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ATP Production

Stages

• 1. Glycolysis

• 2. Transition reaction

• 3. Citric acid cycle

• 4. Electron transport chain

Oxidation of pyruvate

• Intermediate step between glycolysis and the kreb’s cycle
• Pyruvate is further oxidized to form an acetyl group , which is

then bonded to coenzyme A (CoA) to form acetyl-CoA.

• The transition reaction takes place within mitochondria of

cells.

Enzymes involved in the synthesis of acetyl

coenzyme A from pyruvate

Overview of the synthesis

Step 1: Decarboxylation

• Pyruvate combines with TPP and is then decarboxylated to yield hydroxyethyl-TPP
• This reaction, the rate limiting step in acetyl CoA synthesis, is catalyzed by the pyruvate dehydrogenase component (E 1 ) of the multienzyme complex.
• TPP is the prosthetic group of the pyruvate dehydrogenase component.
• The hydroxyethyl group attached to TPP is oxidized to form an acetyl group while being simultaneously transferred to lipoamide, a derivative of lipoic acid that is linked to the side chain of a lysine residue by an amide linkage. Note that this transfer results in the formation of an energy-rich thioester bond
• The oxidant in this reaction is the disulfide group of lipoamide, which is reduced to its disulfhydryl form. This reaction yields acetyllipoamide.

Step 2: Oxidation

• The acetyl group is transferred from acetyllipoamide to CoA to form acetyl CoA.
• Dihydrolipoyl transacetylase (E 2 ) catalyzes this reaction. The energy-rich thioester bond is preserved as the acetyl group is transferred to CoA. Recall that CoA serves as a carrier of many activated acyl groups. Acetyl CoA, the fuel for the citric acid cycle, has now been generated from pyruvate.

Step 3: Formation of Acetyl CoA.

• the oxidized form of lipoamide is regenerated by dihydrolipoyl dehydrogenase (E3).
• The pyruvate dehydrogenase complex cannot complete another catalytic cycle until the dihydrolipoamide is oxidized to lipoamide.
• Two electrons are transferred to an FAD prosthetic group of the enzyme and then to NAD+^.

Step 4. Regeneration of oxidized

lipoamide

Transition Reaction

• The transition reaction oxidizes pyruvate and reduces NAD. It

can be summarized as:

• Note that each glucose yields 2 pyruvate for the transition

reaction.

• As with the NADH + H produced by glycolysis, the NADH H

produced by the transition reaction will eventually enter the

electron transport chain.

• The conversion of pyruvate to acetyl-CoA requires the B

vitamins thiamin, riboflavin, niacin, and pantothenic acid.

• Carbohydrate metabolism depends on the presence of these

vitamins

ATP Production

The four stages of aerobic respiration can be

explained using glucose as an example:

• 1. Glycolysis

• 2. Transition reaction

• 3. Citric acid cycle

• 4. Electron transport chain

Citric Acid Cycle

Kreb’s Cycle

Tricarboxylic Acid Cycle

TCA cycle

pathway

TCA cycle pathway – Step 1

Citrate synthase catalyzes the transfer of an acetyl residue from acetyl

CoA to a carrier molecule, oxaloacetic acid. The product of this reaction,

tricarboxylic acid, gives the cycle its name.

Step 1 – Condensation of Acetyl-CoA and Oxaloacetate to Citrate Synthase^ Citrate TCA cycle pathway – Step 2 Tricarboxylic acid undergoes isomerization to yield isocitrate. In the process, only the hydroxyl group is shifted within the molecule. Due to the properties of aconitase, the isomerization is absolutely stereospecific. Although citrate is not chiral, isocitrate has two chiral centers, so that it could potentially appear in four isomeric f orms.

Step 2 – Isomerization of Citrate to Isocitrate Aconitase TCA cycle pathway – Step 3

The first oxidative step now follows. Isocitrate dehydrogenase oxidizes the hydroxyl

group of isocitrate into an oxo group. At the same time, a carboxyl group is released as

CO2, and 2 - oxoglutarate (also known as α- ketoglutarate) and NADH+H+ are formed.

Step 3 – Formation of a - Ketoglutarate and CO2—First Oxidation dehydrogenase^ Isocitrate

TCA cycle pathway – Step 4 The next step, the formation of succinyl CoA, also involves one oxidation and one decarboxylation. It is catalyzed by a-ketoglutarate dehydrogenase, a multienzyme complex. NADH+H+ is once again formed in this reaction. Step 4 – Formation of Succinyl-CoA and CO2— Second Oxidation α dehydrogenase α dehydrogenase--ketoglutarateketoglutarate TCA cycle pathway – Step 5 The subsequent cleavage of the thioester succinylCoA into succinate and coenzyme A by succinic acid-CoA ligase (succinyl CoA synthetase, succinic thiokinase) is strongly exergonic and is used to synthesize a phosphoric acid anhydride bond (“ substrate level phosphorylation”. However, it is not ATP that is produced but instead guanosine triphosphate (GTP). However, GTP can be converted into ATP by a nucleoside diphosphate kinase.

Step 5 – Formation of Succinate Succinyl CoA synthetase TCA cycle pathway – Step 6 Via the reactions described so far, the acetyl residue has been completely oxidized to CO2. At the same time, however, the carrier molecule oxaloacetate has been reduced to succinate. Three further reactions in the cycle now regenerate oxaloacetate from succinate. Initially, succinate dehydrogenase oxidizes succinate to fumarate.

Step 6 – Formation of Fumarate – Third Oxidation dehydrogenase^ Succinate TCA cycle pathway – Step 7

Water is now added to the double bond of fumarate by fumarate hydratase

(“fumarase”), and chiral (2S)- malate is produced.

Step 7 – Malate Formation: Hydration Fumarase

TCA cycle pathway – Step 8

In the last step of the cycle, malate is again oxidized by malate dehydrogenase into

oxaloacetate, withNADH+H+ again being produced. With this reaction, the cycle is

complete and can start again from the beginning.

Step 8 – Oxaloacetate regeneration – 4 th^ oxidation

Dehydrogenasee^ Malate

Result

• Per acetyl-CoA

– 3 NADH

– 1 FADH 2

– 1 ATP

– 2 CO 2

• Per glucose

– 6 NADH

– 2 FADH 2

– 2 ATP

– 4 CO 2

All ultimately turned into ATP (oxidative phosphorylation…later)