Fatty Acid Catabolism

Chapter 17: Acyl CoA

  • Acyl CoA dehydrogenase: An enzyme involved in the oxidation of fatty acids during their catabolism.

  • R-: Represents the hydrocarbon chain of fatty acids.

  • FAD: Flavin adenine dinucleotide, a cofactor in oxidation-reduction reactions.

  • FADH2: Reduced form of FAD, produced during fatty acid oxidation.

  • c-c-s-CoA Trans A2 Enoyl CoA: An intermediate in fatty acid catabolism through beta-oxidation.

  • R-CH-CH-CH-S-CA-Hydroxy acyl CoA: A specific intermediate structure representing hydroxy acyl-CoA.

  • NAD: Nicotinamide adenine dinucleotide, another important cofactor in redox reactions.

  • Fatty acids: Building blocks of lipids, used as energy sources through catabolism.

  • Enoyl CoA: An intermediate product in the beta-oxidation pathway.

  • Hydratase: An enzyme that adds a water molecule during the reaction.

  • B-Hydroxy acyl CoA dehydrogenase: An enzyme that catalyzes a key step in fatty acid metabolism involving NAD/NADH.

  • Thiolase: The enzyme that catalyzes the final thiolytic cleavage of acyl-CoA products.

  • NADH: The reduced form of NAD, used in metabolic processes as an electron carrier.

  • R-C-scot B-keto-acyl CoA: Represents another acyl-CoA intermediate.

  • Acetyl CoA: A pivotal metabolite in energy metabolism derived from fatty acids.

  • Triglycerides: Also referred to as triacylglycerols (TAGs), the storage form of fatty acids.

  • Fed state: Refers to the metabolic state after consuming food, affecting the storage of fats.

  • Fasted state: Refers to the metabolic state during fasting, emphasizing the mobilization of energy stores.

Phospholipids and Energy Storage

  • Phospholipids: Key components of cell membranes, containing fatty acids and glycerol.

  • Triacylglycerols (TAGs): Fatty acid esters of glycerol, serving as major forms of energy storage in the body.

  • TAG structure: Composed of three fatty acids linked to glycerol via ester bonds.

  • Emulsification: The process of mixing fat with water using emulsifiers that stabilize the mixture; emulsifiers are usually amphipathic substances.

Fatty Acid Metabolism: Overview

  • Outline of Fatty Acid Catabolism:

    1. Digestion and Transport of Dietary Fats

    2. Mobilization and Transport of Stored Fats

    3. Fatty Acid Activation

    4. Fatty Acid Transport into the Mitochondria

    5. Beta-oxidation of Fatty Acids to Acetyl-CoA

    • Covers both saturated and unsaturated fatty acids.

    • Includes special cases such as odd-chain fatty acids and ketone bodies.

    1. Acetyl-CoA oxidation to CO₂ in the Citric Acid Cycle (CAC)

    2. Electron transport chain and ATP production from sources like NADH and FADH2.

Dietary Lipids: Digestion Process

  • Dietary Fats:

    • Bile: Aids in emulsification of fats in the digestive system.

    • Micelle formation: Facilitates the absorption of fatty acids and other lipids.

    • Lipase: Enzyme that hydrolyzes TAGs into free fatty acids and glycerol.

  • Transport Mechanism:

    • Chylomicron formation: Chylomicrons are lipoprotein particles that carry dietary lipids from the intestines to other locations in the body via the lymphatic and circulatory systems.

    • Lipoprotein lipase (LPL): Enzyme that converts TAGs to free fatty acids within tissues.

TAGs Release from Storage in Adipose Tissue

  • Hormonal Regulation:

    • Glucagon and Epinephrine: Activate hormone-sensitive lipase (HSL) for the mobilization of fat stores.

    • Perilipin phosphorylation: Events signal lipases like ATGL to initiate TAG breakdown into DAG and then MAG, ultimately releasing free fatty acids into circulation.

Fatty Acid Activation and Transport

  • Fatty Acid Activation:

    • Activated in the cell through conversion to fatty acyl-CoA using ATP (the process of adenylation).

    • The reaction:

    • extFA+extATP<br>ightarrowextFA−AMP+extPPiext{FA} + ext{ATP} <br>ightarrow ext{FA-AMP} + ext{PPi}

    • extPPiextishydrolyzedforenergyext{PPi} ext{ is hydrolyzed for energy}

    • Fatty acyl-CoA is a high-energy thioester compound necessary for mitochondrial entry for catabolism.

  • Carnitine Shuttle:

    • Transport of activated fatty acyl-CoA into the mitochondria:

    1. Outer membrane: Fatty acyl-CoA + Carnitine → FA-Carnitine + CoA

    2. Inner membrane: FA-Carnitine + CoA → Fatty Acyl-CoA + Carnitine (recycling carnitine).

Beta-Oxidation Process

  • Enzymatic Reactions in the Mitochondrial Matrix:

    1. Dehydrogenation by acyl-CoA dehydrogenase (oxidation).

    2. Hydration by hydratase: incorporate H₂O.

    3. Second dehydrogenation by B-hydroxyacyl-CoA dehydrogenase.

    4. Thiolysis by thiolase: cleaves the acyl-CoA molecule into Acetyl-CoA and a shorter fatty acid.

  • Cycle Completion: Each cycle of beta-oxidation produces:

    • 1 Acetyl-CoA (C2) and shortens the fatty acid chain by 2 carbons.

    • The overall process for saturated even-numbered fatty acids leads to the generation of numerous Acetyl-CoA units, NADH, and FADH2.

Energy Yield from Oxidation

  • Energy-derived ATP from beta-oxidation:

    • Each fatty acid cycle yields:

    • extTotalATP=106ext{Total ATP} = 106

    • Formula for each pair of carbons: extATP=7imesextC−6ext{ATP} = 7 imes ext{C} - 6

  • Details Table: Yield of ATP during oxidation of one mole of Palmitoyl-CoA.

    • Produces:

    • 7 FADH2 → 10.5 ATP

    • 7 NADH → 17.5 ATP

    • Citric acid cycle generates ATP through subsequent processing of Acetyl-CoA.

Special Cases in Fatty Acid Catabolism

  • Unsaturated Fatty Acids: Require adjustments in oxidation steps due to existing double bonds. Isomerase enzymes are required to change the double bond conformation.

  • Polyunsaturated Fatty Acids: Recently require 2,4-dienoyl-CoA reductase for additional steps in their oxidation process, resulting in lower ATP yield.

  • Odd-chain Fatty Acids: Converted to proprionyl-CoA at the end instead of Acetyl-CoA, affecting energy yield; subsequently converted to succinyl-CoA (enters CAC).

Regulation of Fatty Acid Catabolism

  • Fasting vs Fed State Regulation:

    • Fasting state: Lipolysis activated, increasing blood levels of free fatty acids used for energy instead of glucose.

    • Fed state: Excess glucose promotes fatty acid synthesis, inhibiting the transport of fatty acids into mitochondria through malonyl-CoA inhibition.

Hormonal Influences

  • Epinephrine and Glucagon: Promote fatty acid entry into mitochondrial catabolic pathways.

  • Insulin and NADH: Inhibit fatty acid entry when in synthesis state.

Genetic Factors in Fatty Acid Catabolism

  • Medium-Chain Acyl-CoA Dehydrogenase Deficiency: A common genetic defect leading to impaired fatty acid oxidation, causing hypoglycemia and fat accumulation.

Ketone Body Formation

  • Conditions Leading to Ketone Body Formation: Such as inadequate insulin action, high fatty acid catabolism, and limited availability of glucose, resulting in acetyl-CoA shunted to ketone bodies.

  • Physiological Importance: Ketone bodies serve as an alternative fuel source for brain and muscle tissues, especially during fasting or starvation states.

  • Ketoacidosis: Excessive formation of ketone bodies leading to lowered blood pH, with potential severe health consequences.