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Fatty Acid Degradation

Notes

Fatty Acid Degradation

Sections

BETA OXIDATION

  • Occurs in liver and peripheral tissues (mitochondrial matrix)
  • Occurs under low energy conditions (starvation, insulin:glucagon ratio is low)
  • NOT reverse of fatty acid synthesis

TRIACYLGLYCEROL (TAG)

  • Stored in adipose and liver (circulates as lipoprotein)
  • TAG breaks down to glycerol and fatty acids
  • Fatty acids exit adipose and travel to muscle for degradation (provide ATP when energy is low)

TYPES OF FATTY ACIDS

  • Degradation pathways differ depending on chain length and saturation

Saturated long chain fatty acids

  • Model pathway in diagram

Unsaturated fatty acids

  • Already partially oxidized: yield less FADH2 and ATP
  • Req. different enzymes to work with additional double bonds

Branched chain fatty acids

  • Alpha-oxidation: produce acetyl CoA and propionyl CoA

Medium and short chain fatty acids

  • Can be 6-12C long
  • Do NOT need carnitine shuttle to enter matrix
  • Req. medium-chain acyl CoA dehydrogenase (MCAD) for oxidation step

FATTY ACIDS DELIVERY (ADIPOSE TO MUSCLE)

  1. Fatty acids travel from adipose to muscle cell
  2. Fatty acid transporter transports fatty acids into cytosol
  • Carnitine transporter moves carnitine into cytosol
  1. Fatty acyl CoA synthetase: Fatty acid + CoA + ATP --> Fatty acyl CoA + AMP

Carnitine

  • Specialized carrier that transports fatty acids within cell
  • "Car" in carnitine ~ shuttle

CARNITINE SHUTTLE

  1. Carnetine acyl-transferase I (CAT-1): Fatty acyl CoA + Carnitine --> Fatty acyl-carnitine + CoA
  2. Fatty acyl-carnitine enters matrix
  3. CAT-2 (embedded in inner membrane): Fatty acyl-carnitine --> Carnitine + Fatty acyl CoA

BETA-OXIDATION

  • Breaks down fatty acids in 2C increments (acetyl CoA) + shorter chain fatty acid
  • Req. four reactions per 2C increment
  • All reactions occur at beta-carbon (beta-oxidation)

Each 2C increment

i. Oxidation

  • Acyl CoA dehydrogenases (ACAD): family of chain-length specific enzymes
  • Releases FADH2 (~ 2 ATP via oxidative phosphorylation)
    ii. Hydration
    iii. Another oxidation
  • Releases NADH (~ 3 ATP via oxidative phosphorylation)
    iv. Release of 2C (acetyl CoA)
  • Acetyl CoA can enter fatty acid synthesis or citric acid cycle
  • Citric acid cycle: 1 ATP, 1 FADH2 & 3NADH (HIGH ENERGY YIELD!)

ODD CHAIN FATTY ACIDS

  • Final products: 2C Acetyl CoA + 3C propionyl CoA

Propionyl CoA Breakdown

  • Propionyl CoA carboxylase (ABC-carboxylase reaction):
    Propionyl CoA + ATP + biotin + CO2 --> Methylmalonyl CoA (4C)
  • Methyl-malonyl CoA mutase (req. Vit B12 cobalamin): Methylmalonyl CoA --> Succinyl CoA

Product: Succinyl CoA (4C)

  • Citric acid cycle intermediate
  • Gluconeogenic intermediate: only fatty acid that can be converted to glucose

Full-Length Text

  • Here will learn how the body degrades fatty acids for energy.
  • To begin start a table to learn some key features about fatty acid degradation.
  • First, denote that it's often called beta-oxidation (we will learn why, shortly).
  • Denote that it occurs in the liver and peripheral tissues, and in the mitochondria at the cellular level.
  • Denote that it occurs under low energy conditions, such as during starvation, when the insulin to glucagon ratio is low.
    • Fatty acid degradation releases large amounts of energy in the cell.
  • Finally, denote that it is not simply the reverse of fatty acid synthesis, which we'll address throughout the tutorial.

First, let's contextualize fatty acid degradation.

  • Show that triacylglycerol (TAG) is stored in adipose tissue and the liver; it circulates throughout the body in lipoproteins.
  • Then, indicate that TAG breaks down to glycerol and fatty acids.
  • Next, draw a muscle cell membrane (its lipid bilayer).
  • Label the cytosol and extracellular space.
  • Show that fatty acids can exit adipose tissue and travel to the muscle cell for degradation, to provide ATP when energy is low.
  • Now, draw two proteins embedded in the surface of the muscle cell:
    • Fatty acid transporter, which transports fatty acids into the cytosol.
    • Carnitine transporter, which moves carnitine into the cytosol.
  • Write that carnitine is a specialized carrier that transports fatty acids within the cell.
    • The citrate shuttle transports fatty acid precursors in the cell.
    • Use the "Car" in carnitine to remember that it is a carrier.

Now, let's illustrate how fatty acids are broken down in the cell.

  • To begin, draw the double-membrane of a mitochondrion – mitochondria are the primary sites of fatty acid degradation.
    • Label the outer and inner membranes, intermembrane space, and matrix.
  • Return to our table to denote that the degradation pathways differ slightly for the four key types of fatty acids.
    • Saturated long chain fatty acids; indicate that these are our model pathway, way, here.
    • Unsaturated fatty acids
    • Branched chain fatty acids
    • Medium and short chain fatty acids.
  • Now, draw two proteins embedded in the outer mitochondrial membrane:
    • Fatty acyl CoA synthetase
    • Carnitine acyl-transferase I (CAT-1).
  • Next, draw fatty acyl CoA as a curved line attached to a circle to represent a hydrocarbon chain with a terminal carboxyl group.
  • Attach coenzyme A to the carboxyl group.
  • Indicate that Fatty acyl CoA synthase produces this molecule from our fatty acid + CoA, and in the process converts one ATP to AMP.
  • Next, indicate that CAT-1 transfers the fatty acyl group from coenzyme A to carnitine, which can cross the mitochondrial membranes.
  • Show that carnitine enters the matrix with its cargo, whereas the citrate shuttle moves fatty acid precursors in the opposite direction: matrix to cytosol.
  • Next, draw the enzyme carnitine acyl-transferase II (CAT-2) embedded in the inner mitochondrial membrane.
  • Show that it catalyzes the production of fatty acyl CoA and carnitine: the reverse reaction of CAT-1.
  • Show that carnitine then reenters the cytosol to shuttle more fatty acids.
  • Thus, indicate that step 1 of beta-oxidation is the Carnitine Shuttle.
    • As a clinical correlation, shuttle defects cause muscle fatigue and cramps, because the muscle cell cannot use the energy from fats.
  • Next, write that in step 2, beta-oxidation breaks down fatty acids in 2-carbon increments.
  • Indicate that the final product of each increment is 2-carbon acetyl CoA (the substrate of fatty acid biosynthesis) and a shorter chain fatty acid.
    • The shorter chain continues to breakdown in 2-carbon increments.
  • Next, indicate that four reactions are required for each 2-carbon increment.
    • Oxidation, which requires a family of chain-length specific enzymes called acyl CoA dehydrogenases (ACAD).
    • Hydration
    • Another oxidation
    • Release of 2 carbons (acetyl CoA).
  • All four reactions occur at the beta-carbon, hence "beta-oxidation."
  • Indicate that the first oxidation releases an FADH2 and the second releases an NADH, which can produce 2 ATP and 3 ATP respectively via the electron transport chain.
  • Draw a circle of arrows in the matrix to represent the citric acid cycle.
  • Show that acetyl CoA can enter it to produce 1 ATP, 1 FADH2 and 3 NADH, which we highlight (along with the first FADH2 and NADH) to emphasize that beta-oxidation produces a large amount of energy!
  • Show that for odd-numbered fatty acids, instead, we end up with a 2-carbon acetyl coenzyme A and a 3-carbon propionyl coenzyme A.

How does propionyl CoA generate energy?

  • Show that it is first carboxylated by an enzyme called propionyl CoA carboxylase.
  • Indicate that this is an ABC carboxylase reaction that requires ATP, biotin and carbon dioxide.
  • Show that the product is 4-carbon methylmalonyl coenzyme A.
  • Finally, indicate that this intermediate undergoes a molecular rearrangement catalyzed by methyl-malonyl-CoA mutase, which requires vitamin B12 (cobalamin).
  • Show that the product is succinyl-CoA, which is a citric acid cycle intermediate.
    • And also a gluconeogenic intermediate – propionyl coenzyme A is the only fatty acid that can be converted to glucose!

Finally, let's learn the differences in the oxidative pathway for the remaining types of fatty acids.

  • Denote that unsaturated fatty acids are already partially oxidized and thus yield less FADH2 and ATP.
  • And they require different enzymes to work with these additional double bonds.
  • Denote that branched-chain fatty acids undergo "alpha-oxidation" to produce acetyl CoA and propionyl CoA.
  • Finally, denote that medium chain fatty acids, which can be 6 to 12 carbons long, do NOT need the carnitine shuttle to enter the matrix.
  • They also require a special enzyme appropriately named medium-chain acyl-CoA dehydrogenase (MCAD) for the oxidation step.