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Chapter 26

The Organic Chemistry

of the Metabolic Pathways

Organic Chemistry 6th Edition

Paula Yurkanis Bruice

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Metabolism is the set of reactions living organisms carry out to obtain energy and to synthesize complex molecules

catabolism: complex molecules simple molecules + energy

anabolism: simple molecules + energy complex molecules

Metabolism is the combination of catabolism and anabolism

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The Four Stages of Catabolism

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• Compounds that can enter the citric acid cycle are citric acid cycle intermediates, acetyl-coA, and pyruvate.

• Pyruvate enters the cycle by being converted to acetyl-CoA.

• Acetyl-CoA is the only non–citric acid cycle intermediate that can enter the citric acid cycle by being converted to citrate.

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Metabolic Energy Is Measured in Terms of Adenosine Triphosphate (ATP)

ATP is the universal carrier of chemical energy

The energy released from hydrolysis of ATP converts endergonic reactions into exergonic reactions

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A phosphoanhydride bond is broken in this reaction

Thermodynamics of glucose-6-phosphate formation:

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Mechanism for a phosphoryl transfer reaction:

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Without ATP, phosphorylation cannot occur:

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Three Mechanisms for Phosphoryl Transfer Reactions

• Each of the three phosphorus atoms of ATP can undergo nucleophilic attack.

• Each mechanism places a different phosphorylgroup on the nucleophile.

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The pyrophosphate product is further hydrolyzed to ensure irreversibility of the reactions:

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The “High-Energy” Character of Phosphoanhydride Bonds

The hydrolysis of a phosphoanhydride bond is highlyexergonic

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Three Factors Contribute to the Greater Stability of ADP and Phosphate Compared to ATP

1.Greater electrostatic repulsion in ATP

2.More solvation stabilization in the products

3.Greater electron delocalization in the products

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ATP reacts slowly in the absence of enzymes becausethe negative charges on ATP decrease leaving ability

In an enzyme active site, positive centers decrease the overall negative charge

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The Catabolism of Fats

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• A kinase is an enzyme that puts a phosphoryl group on its substrate.

• A dehydrogenase is an enzyme that oxidizes its substrate.

• Dihydroxyacetone phosphate enters the glycolytic pathway and is broken down further.

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Mechanism for the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate:

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A fatty acid has to be activated before it can be metabolized:

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The fatty acyl-CoA is converted to acetyl-CoA via-oxidation:

1. acyl-CoA dehydrogenase2. enoyl-CoA hydratase3. 3-L-hydroxyacyl-CoA dehydrogenase4. -ketoacyl-CoA thiolase

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Reaction mechanisms

Conjugate addition of water:

A retro-Claisen condensation:

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The Catabolism of Carbohydrates

In the first stage of carbohydrate catabolism, polysaccharides are enzymatically hydrolyzed to glucose molecules:

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Glucose is converted to two molecules of pyruvate by the 10-step process known as the glycolytic pathway:

1. Glucose is converted to glucose-6-phosphate (Section 26.1)

2. Glucose-6-phosphate isomerizes to fructose-6-phosphate (Section 24.9)

3. ATP puts a second phosphoryl group on fructose-6-phosphate to yield fructose-1,6-diphosphate

4. The reverse of an aldol reaction (Section 24.9)

5.

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Mechanism of step 5:

Compare this mechanism with the enediol rearrangement shown in Section 22.5

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6. Glyceraldehyde-3-phosphate is oxidized by NAD+ to yield 1,3- diphosphoglycerate (Section 25.1)

7. ATP formation

8. Isomerization

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9. Dehydration

10. ATP formation

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Glycolysis

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The Fates of Pyruvate

Aerobic conditions:

Anaerobic conditions:

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Yeast converts pyruvate to ethanol:

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The Catabolism of Proteins

Amino acids are then converted to acetyl-CoA, pyruvate, or citric acid cycle intermediates

The first stage of protein catabolism is enzymatic hydrolysis of proteins to amino acids:

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An Example of Amino Acid Catabolism

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The Citric Acid Cycle

The acetyl group of each molecule of acetyl-CoA is formed by the catabolism of fats,

carbohydrates, and amino acids

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The Citric Acid Cycle Contains Eight

Reactions

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1. Carbonyl addition and hydrolysis (Sections 18.2 and 17.5)

2. Dehydration and conjugate addition of water (Section 18.18)

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3. Oxidation and decarboxylation (Section 19.19)

4. Oxidation and decarboxylation (Section 25.3)

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5. Addition–elimination reaction followed by phosphate transfer to GDP

6. FAD oxidizes succinate to fumarate (Section 25.2)

7. Conjugate addition of water to the double bond of fumarate forms (S)-malate (Section 5.20)

8. Oxidation of the (S)-malate by NAD+ forms oxaloacetate, returning the cycle to its starting point

Reactions 6, 7, and 8 in the citric acid cycle are similar to reactions1, 2, and 3 in β-oxidation of fatty acids (Section 26.6)

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Oxidative Phosphorylation

For every acetyl-CoA that enters the citric acid cycle,11 molecules of ATP are formed from NADH and FADH2, and one molecule of ATP is formed in the cycle