Chapter 34 — Key Takeaways

What you should leave Chapter 34 with

1. Lipids are biological molecules insoluble in water. Major classes: fatty acids, triglycerides, phospholipids, sterols (cholesterol, hormones), and terpenes.

2. Fatty acids are long-chain carboxylic acids (typically C12-C22). Even-numbered carbons predominate because biosynthesis adds 2 carbons at a time from acetate.

3. Fatty acid notation: $C_xC_y$ where x = total carbons, y = number of C=C bonds. Common examples: - Palmitic acid (16:0): saturated. - Oleic acid (18:1 ω-9): one cis double bond. - Linoleic acid (18:2 ω-6): essential, two cis double bonds. - α-Linolenic acid (18:3 ω-3): essential. - Arachidonic acid (20:4 ω-6): prostaglandin precursor. - EPA (20:5 ω-3), DHA (22:6 ω-3): fish oil components.

4. Cis vs trans: natural fatty acids are nearly all cis-unsaturated. Trans fats (industrial; partially hydrogenated oils) are linked to cardiovascular disease and have been banned in many countries.

5. ω-3 and ω-6 fatty acids are essential because mammals lack the enzymes to introduce double bonds beyond Δ9. Must be obtained from diet.

6. Fatty acid biosynthesis (cytosolic; uses NADPH): - Each cycle adds 2 carbons. - Cycle: Claisen (acetyl-ACP + malonyl-ACP → β-keto-acyl-ACP + CO₂) → reduce → dehydrate → reduce. - 7 cycles → palmitate (16:0). - Decarboxylative Claisen: CO₂ release provides driving force. - Rate-limiting: acetyl-CoA carboxylase (ACC) makes the malonyl-CoA chain extender.

7. β-oxidation (mitochondrial; uses NAD⁺ and FAD; reverse of biosynthesis): - Each cycle removes 2 carbons as acetyl-CoA. - Cycle: dehydrogenate (FAD) → hydrate → oxidize (NAD⁺) → thiolyze (retro-Claisen). - Yields ~106 ATP per palmitate vs. ~32 ATP per glucose — fat is dense energy storage.

8. Triglycerides are triesters of glycerol with 3 fatty acids. Energy storage in adipose tissue.

9. Phospholipids are amphiphilic: polar phosphate-head group + 2 nonpolar fatty acid tails. Self-assemble into bilayers — the basis of cell membranes (~5 nm thick).

10. Cholesterol is a 4-ring sterol that modulates membrane fluidity in animal cells. Also the precursor of:

    • Steroid hormones (testosterone, estradiol, progesterone, cortisol, aldosterone).
    • Vitamin D (from 7-dehydrocholesterol + UV).
    • Bile acids (cholic, chenodeoxycholic).

11. Cholesterol biosynthesis from acetyl-CoA:

    • 3 acetyl-CoA → HMG-CoA (Claisen-like).
    • HMG-CoA + 2 NADPH → mevalonate (HMG-CoA reductase, the rate-limiting step).
    • Mevalonate → IPP/DMAPP (the universal C₅ building blocks of terpenes).
    • IPP + DMAPP → GPP → FPP → squalene (head-to-tail couplings).
    • Squalene + O₂ → 2,3-oxidosqualene (epoxidation).
    • 2,3-Oxidosqualene → lanosterol (cationic polyene cyclization, sets 7 stereocenters in one step).
    • Lanosterol → cholesterol (~25 steps).

12. Squalene cyclization is one of biology's most elegant reactions: a 30-carbon linear hydrocarbon → 4 fused rings + 7 stereocenters in a single enzymatic step. The mechanism is cationic polyene cyclization.

13. Statins inhibit HMG-CoA reductase. They mimic the substrate's transition state (a tetrahedral hemithioester intermediate). Used to lower LDL cholesterol and reduce cardiovascular events.

14. Atorvastatin (Lipitor) was the top-selling drug in pharmaceutical history (~$130 billion lifetime sales). It and other statins are now generic and widely available.

15. Terpenes follow the isoprene rule (Ruzicka 1922): most terpenes consist of isoprene units (C₅) linked head-to-tail.

    • Mono (C₁₀): limonene, menthol, α-pinene.
    • Sesqui (C₁₅): farnesene, artemisinin.
    • Di (C₂₀): retinol (vitamin A), Taxol.
    • Tri (C₃₀): squalene, lanosterol.
    • Tetra (C₄₀): β-carotene.
    • Polyterpenes: natural rubber.

16. Natural rubber is cis-1,4-polyisoprene (~10,000-20,000 isoprene units). The cis configuration gives elasticity. Vulcanization (Goodyear 1839) cross-links chains via S-S bridges using sulfur — the chemistry of Ch 16 alkene addition applied at industrial scale.

17. Eicosanoids (prostaglandins, leukotrienes, thromboxanes) are made from arachidonic acid (20:4 ω-6). They mediate inflammation, pain, blood clotting. Cyclooxygenase (COX) makes prostaglandins; aspirin (Ch 26 case study) inhibits COX.

18. Vitamin A (retinol) is a diterpene; its precursor β-carotene is a tetraterpene. β-Carotene is cleaved to give two retinol molecules.

19. Vitamin D is made from 7-dehydrocholesterol + UV light + thermal isomerization (in the skin).

20. Mastery of Chapter 34 connects organic chemistry to:

    • Cardiovascular disease (statins, cholesterol).
    • Diet and nutrition (fatty acids, ω-3, trans fats).
    • Cell membrane biology (phospholipids).
    • Hormone biosynthesis (steroids).
    • Industrial materials (rubber, polymers).
    • Natural product chemistry (terpenes, alkaloids).

Cross-references

• Chapter 26 — Acyl substitution; ester/amide formation.
• Chapter 27 — α-Carbon chemistry; enolates.
• Chapter 28 — Aldol/Claisen condensations; the Claisen drives fatty acid biosynthesis.
• Chapter 29 — Michael addition; some lipid reactions.
• Chapter 32 — Carbohydrates; glycolipids.
• Chapter 33 — Proteins; lipoproteins.
• Chapter 35 — Drug design (statins, NSAIDs).
• Chapter 36 — Drug case studies.
• Appendix A — Lipid structure references.
• Appendix C — Fatty acid table.

Study tip

For each lipid you encounter, ask: 1. Class: fatty acid, triglyceride, phospholipid, sterol, terpene? 2. Function: energy storage, membrane material, signaling molecule, structural? 3. Biosynthesis: from acetyl-CoA via what pathway? (Fatty acid synthase or mevalonate?) 4. Pharmacological connection: does any drug class target this lipid?

If you can answer these for cholesterol, palmitate, oleate, phosphatidylcholine, and limonene, you've internalized Chapter 34.