Lipid Biosynthesis Study Notes

Chapter 21: Lipid Biosynthesis

Key Inputs:
- Acetyl CoA: sourced from mitochondria.
- Activation: requires malonyl CoA.
- Energy Input: ATP required for the process.
- Reduction Agent: NADPH utilized for reduction during synthesis.
Location: Occurs in the cytosol of animal cells and yeast cells, involves:
- Fatty Acid Oxidation: Converts fatty acids into acetyl-CoA, providing substrates for energy metabolism.
- Ketone Body Synthesis: Involves production of ketone bodies from fatty acids.
Fatty Acid Elongation: Takes place in the endoplasmic reticulum, along with phospholipid synthesis.
Sterol Synthesis: Involves late-stage processes of fatty acid metabolism and isoprenoid synthesis.

Sources of Acetyl CoA: Derived from various metabolic pathways, crucial for fatty acid synthesis:
- From Glycolysis: Glucose metabolized into pyruvate → Acetyl-CoA.
- Amino Acids: Certain amino acids are converted to pyruvate and subsequently to Acetyl-CoA:
  - Ala, Gly, Ser, Thr, Cys → Pyruvate → Acetyl-CoA
  - Leu, Ile, Phe, Tyr → Acetyl-CoA
  - Lys → Acetyl-CoA
  - Glu, Pro, Arg → 𝛼-ketoglutarate → Acetyl-CoA
  - Val, Met → Succinyl-CoA
  - Asp → Oxaloacetate
NADPH Production:
- Malic Enzyme Reaction: Malate + NADP+ ⇌ Pyruvate + NADPH + CO2 + H⁺ (produces one NADPH per Acetyl-CoA transferred from mitochondria).
- Pentose Phosphate Pathway: Active in generating NADPH for fatty acid synthesis.

Transport Mechanism:
- One ATP required for the transport of each molecule of Acetyl CoA into the cytosol.
- Citrate Transporter: Facilitates transport across inner and outer mitochondrial membranes, resulting in the formation of:
  - Citrate + CoA-SH → Acetyl-CoA + Oxaloacetate
  - Intermediates include malate, transketolase, and decarboxylation reactions to reform Acetyl-CoA.
Diagrams: Include schematic diagrams showing transport pathways and enzymatic reactions.

Role in Fatty Acid Synthesis:
- Acts as a commitment step that activates Acetyl-CoA for entry into fatty acid synthesis pathways.
- Catalysed by Acetyl CoA Carboxylase, which requires biotin covalently linked to a lysine residue, functioning similarly to other carboxylase enzymes (e.g., pyruvate carboxylase).

Mechanism Overview:
- The growing fatty acid chain is initially attached to Fatty Acid Synthase (FAS), then transferred to Acyl Carrier Protein (ACP), allowing for efficient elongation and modification.

Functions:
- Has similar functionality to CoA, containing a phosphopantetheine group, carrying the growing fatty acyl group during fatty acid synthesis.
- Tethered to FAS through covalent linkage, allowing for enzyme function and facilitating movement between various metabolic enzymes.

Types:
- FAS I (Vertebrates): A single polypeptide, produces a single saturated product.
- FAS II (Plants and Bacteria): Composed of separate enzymes that can be swapped, producing many products with varying lengths and saturation (both saturated and unsaturated).
FAS Reactions: Break down the five main enzymatic activities:
- KS: β-ketoacyl-ACP synthase
- KR: β-ketoacyl-ACP reductase
- DH: β-hydroxyacyl-ACP dehydratase
- ER: Enoyl-ACP reductase
- MAT: Malonyl/Acetyl CoA-ACP transferase

Example: For palmitic acid (16 carbons):
- Input Calculation: Requires:
  - 8 Acetyl-CoA from mitochondria.
  - 7 cycles of synthesis (extraction of every 2 carbons).
  - Total energetic costs include:
  - 8 Acetyl-CoA (mito) to 8 Acetyl-CoA (cyto)
  - 15 ATP total, requires 8 ATP forms initial Acetyl-CoA and 7 to convert to malonyl-CoA.
  - 14 NADPH required with each cycle consuming 2 NADPH.

Primary Regulators:
- Citrate: An important regulator, converts the dephosphorylated enzyme to its active state by binding.
- Palmitoyl-CoA: Inhibits the enzyme at high concentrations.
- Insulin: Activates protein phosphatase, leading to dephosphorylation and reactivation of Acetyl-CoA carboxylase.
- Influence on Metabolic Pathways: Also inhibits phosphofructokinase-1 (PFK-1), drawing substrates into the pentose phosphate pathway, resulting in further NADPH production necessary for synthesis.

Cost Calculation: Starting with 4 glucose to yield 1 palmitic acid involves counting:
- 8 Acetyl-CoA needed.
- Resulting in 15 ATP and 14 NADPH for each cycle of synthesis.
NADPH Generation: Achieved predominantly through the malic enzyme pathway; it reuses existing transport pathways and keeps carbon waste to a minimum during synthesis.

Each molecule of NADPH generated via malic enzyme equates to:
- -1 NADH and provides -1 ATP in terms of cost.
- The typical yield from NADH conversion to ATP is 2.5 ATP, showcasing efficiency gains that can occur through direct use of malic enzyme.
Notable Advantage: Prevents loss of CO2 from metabolic pathways while storing more carbon as fatty acids during synthesis.

Elongation Process: Takes place primarily in the endoplasmic reticulum and uses enzymes similar to FAS; carbon extensions come specifically from malonyl CoA.
Desaturation:
- Mechanism: Involves the oxidation process using O2, reducing double bonds in hydrocarbons; NADPH supplies electrons for reduction.
- Animals possess specific desaturases (∆5, ∆6, ∆9) that prevent ω-3 fatty acid production while allowing for dietary elongations.
- The consumption of α-linolenic acid is critical for human production of EPA, an important fatty acid. The conversion efficiency is below 1% for dietary intake.

Plants have unique desaturation capabilities owing to FAS II, which informs the fatty acid profile of oils (coconut predominantly lauric acid; olive oil dominated by oleic acid). Key plant-derived fatty acids have desaturases that produce essential fatty acids, crucial for various biological functions.

Arachidonic Acid: Serves as a precursor for eicosanoid synthesis and is found in membrane phospholipids.
- Cyclooxygenase (COX): Key player in this pathway, with both COX-1 and COX-2 isoforms having distinct functions; targets of various anti-inflammatory drugs, especially aspirin, which acts on COX-1 and COX-2 irreversibly.