Fatty Acid Catabolism

• Fatty acids

  Three fatty acids are ester-linked to a glycerol backbone
• Why metabolise fatty acids?

  • They contain a lot of energy
  • They form a dense energy store
• Glucose storage

  Glucose → Glycogen + 2x mass of water
• Fatty acid storage

  Fatty acids → Triglycerides + no water
• Fatty acids are stored in adipose tissue


  as triglycerides
• Fatty acid are released from HSA and travel to the outer membrane of a mitochondrion where they are activated
• Fatty Acid activation

  1. Fatty Acid + Coenzyme A ⇢ Acyl CoA

  2. ATP-consuming process catalysed by Acyl CoA synthetase

  3. Conversion of AMP to ADP requires another ATP (-2 overall)
• Mitochondrial entry

  1. CoA must be swapped for carnitine to cross the inner mitochondrial membrane

  2. Acyl-carnitine is transported across the bilayer by a Translocase antiporter

  3. Acyl chain is reattached to CoA once in the matrix

  4. Carnitine Acyltransferase I (OMM)

  5. Acyl-CoA synthetase

  6. Carnitine Acyltransferase II (IMM)

  7. Acyl-CoA can cross outer mitochondrial membrane
• β oxidation: overview

  1. FAs (e.g. C16:0) are catabolised in 2C units

  2. First cleavage next to β carbon

  3. Products: Acetyl CoA and Acyl CoA (14C)

  4. Round 2 of β oxidation

  5. Four step process to release each 2C from FA
• β oxidation – detailed mechanism


  Step 1: dehydrogenase

  Step 2+3: hydratase

  Step 4: thiolase
• FAD, NAD+ involved in β oxidation
• β oxidation – overview

  Steps 1-4 repeat

  #cycles = (#carbons/2) - 1 = (C16/2) – 1 = 7 cycles for palmitic acid

  Final cleavage yields 2x Acetyl CoA

  Each cycle: 1x Acetyl CoA, 1x FADH2, 1x NADH
• β oxidation – summary

  The complete oxidation of palmitic acid (16C) requires 7 cycles of β oxidation:

  Palmitic acid + 8 CoA + 7 FAD + 7 NAD+ → 8 Acetyl CoA + 7 FADH2 + 7 NADH + 7H+

  96 ATP - 2 ATP = 129 ATP

  1xGlucose = 38 ATP, 3xGlucose (18C) = 114 ATP
• Longer chain Fatty Acid simply have more cycles of β oxidation
• Polyunsaturated Fatty Acid need additional isomerase enzymes to convert cis double bond to trans double bond
• Ketone bodies

  When Acetyl CoA builds up in the liver beyond the capacity of the TCA cycle to use it, ketone bodies are made
• Under conditions of prolonged fasting/starvation a high level of Triglyceride hydrolysis occurs and free Fatty Acid levels rise
• Ketone bodies used as fuel are Acetoacetate, β hydroxybutyrate, Acetone is lost in breath/sweat/urine (energy lost)
• Ketogenesis

  Three Acetyl CoAs are joined

  Reversal of last step of β oxidation
• What is the basic structure of triglycerides stored in adipose tissue?


  Triglycerides consist of three fatty acids ester-linked to a glycerol backbone
• Why are fatty acids considered dense energy stores compared to glucose?


  Fatty acids, such as palmitic acid, contain more energy per gram (38kJ/g) than glucose (17kJ/g) and are stored as triglycerides without water, making them a denser energy source
• Describe the process of lipolysis in adipose tissue

  Lipolysis involves the hydrolysis of triglycerides into free fatty acids (FFAs) and glycerol, mediated by enzymes such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL)
• What is the role of carnitine in fatty acid catabolism within mitochondria?


  Carnitine is crucial for transporting fatty acids across the inner mitochondrial membrane by swapping CoA for carnitine to form acyl-carnitine, which is then translocated by a translocase antiporter
• What are the end products of one cycle of β-oxidation of fatty acids?

  One cycle of β-oxidation produces one molecule each of Acetyl CoA, FADH2, and NADH
• How many ATP molecules are generated from the complete oxidation of palmitic acid?

  The complete oxidation of palmitic acid (16 carbons) generates 129 ATP molecules, after accounting for energy costs
• How do ketone bodies form and what are their types?

  Ketone bodies form when Acetyl CoA accumulates in the liver beyond the TCA cycle's capacity, leading to the production of Acetoacetate, β-hydroxybutyrate, and acetone, which is excreted
• What is the energy yield comparison between the oxidation of glucose and palmitic acid (a fatty acid)?

  The oxidation of one glucose molecule yields 38 ATP, whereas the oxidation of palmitic acid yields 129 ATP, demonstrating that fatty acids are a more potent energy source per molecule
• What initiates the process of fatty acid catabolism in cells?

  Fatty acid catabolism begins with the activation of fatty acids, which involves the conversion of free fatty acids to acyl CoA, an ATP-consuming process catalyzed by Acyl CoA synthetase
• What role does Acyl-CoA synthetase play in fatty acid metabolism?

  Acyl-CoA synthetase catalyzes the activation of fatty acids by attaching Coenzyme A to them, which is necessary for the fatty acids to enter subsequent metabolic pathways, including β-oxidation
• Explain the role of the enzyme carnitine acyltransferase I in fatty acid metabolism

  Carnitine acyltransferase I is responsible for the transfer of the acyl group from acyl-CoA to carnitine, forming acyl-carnitine, which facilitates the transport of fatty acids into the mitochondrial matrix for β-oxidation
• Describe the function of β-oxidation in the mitochondrial matrix


  β-oxidation is a metabolic process in the mitochondrial matrix where fatty acids are broken down into 2-carbon units, resulting in the production of Acetyl CoA, FADH2, and NADH, which enter the TCA cycle and electron transport chain to generate ATP
• What happens to the fatty acids once they are inside the mitochondria?

  Once inside the mitochondria, fatty acids undergo β-oxidation, where they are progressively broken down into Acetyl CoA, which can enter the TCA cycle or lead to ketone body formation under certain conditions
• How does the number of cycles in β-oxidation relate to the length of the fatty acid chain?

  The number of cycles in β-oxidation is determined by the number of carbon atoms in the fatty acid; each cycle removes two carbon atoms. For a fatty acid with 16 carbons, like palmitic acid, there are 7 cycles of β-oxidation
• How are longer chain fatty acids and polyunsaturated fatty acids (PUFAs) handled differently in β-oxidation?

  Longer chain fatty acids undergo more cycles of β-oxidation, generating more energy. PUFAs require additional enzymes, like isomerases, to convert cis double bonds to trans double bonds before they can continue through β-oxidation
• What is the significance of ketogenesis during prolonged fasting?

  During prolonged fasting, when carbohydrate stores are depleted, ketogenesis becomes important as it converts excess Acetyl CoA into ketone bodies, which serve as an alternative energy source, particularly for the brain and heart
• Why are ketone bodies preferred over glucose?

  The majority of the body runs on fatty acids (the heart prefers ketone bodies) because they require little conversion to enter TCA cycle, hence they are a rapid source of energy
• What is Ketogenesis


  Creation of ketone bodies (still count as fatty acid catabolism because they are made from breaking down fatty acids)
• What does a high amount of acetone suggest?

  Type 1 diabetes