Fatty acid metabolism II FOR KLE- no audio

Course Overview

• Course Code: LSC-10064

• Topic: Fatty Acid Metabolism II: Mobilization, Degradation & Oxidation

• Instructor: Dr. David Watson

• Contact Info: Room 303b, Email: d.watson@keele.ac.uk

Learning Outcomes

• Fatty Acid Structure & Roles:

  • Understand the structure of fatty acids.

  • Explain the physiological roles these molecules play in metabolism.

• Anabolic Pathways:

  • Describe pathways for fatty acid synthesis and storage.

• Catabolic Pathways:

  • Detail the processes for mobilizing and degrading fatty acids and their role in energy production via beta-oxidation.

• Regulation of Fatty Acid Metabolism:

  • Outline the regulatory processes influencing fatty acid metabolism.

• Further Reading:

  • Berg et al., Biochemistry (chapter 22).

  • Garret and Grisham (module e-book, chapters 23 and 24).

Comparison: Fatty Acid Synthesis vs. Degradation

• General Overview:

  • Synthesis:

    • Elongates the fatty acid chain.

    • Involves the addition of 2-carbon units derived from activated Malonyl ACP.

  • Degradation:

    • Shortens the fatty acid chain by removing 2-carbon units.

    • Released units are acetyl CoA.

Key Differences

• Subcellular Location:

  • Synthesis: Cytosol

  • Degradation: Mitochondrial matrix

• Intermediates:

  • Synthesis: Covalently linked to acyl carrier protein (ACP)

  • Degradation: Covalently linked to coenzyme A

• Enzyme Complexes:

  • Synthesis: Utilizes fatty acid synthase (a large enzyme complex).

  • Degradation: Composed of separate enzymes, not a multi-enzyme complex.

• Cofactors/Coenzymes:

  • Synthesis: NADPH as the reductant

  • Degradation: NAD+ and FAD as oxidants

Fatty Acid Degradation Process

• Overview:

  • Converts aliphatic compounds into activated acetyl units (acetyl CoA).

  • Involves several enzymatic steps:

    1. Oxidation: Introduces a double bond.

    2. Hydration: Adds water across the double bond.

    3. Oxidation: Converts the alcohol group into a ketone.

    4. Thiolysis: Cleaves with CoA, leading to the formation of acetyl CoA.

  • Cycle of Repetition:

    • This process repeats for unsaturated, even-chained fatty acids (e.g., Palmitate, C16:0).

    • Sequential shortening leads to the entry of acetyl CoA into the TCA cycle.

Utilization of Fatty Acids as Fuel

• Triglyceride Breakdown:

• Palmitate as a Fuel Source: Free fatty acids and glycerol yield energy in glucose and TCA cycle.

• Production of ATP: Particularly in the liver, through ketone bodies and other metabolites.

Step 1: Mobilization of Lipids

• Hydrolysis of TAG:

  • TAG (Triacylglycerol) hydrolyzed into fatty acids and glycerol.

  • Released from adipose tissue during fasting states.

• Regulation by Hormones:

  • Hormonal activation triggers a protein kinase cascade.

  • Activates lipases within the adipocyte.

Glycerol Utilization

• Glycerol from Hydrolysis:

  • Transferred to the liver and converted to glyceraldehyde-3-phosphate.

  • Glyceraldehyde-3-phosphate can enter glycolysis and gluconeogenesis.

• Transport via Serum Albumin:

  • Free fatty acids are bound by serum albumin, ensuring solubility for transport through the bloodstream.

Step 2: Activation and Transportation

• Importance of Location:

  • Fatty acid synthesis occurs in the cytosol; degradation in mitochondria.

• Activation Process:

  • Occurs on the outer mitochondrial membrane.

  • Carnitine Shuttle:

    • Acyl CoA reacts with carnitine to form acyl carnitine via carnitine acyltransferase-1.

    • Acyl carnitine is transported across the mitochondrial membrane.

    • Converted back to acyl CoA for further degradation.

Compartmentation and Regulation

• Role of Malonyl CoA:

  • Functions as an allosteric inhibitor of Carnitine Acyltransferase-1 (CAT1).

  • Avoids simultaneous fatty acid degradation and synthesis.

Step 3: Fatty Acid Catabolism

• Process of Oxidation:

  • i) Oxidation by FAD reduces (oxidation to FADH2).

  • ii) Hydration.

  • iii) Oxidation by NAD+ (reducing to NADH), forming a ketone group.

  • iv) Thiolysis by CoA.

• Pathway Characterization:

  • Known as beta-oxidation.

Specifics on β-Oxidation

• Saturation:

  • Degrades saturated fatty acids with even-numbered carbon chains (e.g., palmitate, C16:0).

  • Each cycle releases 2-carbon units (acetyl CoA).

• Odd-Chain Fatty Acids:

  • Yield 3-carbon units (propionyl CoA) at the final thiolysis step.

  • Require conversion of propionyl CoA to succinyl CoA by specific enzymes.

• Additional Processing for Unsaturated FAs:

  • Requires isomerase and reductase enzymes for degradation.

Fate of Acetyl CoA

• Energy Production Pathways:

  • Acetyl CoA enters TCA cycle, oxidative phosphorylation, and generates ATP.

  • Starvation Concerns:

  • Mobilized fatty acids have limited uptake into the brain during fasting, complicating energy production as glycogen and glucose levels drop.

• Formation of Ketone Bodies:

  • Liver synthesizes ketone bodies (acetone, acetoacetate, β-hydroxybutyrate) from excess acetyl CoA.