13. Fatty Acid Metabolism

What are the two reasons why triacyclglycerols are a more efficient form of energy storage than glycogen?

More packed + More reduced

• 6x more energy per gram

What is the cell type in which triacylglycerols are stored?

Adipocyte - White adipose tissue

What is lipolysis?

Hydrolysis of triacylglycerols (TAG) that is thermodynamically favorable

What are the products of hydrolysis of triacylglycerols?

3 Fatty Acids (FA) + 1 Glycerol

Why must cells efficiently convert free fatty acids to acyl-CoA?

Free fatty acids form damaging detergent-like micelles (damage/disrupt membrane and cell)

How are free fatty acids transported in blood circulation?

Bind to a protein called serum albumin

How are free fatty acids transported in cells?

Rapidly converted into AcylCoA

What is fatty acid oxidation?

Catabolism of fatty acids for ATP

1. Activation of FA - conversion of FA → AcylCoA (2 ATP used)

2. Cytosol → Mitochondria via Carnitine Shuttle

3. β-Oxidation - AcylCoA → multiple AcetylCoA → CAC

What are the three chemical steps through which fatty acids are activated for β-Oxidation by formation of AcylCoA?

1. Adenylation: FA + ATP → Acyladenylate + PP_i

2. Thioester Bond Formation: Acyladenylate + H-SCoA → Acyl-CoA + AMP

   • AMP + ATP ←→ ADP + ADP

3. Hydrolysis of Pyrophosphate: PP_i + H₂O → 2 P_i

   • ΔG°' = -19 kJ/mol → makes activation of FA favorable

What is the reaction in β-Oxidation that ensure overall biochemical standard free energy is large and negative?

Hydrolysis of Pyrophosphate: PP1 + H₂O → 2 P_i

• ΔG°' = -19 kJ/mol → makes activation of FA favorable

Where is the site of β-Oxidation?

Mitochondrial Matrix

What is the feature of the transport of fatty acyl groups from the cytosol to the matrix?

Carnitine shuttle

• Acyl-CoA loses HSCoA and add Acyl to Carnitine in cytosol

• Acyl-Carnitine lose Acyl to HSCoA to form Acyl-CoA in matrix

What is the chemical mechanism for Step 4 of β-oxidation?

Thiolysis

• Break c-c bond with CoA-SH to release acetyl-CoA and generate new Acyl-CoA

• Far from equilibrium

How does a pair of electrons enter mitochondrial ETC from FADH₂, the enzyme-bound reduced cofactor in Step 1 of β-oxidation?

FADH₂ + Q → FAD⁺ + QH₂ | QH₂ → Enter Complex III of ETC

What is the ATP yield for β-oxidation with experimental P:O values?

4 ATP per round

• 1 QH₂ + 1 NADH

How does the ATP yield from β-oxidation of an unsaturated fatty acid differ from a saturated fatty acid w/ the same # of carbons?

Unsaturated < Saturated ATP Yield

• More oxidized = Less reduced

• # of ATP depends on where double bond is

What happens when an unsaturated fatty acid has an odd # of double bonds?

Step 1 is skipped = 1 less QH₂ made (-1.5 ATP)

What happens when an unsaturated fatty acid has an even # of double bonds?

1 less NADH made (-2.5 ATP)

What is the nutritional state that favors fatty acid synthesis?

Well-Fed/High Blood Glucose Levels → High Insulin signals to stimulate FA synthesis

What can carbohydrates be?

Metabolites for FA synthesis but FA cannot be carbohydrates

What is fatty acid synthesis’s cellular location, redox cofactors, and type of thioester?

• Cytosol

• NADPH

• Protein S (thiol group)

What is β-oxidation’s cellular location, redox cofactors, and type of thioester?

• Matrix

• NADH + QH₂

• Coenzyme A (CoA)

How are acetyl units moved from the mitochondrial matrix to the cytosol and how much ATP does it consume per acetyl unit??

Citrate Shuttle

1. Matrix: Oxaloacetate + Acetyl CoA → HS-Coa + Citrate

2. Citrate from Matrix → Cytosol

3. Cytosol: Citrate + HS-Coa + ATP → Acetyl CoA + Oxaloacetate + ADP + P_i

• 1 ATP per acetyl unit

What steps of β-oxidation can be reversed in FA synthesis and which step requires a workaround?

• Steps 1-3 can be reversed

• Step 4 needs a workaround

What is happening during the first round of fatty acid synthesis?

Malonyl-CoA + Acyl Carrier Protein (ACP) → Malonyl ACP + CoA

• Acetyl group transferred to another site on fatty acid synthase

• Both covalently bound via thioester linkages

What are the events that happen to enable another round of FA synthesis?

Acyl group is transferred from ACP back to E-SH to free up ACP for another Malonyl-CoA

What is the amount of ATPs used in FAS?

7 ATP

What is the nutritional and pathological state that lead to ketogenesis?

• Starvation

• Keto Diet/Low Carb Intake

• Diabetes

What is the molecular "building block” for ketogenesis?

Ketone Bodies (Acetoacetate + 3-hydroxybutyrate)

• Portable + Highly Soluble

• Pass BBB which prevents FA to enter brain

Where does ketogenesis takes place (organelle + tissue)?

• Mitochondria (matrix)

• Liver Tissue

What are the steps related to ketogenesis?

• Condensation

• Condensation

• Cleavage

• Reduction

What are the steps related to ketolysis?

• Oxidation

• Activation

What are the starting and ending molecules for ketogenesis?

Start: 2 Acetyl-CoA

End: Acetoacetate → 3-hydroxybutyrate (2 Ketone Bodies)

What are the starting and ending molecules for ketolysis?

Start: 3-hydroxybutyrate → Acetoacetate

End: 2 Acetyl-CoA

How are 3-hydroxybutyrate and acetoacetate related?

They are interconvertible via redox reaction + both can leave liver and enter bloodstream to travel to brain or muscle

What is the ATP yield from the complete oxidation of 3-hydroxybutyrate?

22.5 ATP