Learning Objectives of Class 38

• Objective 1: Describe the synthesis of triacylglycerols (TAG).

• Objective 2: Describe the synthesis of membrane glycerophospholipids.

• Objective 3: Describe the synthesis of eicosanoids (specifically prostaglandins) and how Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) inhibit the synthesis of prostaglandins.

• Objective 4: Explain the body-mass homeostasis model and the role of leptin.

Key Components in Lipid Synthesis

• Acetyl-CoA: A key precursor for the synthesis of lipids.

• Triacylglycerol (TAG): A major energy storage form of lipids.

• Phospholipids (PL): Essential components of cell membranes.

• Eicosanoids: Hormones derived from fatty acids that have a variety of biological functions.

Synthesis Pathway Overview

• Lipids are derived from acyl-CoA with the following steps:

  • Acetyl-CoA → Glycerol-3-Phosphate

  • Glycerol-3-Phosphate → Phosphatidic Acid

  • Phosphatidic Acid → Diacylglycerol → Triacylglycerols (TAG) and Phospholipids (PL)

• Key site: The liver is the primary site of TAG synthesis.

Details of Synthesis Processes

1. Synthesis of Glycerol-3-Phosphate

• Derived from Dihydroxyacetone phosphate (DHAP), which is formed from glycolysis.

  • Enzymatic pathway:

  • Glucose → Dihydroxyacetone phosphate (DHAP)

  • Converts into glycerol-3-phosphate using glycerol-3-phosphate dehydrogenase:

    • $ext{NAD}^+ + ext{H}_2 ext{O} <br>ightarrow ext{NADH} + ext{H}^+$

2. Synthesis of Phosphatidic Acid

• Required for both TAG and phospholipid synthesis.

• Steps involved:

  1. Activation of a fatty acid to form Acyl-CoA.

  2. Transfer of the fatty acyl group to glycerol-3-phosphate forming monoacylglycerol-3-phosphate.

  3. Activation of a second fatty acid.

  4. Transfer of the second fatty acyl group to monoacylglycerol-3-phosphate.

  5. Formation of phosphatidic acid.

• Fatty acid activation: Requires the breaking of two high-energy phosphate bonds:

  • The reaction is energetically favorable with $ext{ΔG'} ≈ -65 ext{ kJ/mol}$.

3. Synthesis of Triacylglycerol (TAG)

• Process involves conversion of phosphatidic acid:

  • Phosphatidic acid is dephosphorylated by phosphatidic acid phosphatase to form diacylglycerol.

  • Then, acyl transferase adds a third fatty acid to form TAG.

• Key regulatory enzyme: Phosphatidic Acid Phosphatase (PAP) influences lipid metabolism.

  • Different lipid types synthesized depending on PAP activity.

  • Loss of PAP in mice results in significant weight loss due to altered lipid synthesis pathways.

4. Synthesis of Phospholipids (PL)

• Involves the reaction of activated CDP-alcohol with diacylglycerol to produce glycerophospholipids:

  1. Activated alcohol is phosphorylated and interacts with CTP.

  2. Common structure of glycerophospholipids:

  • General form: $ext{Glycerophospholipid} = ext{Glycerol} + 2 ext{Fatty Acids} + ext{Phosphate} + ext{Alcohol}$.

5. Synthesis of Eicosanoids

• Prostaglandin synthase catalyzes the conversion of arachidonate to a variety of eicosanoid hormones:

• Arachidonate (20-carbon fatty acid) is a precursor for these hormones.

• Functions of Eicosanoids include roles in:

  • Reproductive function, inflammation, fever, pain regulation.

  • Blood clot formation and blood pressure regulation.

Prostaglandin Synthesis

• The enzyme prostaglandin synthase (also known as cyclooxygenase, COX) has two activities:

  • Cyclooxygenase activity that facilitates the conversion of arachidonate into prostaglandins.

  • Peroxidase activity that contributes to processing eicosanoids.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

  • Aspirin acts as an irreversible inhibitor of COX by acetylating a serine residue in the active site, thus preventing prostaglandin synthesis.

  • Ibuprofen and naproxen act as competitive inhibitors of COX, blocking arachidonate from binding.

Body-Mass Homeostasis Model

• Body-mass regulation involves feedback mechanisms:

  • Eating behavior is inhibited when body weight exceeds a set point and increased when it is below.

• Leptin:

  • A hormone produced by adipose tissue, communicated with the brain to reduce appetite.

  • Identified initially in obese mice (ob/ob) indicating its role in energy balance:

  • These mice showed increased food intake, temperature dysregulation, and insulin resistance due to lack of leptin.

  • **Leptin Resistance:

  • Despite elevated leptin levels, many obese individuals do not decrease appetite, indicating defectiveness downstream in leptin signaling.

  • DB gene:

  • Encodes the leptin receptor important in sensing leptin levels, and mutations lead to obesity and diabetes in mice.