Beta Oxidation and Fatty Acids

Beta Oxidation

• Beta oxidation is the process in which fatty acids are broken down into acetyl CoA.
• Acetyl CoA enters the TCA cycle to produce energy.
• Fatty acids are categorized by the length of their carbon chain:
  • Very long chain fatty acids: >20 carbons
  • Long chain fatty acids: C12-C20
  • Medium chain fatty acids: C6-C12
  • Short chain fatty acids: C4

Fatty Acid Transport

• Fatty acids are not soluble in water.
• Fatty acids are transported in the blood by complexing with albumin.
• Inside cells, fatty acids are attached to fatty acid binding protein (FABP).

Key Fatty Acids

• Palmitic acid (16:0): Hexadecanoic acid, a saturated fatty acid.
• Palmitoleic acid (16:1): cis-9-hexadecenoic acid, a monounsaturated fatty acid.
• Stearic acid (18:0): Octadecanoic acid, a saturated fatty acid.
• Oleic acid (18:1): cis-9-octadecenoic acid, a monounsaturated fatty acid.
• Linoleic acid (18:2): cis,cis-9,12 octadecenoic acid, a polyunsaturated fatty acid.
• Linolenic acid (18:3): cis,cis,cis-9,12,15-octadecatrienoic acid, a polyunsaturated fatty acid.
• Arachidonic acid (20:4): cis,cis,cis,cis-5,8,11,14-eicosatetraenoic acid, a polyunsaturated fatty acid.

Essential Fatty Acids

• Mammals lack the enzymes to introduce double bonds beyond carbon 9 in the fatty acid chain.
• Mammals cannot synthesize linoleate, linolenate, and arachidonate.
• These three fatty acids are called essential fatty acids.

Fatty Acid Activation

• Fatty acids must be esterified to Coenzyme A before they can be metabolized.
• Acyl-CoA Synthases (Thiokinases) catalyze the activation of long-chain fatty acids.
• This process is ATP-dependent and occurs in two steps.
• Different Acyl-CoA Synthases exist for fatty acids of different chain lengths.

Beta-Oxidation

• Beta-oxidation is a four-step process that occurs in the mitochondria.

Beta-Oxidation Steps

• 1) Dehydrogenation: FAD-linked reaction catalyzed by Acyl-CoA dehydrogenase leading to a trans-double bond.
  • Long chain fatty acyl CoA dehydrogenase (LCAD) acts on chains greater than C12.
  • Medium chain fatty acyl CoA dehydrogenase (MCAD) acts on chains of C6 to C12.
  • Short chain fatty acyl CoA dehydrogenase (SCAD) acts on chains of C4 to C6.
• 2) Hydration: Hydration of the double bond is catalyzed by Enoyl-CoA hydratase, yielding L-3-hydroxyacyl-CoA and 1 NADH.
• 3) 2nd Dehydrogenation: NAD-linked reaction catalyzed by β-hydroxyacyl-CoA dehydrogenase leading to a ketone.
• 4) Thiolytic Cleavage: Thiolytic cleavage of the thioester is catalyzed by β-ketoacyl-CoA thiolase, yielding 1 acetyl-CoA and a shortened fatty acid (acyl-CoA).

Beta-Oxidation Outcomes

• Each round of β-oxidation yields 1 FADH2, 1 NADH, and 1 acetyl-CoA.
• The cycle repeats shortening the fatty acid by 2 carbons until it is completely broken down into acetyl-CoA.
• Odd-numbered carbon fatty acids produce propionyl-CoA in the last round.
• Odd-chain fatty acids are less common and require specific enzymes for further metabolism.

Carnitine Deficiency

• Deficiency of the carnitine translocase can lead to defects in long-chain fatty acid transport.
• This condition can cause muscle cramps, especially during fasting, exercise, or high-fat diets.
• Carnitine deficiency is reported in preterm infants, resulting in impaired fatty acid oxidation and hypoglycemia.

Clinical Application of Beta-Oxidation

• Beta-oxidation is essential for energy production from fatty acids.
• Defects in this process can lead to various metabolic disorders.

Fatty Acid Synthase Complex

• This complex is important for building fatty acids.
• Several enzymes work together to complete fatty acid synthesis.
• The thio-esterase is involved in releasing the palmitate synthesized.

Steps in Fatty Acid Synthesis

• Step 1: Carboxylation of Acetyl-CoA: Acetyl CoA is carboxylated to form malonyl CoA by acetyl CoA carboxylase, a rate-limiting enzyme.
• Step 2: Transfer to FAS: Acetyl CoA and malonyl CoA bind to the fatty acid synthase complex.
  • Acetyl transacylase transfers acetyl groups to the condensing enzyme (CE).
  • Malonyl transacylase transfers malonyl groups to the ACP (acyl carrier protein).
• Step 3: Condensation: Condensation of acetyl and malonyl units to form β-ketoacyl-ACP, releasing CO2.
• Step 4: Reduction: β-ketoacyl-ACP is reduced by NADPH-dependent β-ketoacyl reductase to form β-hydroxy fatty acyl-ACP.
• Step 5: Dehydration: β-hydroxy fatty acyl-ACP is dehydrated by a dehydratase to form enoyl-ACP.
• Step 6: 2nd Reduction: Enoyl-ACP is reduced by enoyl reductase (ER) using NADPH to form butyryl-ACP.

Cyclical Reactions Of Fatty Acid Synthesis

• The cycle continues until the desired fatty acid length is reached.
• Repeated cycles elongate the fatty acid chain by two carbons.
• Fatty acids are then released and used as building blocks for other molecules.