) produced in the pathway.
Point out the key regulatory reactions of the cycle.

Oxaloacetate
Citrate
Isocitrate
Alpha-ketoglutarate
Succinyl CoA
Succinate
Fumarate
Malate
Citrate Synthase
Isocitrate
Dehydrogenase
Alpha-ketoglutarate
Dehydrogenase
Succinyl CoA
Synthetase
Aconitase
Succinate
Dehydrogenase
Fumarase
Malate
Dehydrogenase
Two-carbon units (acetyl CoA) are brought into the citric acid cycle for oxidation and subsequent ATP production.
Reaction has a negative delta G = potential for regulation
Since this condensation initiates the citric acid cycle, wasteful side reactions such as hydrolysis of acetyl CoA must be prevented. Citrate synthase exhibits sequential, ordered kinetics and induced fit that both prevent side reactions.
Relocates the hydroxyl group on citrate for subsequent oxidation
Delta G is close to zero - reaction is readily reversible
The rate of alpha-ketoglutarate formation is important in determining the rate of the citric acid cycle.
NADH is produced.
CO2 is given off, and a fully oxidized carbon is lost.
Reaction has a negative delta G = potential for regulation
NADH is produced
CO2 is given off, and a fully oxidized carbon is lost.
Reaction has a negative delta G, so along with the previous step, this is another point of citric acid cycle regulation.
Since succinate is a symmetric molecule, the identity of carbons from the acetyl unit is lost.
GTP or ATP is produced
Only step in the citric acid cycle that directly yields a high phosphoryl-transfer potential compound (substrate phosphorylation)
Nucleoside diphosphokinase GTP + ADP GDP + ATP
Unlike other enzymes of the citric acid cycle, succinate dehydrogenase is embedded in the inner mitochondrial membrane (direct link to the electron-transport chain)
Two hydrogen atoms (a proton and an electron) are removed in an oxidation step.
FADH2 is produced because the free energy change is insufficient to reduce NAD+.
...to an oxidation state of "-1".
These carbons go from an oxidation state of “-2”…
The reaction is a stereospecific trans addition of H+ and OH- to form only L-malate.
Overall oxidation state of the molecule doesn’t change, the reaction just prepares for oxidation in the next step (but… one of the carbons has been oxidized to the level of a hydroxyl group).
Both carbons have an oxidation state of “-1”.


Net oxidation state for these two carbons = “-2”
Net oxidation state for these two carbons = “-2”.
This carbon is oxidized to “0”.
This carbon is reduced to “-2”.
NADH is formed.
Oxaloacetate is regenerated and the citric acid cycle is complete
The standard free energy for the reaction is quite positive (DGo′ = +31.4 kJ/mol) so how is the reaction driven?
Structure learning tip: One can think of citrate as a three carbon chain, with a carboxylic acid group added on at each carbon. The center carbon also contains a hydroxyl group, which is important to note in the next compound: isocitrate.
Structure learning tip: One can think of citrate as a three carbon chain, with a carboxylic acid group added on at each carbon. The center carbon also contains a hydroxyl group, which is important to note in the next compound: isocitrate.
Structure learning tip: For isocitrate, base the structure off of citrate and simply move the hydroxyl from the central carbon of the “three carbon chain” to one of the peripheral ones.
Structure learning tip: For isocitrate, base the structure off of citrate and simply move the hydroxyl from the central carbon of the “three carbon chain” to one of the peripheral ones.
Structure learning tip: From this point, base the structures off of succinate. It’s an easy molecule to learn as it’s symmetrical, and it’s just two methylene groups (–CH2–) with a carboxylic acid attached to each one. a-KG has and extra carbonyl stuck in on the end of the methylenes. Another easy way to learn a-KG is to know that it is the corresponding keto acid to glutamate – simply replace the amino group (and the proton on the a-carbon) in Glu and you have a-KG.
Structure learning tip: From this point, base the structures off of succinate. It’s an easy molecule to learn as it’s symmetrical, and it’s just two methylene groups (–CH2–) with a carboxylic acid attached to each one. a-KG has and extra carbonyl stuck in on the end of the methylenes. Another easy way to learn a-KG is to know that it is the corresponding keto acid to glutamate – simply replace the amino group (and the proton on the a-carbon) in Glu and you have a-KG.
Structure learning tip: Again, base the structures off of succinate as described for a-KG. The carboxyl of a-KG has been replaced by S-CoA.
Structure learning tip: Again, base the structures off of succinate as described for a-KG. The carboxyl of a-KG has been replaced by S-CoA.
Structure learning tip: Succinate is an easy molecule to learn as it’s symmetrical, and it’s just two methylene groups (–CH2–) with a carboxylic acid attached to each one.
Structure learning tip: Succinate is an easy molecule to learn as it’s symmetrical, and it’s just two methylene groups (–CH2–) with a carboxylic acid attached to each one.
Structure learning tip: The final three reactions of the pathway are very simple – succinate is subjected to a classic biochemical oxidation.

Oxidize the central carbons forming a double bond (fumarate)
Oxidize one of the carbons to the hydroxyl level (malate)
Oxidize that carbon to the carbonyl level (oxaloacetate)

The cycle is done and you are back where you started!
Structure learning tip: The final three reactions of the pathway are very simple – succinate is subjected to a classic biochemical oxidation.

Oxidized the central carbons forming a double bond (fumarate)
Oxidized one of the carbons to the hydroxyl level (malate)
Oxidize that carbon to the carbonyl level (oxaloacetate)

The cycle is done and you are back where you started!
Structure learning tip: The final three reactions of the pathway are very simple – succinate is subjected to a classic biochemical oxidation.

Oxidized the central carbons forming a double bond (fumarate)
Oxidized one of the carbons to the hydroxyl level (malate)
Oxidize that carbon to the carbonyl level (oxaloacetate)

The cycle is done and you are back where you started!
Structure learning tip: The final three reactions of the pathway are very simple – succinate is subjected to a classic biochemical oxidation.

Oxidized the central carbons forming a double bond (fumarate)
Oxidized one of the carbons to the hydroxyl level (malate)
Oxidize that carbon to the carbonyl level (oxaloacetate)

The cycle is done and you are back where you started!
Structure learning tip: The final three reactions of the pathway are very simple – succinate is subjected to a classic biochemical oxidation.

Oxidized the central carbons forming a double bond (fumarate)
Oxidized one of the carbons to the hydroxyl level (malate)
Oxidize that carbon to the carbonyl level (oxaloacetate)

The cycle is done and you are back where you started!
Just like the a-KG/Glu keto/amino acid pair, oxaloacetate is the corresponding keto acid to aspartate – simply replace the amino group (and the proton on the a-carbon) in Asp and you have oxaloacetate!
Part of the aerobic processing of glucose that generates greater than 90% of the energy used by aerobic cells in humans
The final common pathway for the oxidation of fuel molecules (carbohydrates, fatty acids, and amino acids).
Also a supplier of precursors for building amino acids, nucleotide bases etc.
“The metabolic hub of the cell”
Takes place in the matrix of the mitochondria
A cyclic process that is fairly efficient in terms of energy production
Key Aspects of the Citric Acid Cycle
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