CH 27 (1): Fatty Acid Degradation
Chapter 27: Fatty Acid Degradation
27.1 Overview of Fatty Acid Processing
Fatty acids are metabolized through three main stages:
Degradation of Triacylglycerols (TAG):
TAGs in adipose tissue are broken down to release fatty acids and glycerol into the bloodstream for transport to tissues that require energy.
Activation and Transport:
Fatty acids are activated and transported into mitochondria for oxidation.
Degradation to Acetyl CoA:
Fatty acids are degraded to acetyl CoA, which enters the citric acid cycle.
27.2 Lipolysis and Fatty Acid Mobilization
Lipolysis Steps:
Hormonal Activation:
TAGs in adipose tissues convert to free fatty acids (FFAs) in response to hormones like epinephrine and glucagon.
Protein Kinase A (PKA) is activated, leading to phosphorylation of perilipin, which initiates TAG degradation by rearranging lipid droplets.
Enzymatic Breakdown:
Adipocyte triacylglycerol lipase (ATGL) removes a fatty acid from TAG, producing Diacylglycerol (DAG).
Hormone-sensitive lipase (HS lipase) removes a fatty acid from DAG to yield Monoacylglycerol (MAG).
MAG lipase further breaks down MAG to release glycerol.
Transport Mechanism:
Free fatty acids bind to albumin for transport in the bloodstream due to their poor solubility in water.
Glycerol is absorbed by the liver for glycolysis or gluconeogenesis.
27.3 Activation and Transport into Mitochondria
Step 2 Activation:
Fatty acids are activated by reacting with ATP to form acyl adenylate and release pyrophosphate.
Coenzyme A (CoA) attacks acyl adenylate forming acyl CoA and AMP.
Transport via Carnitine:
Acyl CoA is linked to carnitine for transport across the mitochondrial membrane via carnitine acyltransferase I, then transferred back to CoA by carnitine acyltransferase II in the mitochondria.
27.4 β-Oxidation Process
Step 3: Fatty Acid Oxidation
Repeated Steps of β-Oxidation:
Oxidation at β-Carbon: Catalyzed by acyl CoA dehydrogenase, producing trans-Δ2-enoyl CoA and FADH2.
Hydration: Enoyl CoA hydratase converts trans-Δ2-enoyl CoA to L-3-hydroxyacyl CoA.
Oxidation: L-3-hydroxyacyl CoA dehydrogenase converts L-3-hydroxyacyl CoA to 3-ketoacyl CoA, producing NADH.
Cleavage: β-ketothiolase cleaves 3-ketoacyl CoA to yield acetyl CoA and a fatty acid chain that is two carbons shorter. This process is known as β-oxidation.
27.5 Principal Reactions Required for Fatty Acid Degradation
Key Step Reactions:
Fatty Acid + CoA + ATP → acyl CoA + AMP + PPi
Carnitine + acyl CoA → acyl carnitine + CoA
Acyl CoA + E-FAD → trans-Δ2-enoyl CoA + E-FADH2
trans-Δ2-Enoyl CoA + H₂O → L-3-hydroxyacyl CoA
L-3-hydroxyacyl CoA + NAD⁺ → 3-ketoacyl CoA + NADH + H⁺
3-ketoacyl CoA + CoA → acetyl CoA + acyl CoA
Energy Yield:
The complete oxidation of palmitate (C16) yields 106 molecules of ATP, after accounting for energy used in activation processes; net contribution to cellular respiration can yield up to 108 ATP molecules.
Three Stages of Fatty Acid Processing:
Degradation of Triacylglycerols (TAG): TAGs in adipose tissue are broken down to release fatty acids and glycerol into the bloodstream for transport to tissues that require energy.
Activation and Transport: Fatty acids are activated and transported into mitochondria for oxidation.
Degradation to Acetyl CoA: Fatty acids are degraded to acetyl CoA, which enters the citric acid cycle.
Mechanism for Converting TAGs into Free Fatty Acids and Glycerol:
Hormonal activation initiates lipolysis, converting TAGs into free fatty acids (FFAs) and glycerol. Hormones like epinephrine and glucagon activate protein kinase A (PKA), leading to phosphorylation of perilipin and subsequent degradation of TAG.
Hormones Involved in TAG Degradation:
Epinephrine and glucagon are key hormones that stimulate the breakdown of TAGs in adipose tissue.
Molecules and Enzymes Involved in TAG Degradation:
Adipocyte triacylglycerol lipase (ATGL) removes a fatty acid from TAG.
Hormone-sensitive lipase (HS lipase) converts diacylglycerol (DAG) to monoacylglycerol (MAG).
MAG lipase further breaks down MAG into glycerol.
Activation of Fatty Acids by Coenzyme A:
Fatty acids are activated by reacting with ATP to form acyl adenylate, releasing pyrophosphate. Coenzyme A then attacks acyl adenylate to form acyl CoA and AMP.
Formation Process of Acyl Adenylate:
The reaction occurs when a fatty acid reacts with ATP, resulting in the formation of acyl adenylate, which is an intermediate in the activation process.
Transport of Fatty Acids into Mitochondria via Carnitine:
Acyl CoA is linked to carnitine for transport across the mitochondrial membrane via carnitine acyltransferase I. Inside the mitochondria, acyl CoA is regenerated when carnitine is converted back to CoA through the action of carnitine acyltransferase II.
Four Repetitive Steps of β-Oxidation:
Oxidation at β-Carbon: Catalyzed by acyl CoA dehydrogenase, producing trans-Δ2-enoyl CoA and FADH2.
Hydration: Enoyl CoA hydratase converts trans-Δ2-enoyl CoA to L-3-hydroxyacyl CoA.
Oxidation: L-3-hydroxyacyl CoA dehydrogenase converts L-3-hydroxyacyl CoA to 3-ketoacyl CoA, producing NADH.
Cleavage: β-ketothiolase cleaves 3-ketoacyl CoA to yield acetyl CoA and a shorter fatty acid chain.
Chemical Reactions at Each Step of β-Oxidation:
Each step involves different types of reactions: oxidations, hydration, and cleavage.
Production of Acetyl CoA, NADH, and FADH₂ during β-Oxidation:
The complete β-oxidation of fatty acids yields multiple molecules of acetyl CoA, typically one NADH and one FADH₂ for each cycle of the process, depending on the length of the fatty acid chain.
ATP Yield Calculation from β-Oxidation:
The complete oxidation of palmitate (C16) yields 106 molecules of ATP, factoring in the energy used during activation, with a maximum possible contribution up to 108 ATP molecules during cellular respiration.