Chapter 34 — Exercises

Fifty-five problems on lipids, fatty acid biosynthesis, terpenes, and steroids. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Fatty acid structure

34.1∗ (routine) Draw palmitic acid (C16:0). Identify it as saturated.

34.2 (routine) Draw oleic acid (C18:1, cis-Δ9). Identify the double bond and the cis configuration.

34.3∗ (routine) Identify each fatty acid: (a) C18:0 — saturated 18-carbon (b) C18:1 ω-9 — oleic (c) C18:2 ω-6 — linoleic (essential) (d) C18:3 ω-3 — α-linolenic (essential) (e) C20:4 ω-6 — arachidonic (f) C22:6 ω-3 — DHA

34.4 (routine) Why are most natural fatty acids cis-unsaturated? What does cis vs trans do to the chain shape?

34.5 (moderate) Trans fats (formed by partial hydrogenation of vegetable oils) are linked to cardiovascular disease. Why? What's the difference in physical properties between cis and trans fatty acids?

34.6 (challenge) Most natural fatty acids have an even number of carbons. Why? Connect to biosynthesis.

Section B — Fatty acid biosynthesis

34.7∗ (routine) Outline one cycle of fatty acid biosynthesis: acetyl-ACP + malonyl-ACP → butyryl-ACP. Show the four enzymatic steps.

34.8 (routine) Why is malonyl-CoA the chain extender (not acetyl-CoA)? What is the thermodynamic driving force?

34.9 (routine) How many ATP and NADPH are consumed to make palmitate (16:0)?

34.10 (moderate) Where in the cell does fatty acid biosynthesis occur? Compare to β-oxidation.

34.11 (moderate) Acetyl-CoA carboxylase (ACC) is the rate-limiting step of fatty acid biosynthesis. What does it do? Why is it the rate-limiting step?

34.12 (challenge) How is fatty acid biosynthesis regulated by cellular energy status (high vs low ATP, citrate levels)?

Section C — β-oxidation

34.13∗ (routine) Outline one cycle of β-oxidation: palmitoyl-CoA → myristoyl-CoA + acetyl-CoA. Show the four enzymatic steps.

34.14 (routine) Calculate the ATP yield from oxidation of palmitate (16:0) to CO₂ + H₂O. Compare to glucose (~32 ATP).

34.15 (moderate) Where in the cell does β-oxidation occur? What is the role of carnitine in transporting fatty acids?

34.16 (moderate) Why does β-oxidation use FAD for the first dehydrogenation but NAD⁺ for the third? Connect to ΔG considerations.

34.17 (challenge) Fatty acids with odd carbon number are oxidized to give propionyl-CoA (a 3C unit). What is the fate of propionyl-CoA in metabolism?

34.18 (challenge) Branched-chain fatty acids (with methyl groups) cannot be β-oxidized normally. What alternative pathway is used? (Hint: α-oxidation.)

Section D — Triglycerides and phospholipids

34.19∗ (routine) Draw the structure of a triglyceride (1-palmitoyl-2-oleoyl-3-stearoyl-glycerol). Identify the three ester bonds.

34.20 (routine) Draw the structure of phosphatidylcholine (POPC: 1-palmitoyl-2-oleoyl-PC). Identify the polar head and nonpolar tails.

34.21 (moderate) Why does phospholipid spontaneously form a bilayer in water? Identify the entropic and enthalpic contributions.

34.22 (moderate) Why is the typical thickness of a lipid bilayer ~5 nm? Connect to fatty acid chain length.

34.23 (moderate) Why is cholesterol incorporated into cell membranes? What does it do to fluidity?

34.24 (challenge) Sphingolipids are different from glycerolipids — based on sphingosine instead of glycerol. Sketch sphingomyelin's structure. Where in the body is it found?

Section E — Terpenes

34.25∗ (routine) Draw isoprene. Identify the C₅ skeleton.

34.26 (routine) Draw limonene (a monoterpene). Identify the two isoprene units in head-to-tail arrangement.

34.27 (routine) Draw α-pinene, menthol, geraniol — three more monoterpenes. Identify the isoprene units.

34.28∗ (moderate) Outline the mevalonate pathway: 3 acetyl-CoA → IPP. Identify each step.

34.29 (moderate) Why does the mevalonate pathway start with 3 acetyl-CoA rather than 1? What chemistry connects them (Claisen condensations)?

34.30 (moderate) Identify the carbon count of: monoterpene, sesquiterpene, diterpene, triterpene, tetraterpene.

34.31 (challenge) Squalene is the linear C₃₀ precursor to cholesterol. Sketch squalene with its 6 isoprene units indicated. What is the connectivity (head-to-head + tail-to-tail)?

34.32 (challenge) Outline the cationic polyene cyclization of 2,3-oxidosqualene to lanosterol. Identify the carbocation intermediates.

Section F — Cholesterol and steroids

34.33∗ (routine) Draw cholesterol's structure. Identify: (a) the 4-ring skeleton (ABCD). (b) the 8-carbon side chain. (c) the 3β-OH. (d) the C5-C6 double bond.

34.34 (routine) What are the three main steroid hormones? Sketch testosterone, estradiol, cortisol.

34.35 (moderate) Why does cholesterol's biosynthesis involve so many steps (~25 from acetyl-CoA)? Identify the kinds of reactions.

34.36 (moderate) Vitamin D is made from 7-dehydrocholesterol via UV light + thermal isomerization. Sketch the chemistry. Why does this require sunlight?

34.37 (challenge) Bile acids (cholic acid, chenodeoxycholic acid) are made from cholesterol in the liver. What is their function in digestion?

Section G — Statins

34.38∗ (routine) What is the rate-limiting step of cholesterol biosynthesis? What enzyme catalyzes it?

34.39 (routine) Statins inhibit HMG-CoA reductase. How do they work? Are they competitive or non-competitive inhibitors?

34.40 (routine) Compare lovastatin (the natural product), simvastatin (semi-synthetic), and atorvastatin (synthetic). Each is an HMG-CoA reductase inhibitor; how do they differ structurally?

34.41 (moderate) Why does statin therapy require liver function monitoring? What is the side-effect pattern?

34.42 (challenge) Akira Endo discovered the first statin (compactin/mevastatin) in 1976 from a fungus. Sketch the discovery story: he isolated extracts that inhibited HMG-CoA reductase; the bioactive compound was a fungal natural product.

34.43 (challenge) Statins reduce LDL cholesterol by up to 60%. They also reduce cardiovascular mortality by 25-35%. Why is the clinical benefit so substantial?

Section H — Other lipid pharmacology

34.44∗ (routine) Identify fish oil benefits: ω-3 fatty acids (EPA, DHA) reduce inflammation. Why are they "essential" (must be obtained from diet)?

34.45 (routine) Eicosanoids (prostaglandins, leukotrienes) are made from arachidonic acid (C20:4 ω-6). What is the pharmacological significance?

34.46 (moderate) Aspirin, ibuprofen, and other NSAIDs inhibit cyclooxygenase (COX) — the enzyme that makes prostaglandins from arachidonic acid. Connect to Ch 26 case study (aspirin).

34.47 (challenge) Leukotriene receptor antagonists (montelukast) are used for asthma. How do they work?

Section I — Spectroscopy and identification

34.48∗ (routine) A fatty acid has IR 3000 (broad, COOH) + 1715 (C=O). ¹H NMR: triplet at δ 0.9 (3H), broad singlet at δ 12 (1H). Identify the class (saturated long-chain fatty acid).

34.49 (routine) Distinguish between palmitic acid (C16:0) and oleic acid (C18:1) using IR and ¹H NMR.

34.50 (challenge) ¹H NMR of cholesterol: identify the diagnostic signals (the H6 vinyl, the H3α-OH, the angular methyls).

Section J — Industrial and applications

34.51 (routine) Industrial uses of fatty acids: soap (saponification of triglycerides + NaOH or KOH); biodiesel (transesterification of triglycerides + methanol). Sketch each.

34.52 (routine) Margarine is made by partial hydrogenation of vegetable oil. Sketch the chemistry. Why is the trans-fat content concerning?

34.53 (moderate) Vitamin A (retinol) is a diterpene. Sketch its structure. Why is its precursor β-carotene (a tetraterpene) cleaved to give two retinol molecules?

34.54 (challenge) Natural rubber is cis-polyisoprene. Sketch the polymer. Why does cis-polyisoprene give elastic rubber, while trans-polyisoprene gives the rigid material gutta-percha?

34.55 (challenge) Synthetic statins like atorvastatin are blockbuster drugs. Outline a synthesis using a Paal-Knorr pyrrole + asymmetric reduction (covered in Ch 31 case study 1).

Notes for instructors: Common stumbling blocks for Chapter 34: (1) Confusing fatty acid biosynthesis (cytosol, NADPH) with β-oxidation (mitochondria, NAD⁺/FAD). (2) Forgetting the role of malonyl-CoA in chain extension. (3) Miscounting isoprene units in terpenes. (4) Failing to recognize the importance of squalene cyclization. Computational exercises: build squalene in Avogadro and visualize the geometry needed for the cationic cyclization.