BETA OXIDACIÓN

Beta-Oxidation of Fatty Acids: A Key Catabolic Pathway

Introduction to Beta-Oxidation

• The presentation introduces beta-oxidation as the primary catabolic pathway for fatty acids, defining it as the main degradation route.

• It explains the nomenclature of fatty acids, where carbon 1 corresponds to the carboxyl group, and subsequent carbons are numbered sequentially.

Nomenclature and Activation

• The term "beta-oxidation" is derived from the oxidation of carbon 3 (beta carbon), with further nomenclature using Greek letters for additional carbons.

• Before beta-oxidation can occur, fatty acids must be activated in the cytosol by binding to coenzyme A (CoA), forming acyl-CoA through a reaction catalyzed by acyl-CoA synthetase.

Transport into Mitochondria

• The transport of activated acyl-CoA into mitochondria requires two enzymes: Carnitine acyltransferase 1 (CAT1) and Carnitine acyltransferase 2 (CAT2).

• CAT1 transfers the acyl group from CoA to carnitine, forming acyl-carnitine, which can then enter the mitochondrial matrix via a transport system.

Reactions Involved in Beta-Oxidation

First Reaction: Oxidation

• The first step involves oxidizing acyl-CoA using an enzyme called acyl-CoA dehydrogenase, producing trans-delta2-enoyl-CoA while reducing FAD to FADH2.

Second Reaction: Hydration

• In this step, water is added to trans-delta2-enoyl-CoA through hydration catalyzed by enoyl-CoA hydratase, resulting in beta-hydroxyacyl-CoA.

Third Reaction: Second Oxidation

• Beta-hydroxyacyl-CoA undergoes another oxidation facilitated by beta-hydroxyacyl-CoA dehydrogenase, converting it into beta-ketoacyl-CoA while reducing NAD+ to NADH.

Fourth Reaction: Cleavage

• The final reaction involves thiolysis where beta-ketoacyl-CoA is cleaved by thiolase. This results in the release of acetyl-CoA and a shortened fatty acid chain that re-enters the cycle.

Summary of Beta-Oxidation Steps

• To summarize:

• First Reaction: Oxidation with FAD as hydrogen acceptor.

• Second Reaction: Hydration incorporating water.

• Third Reaction: Second oxidation with NAD+ as hydrogen acceptor.

Beta-Oxidation of Fatty Acids

Overview of Beta-Oxidation Process

• The beta-oxidation process involves the participation of FAL and NAD, leading to the release of acetyl-CoA. This cycle occurs indefinitely with saturated fatty acids.

• The process includes an initial oxidation, hydration, a second oxidation, and finally the incorporation of CoA to liberate acetyl-CoA. The remaining chain then repeats this cycle.

Comparison Between Even and Odd Chain Fatty Acids

• In even-chain fatty acids, the cycle continues without issues by removing two carbon units until complete metabolism.

• For odd-chain fatty acids (e.g., 13 carbon atoms), after several cycles, a 5-carbon molecule remains which cannot undergo beta-oxidation.

Conversion of Propionyl-CoA

• The final product from odd-chain fatty acid oxidation is propionyl-CoA (3 carbons), which can enter gluconeogenesis to form glucose.

• Propionyl-CoA undergoes carboxylation using CO2 and ATP via propionyl-CoA carboxylase to yield S-methylmalonyl-CoA.

Isomerization in Beta-Oxidation

• S-methylmalonyl-CoA is converted into succinyl-CoA through isomerization processes involving specific enzymes that rearrange molecular structures for further metabolism.

Beta-Oxidation of Unsaturated Fatty Acids

Mono-unsaturated Fatty Acids

• When dealing with mono-unsaturated fatty acids (e.g., 14 carbon atoms with a double bond at position 6), normal beta-oxidation occurs initially.

• After removing two carbons, an enzyme transforms the double bond from position 3 to position 2, creating a trans configuration suitable for continued oxidation.

Polyunsaturated Fatty Acids

• Polyunsaturated fatty acids like linoleic acid (18 carbons with two double bonds at positions 9 and 12) also undergo standard beta-oxidation.

• Following multiple rounds of oxidation, adjustments are made to maintain proper positioning of double bonds for effective catabolism.

Challenges in Oxidizing Polyunsaturated Fatty Acids

• With polyunsaturated fats having more than one double bond, specific enzymes facilitate transformations necessary for continued metabolic processing.

Fatty Acid Metabolism and β-Oxidation

Overview of Fatty Acid Structure and Enzymatic Action

• The discussion begins with the identification of a fatty acid with double bonds at carbon positions 2 and 4, indicating an oxidized state. An enzyme named "2,4-dienoyl-CoA reductase" is involved in reducing these double bonds by incorporating hydrogen atoms.

• The reduction process involves adding hydrogen from NADPH to the double bonds at carbons 2 and 4, resulting in a new molecule with a single double bond at position 3.

Mechanism of Fatty Acid Oxidation

• The enzyme creates an intermediate bond between carbons 2 and 4, leading to a monounsaturated fatty acid structure. This allows for further oxidation processes to metabolize the fatty acid completely.

Acetyl-CoA Production from Stearic Acid

• Using stearic acid (18 carbon atoms), it is explained that each cycle of β-oxidation removes two carbon atoms as acetyl-CoA. Thus, from one molecule of stearic acid, nine acetyl-CoA molecules are produced.

• Each cycle continues until reaching a four-carbon fragment which produces two acetyl-CoA molecules in the final step.

Calculation of Cycles and Energy Yield

• For stearic acid (18 carbons), after eight cycles (9 - 1), we obtain nine acetyl-CoA molecules through repeated cycles of β-oxidation.

• The calculation method involves dividing the total number of carbon atoms by two to determine how many acetyl-CoA units can be generated while subtracting one for the last cycle.

Energy Balance During β-Oxidation

• Each complete cycle yields energy: one FADH₂ (equivalent to 2 ATP) and one NADH (equivalent to 3 ATP). Therefore, each round generates five ATP total.

• Initial activation costs two ATP; thus, this must be subtracted from the total yield when calculating net energy gain during fatty acid catabolism.

Example Calculations for Different Fatty Acids

• For caprylic acid (8 carbons): After initial activation cost, four acetyl-CoA are produced yielding significant ATP through subsequent Krebs cycle integration.

• Palmitic acid (16 carbons): Following similar calculations results in a higher net yield due to more cycles completed before reaching smaller fragments.

Regulation of β-Oxidation Pathway

Understanding Beta-Oxidation and Its Regulation

Mechanisms of Energy Regulation in Beta-Oxidation

• The process of beta-oxidation is interpreted by the cell as an increase in energy, leading to the inhibition of beta-oxidation when energy levels are sufficient.

• The final reaction, involving thiolase, is also inhibited due to elevated acetyl-CoA levels, which signal an increase in energy availability.

• Conclusively, beta-oxidation serves as a catabolic pathway for oxidizing fatty acids to produce acetyl-CoA, which can be directed towards various metabolic fates.

Location and Energy Yield of Beta-Oxidation

• Beta-oxidation occurs specifically in the mitochondrial matrix, highlighting its importance within cellular respiration.

• This process generates significant amounts of ATP, stimulating anabolic pathways such as fatty acid biosynthesis while inhibiting catabolic processes (CAT1).