Module 6: The Cytosol – Lipogenesis & Nucleotide Synthesis

The Cytosol – Lipogenesis (Synthesis of Fatty Acids)

  • Topic focus: lipogenesis for energy storage; occurs in the cytosol, mainly in liver and adipose tissue.

  • Role of acetyl-CoA: building block for fatty acids; generated from glucose metabolism; transported to the cytosol via the citrate shuttle.

  • Key steps (3 stages):

    • Stage 1: Transfer of acetyl-CoA from mitochondria to cytosol (citrate shuttle).

    • Stage 2: Activation of acetyl-CoA to malonyl-CoA (via acetyl-CoA carboxylase).

    • Stage 3: Elongation cycle adding two-carbon units from acetyl-CoA; requires NADPH.

  • Synthesis to triglycerides: fatty acids are synthesized and incorporated with glycerol to form triglycerides (TG).

    • Glycerol-3-phosphate (predominantly from glycolysis) combines with three fatty acyl-CoAs; dephosphorylation yields triglyceride.

  • Storage and energy context:

    • Fats are the main long-term energy store; triglycerides are more energy-dense than glycogen.

    • Energy densities: 9\ \mathrm{kcal/g} for fats vs 4\ \mathrm{kcal/g} for glycogen.

  • Glycogen storage context (recap):

    • Muscle stores ≈ 300-400\ \mathrm{g}; liver stores ≈ 80\ \mathrm{g}.

    • Glycogen binds water: ≈ 2\ \mathrm{g}\ water\ per\ 1\ g\ glycogen, which increases total weight.

    • Once glycogen stores are full, excess glucose is stored as fat.

  • Lipids: structure and sources

    • Triglycerides consist of a glycerol backbone with three fatty acids (esterified).

    • Fat sources: dietary fats, fats synthesized for export, fats stored in adipocytes.

    • In liver, glycerol-3-phosphate derived from glucose is esterified with fatty acyl-CoAs to form triglycerides.

  • Tissue involvement in fat metabolism:

    • Liver: central hub for lipid metabolism; converts excess carbohydrates/proteins to fatty acids/triglycerides; can produce ketone bodies during fasting.

    • Adipose tissue: primary fat storage site; releases free fatty acids during fasting/exercise.

    • Muscle: major consumer of fatty acids; beta-oxidation for energy during exercise.

The Cytosol – Synthesis of Nucleotides

  • Nucleotide basics: building blocks for DNA and RNA; each nucleotide contains a sugar, a base, and a phosphate group. Bases are classified as:

    • Purines: two-ring structures (A, G).

    • Pyrimidines: single-ring structures (C, U, T).

  • Purine synthesis (PRPP-centric):

    • Start with ribose 5-phosphate and form phosphoribosyl pyrophosphate (PRPP).

    • Build the purine ring on PRPP using amino acids (glycine, glutamine, aspartate), CO₂, and one-carbon units from folate to form inosine monophosphate (IMP).

    • IMP is then converted to AMP and GMP.

  • Pyrimidine synthesis: two-phase process

    • Phase 1: Build the pyrimidine ring (orotate) from glutamine, aspartate, and bicarbonate.

    • Phase 2: Attach the ring to PRPP to form orotate-PRPP, producing UMP; UMP is then converted to UDP/UTP and ultimately to CTP or TMP (thymidine monophosphate).

  • Quick summary (today):

    • Fatty acids: synthesized in cytosol from excess glucose via acetyl-CoA; ultimately stored as triglycerides in adipocytes; requires NADPH; three-stage process transfers acetyl-CoA to cytosol, activates to malonyl-CoA, and elongates the chain.

    • Nucleotides: Purine synthesis builds the base on PRPP to IMP, then AMP/GMP; Pyrimidine synthesis builds the ring first and then attaches it to PRPP to form UMP, then UDP/UTP, CTP/TMP.