Lipid Chemistry & Classification

Major Biological Functions of Lipids

• Energy storage: Triacylglycerols yield $\sim 9$ kcal/g upon oxidation, compared to $\sim 4$ kcal/g for carbohydrates and proteins -- more than double the energy density
• Membrane structure: Phospholipids and cholesterol form the structural basis of all biological membranes
• Signaling: Steroid hormones, eicosanoids, phosphatidylinositol derivatives, and sphingolipid second messengers (ceramide, sphingosine-1-phosphate)
• Thermal insulation: Subcutaneous adipose tissue reduces heat loss
• Mechanical protection: Visceral fat cushions internal organs
• Electrical insulation: Myelin sheaths (sphingomyelin, cerebrosides) insulate axons for rapid nerve conduction

Saturated Fatty Acids

Saturated fatty acids contain no carbon-carbon double bonds. The hydrocarbon chain adopts an extended, fully staggered conformation that allows tight packing and strong van der Waals interactions between adjacent chains.

Unsaturated Fatty Acids

Unsaturated fatty acids contain one or more cis double bonds, each of which introduces a $\sim 30°$ kink in the hydrocarbon chain. This disrupts the regular packing of chains, weakens intermolecular forces, and lowers the melting point.

Omega ($\omega$) Nomenclature and Essential Fatty Acids

The omega system numbers carbons from the methyl end ($\omega$-carbon) of the chain. The $\omega$ number indicates the position of the first double bond from the methyl terminus.

• $\omega$-3: $\alpha$-linolenic acid (C18:3) -- precursor to EPA and DHA; found in flaxseed, fish oils
• $\omega$-6: Linoleic acid (C18:2) -- precursor to arachidonic acid; found in vegetable oils
• $\omega$-9: Oleic acid (C18:1) -- not essential; can be synthesized by humans

Humans lack $\Delta^{12}$ and $\Delta^{15}$ desaturases and therefore cannot introduce double bonds beyond $\Delta^9$. This makes linoleic acid ($\omega$-6) and $\alpha$-linolenic acid ($\omega$-3) essential fatty acids that must be obtained from the diet.

Formation and Hydrolysis

TAGs are formed by three successive esterification reactions between glycerol and fatty acyl-CoA derivatives. The reverse reaction -- hydrolysis -- is catalyzed by lipases. Alkaline hydrolysis is known as saponification:

Soaps are sodium or potassium salts of fatty acids. Their amphipathic nature allows them to emulsify fats, forming micelles that can be dispersed in water.

Energy Content

The complete oxidation of tripalmitin ($\text{C}_{51}\text{H}_{98}\text{O}_{6}$) yields approximately 106 molecules of ATP per molecule. The overall reaction:

Each palmitate (C16:0) generates $\sim 106$ ATP via $\beta$-oxidation followed by the TCA cycle and oxidative phosphorylation. Three palmitoyl chains plus glycerol backbone metabolism yield the full energy output of tripalmitin.

Characterization of Fats

• Iodine number: Grams of $\text{I}_2$ absorbed per 100 g of fat. Measures the degree of unsaturation. Higher iodine number = more double bonds (oils > fats).
• Saponification number: Milligrams of KOH required to saponify 1 g of fat. Inversely related to average fatty acid chain length -- shorter chains require more KOH per gram because there are more ester bonds per unit mass.
• Acid number: Milligrams of KOH required to neutralize free fatty acids in 1 g of fat. Indicates the degree of hydrolytic rancidity.

Glycerophospholipids

Glycerophospholipids are built on a glycerol-3-phosphate backbone. Position $sn$-1 typically carries a saturated fatty acid, while $sn$-2 carries an unsaturated fatty acid. The phosphate group at $sn$-3 is esterified to a polar head group:

Cardiolipin is found almost exclusively in the inner mitochondrial membrane, where it plays a key role in the function of the electron transport chain, particularly cytochrome $c$ oxidase.

Sphingolipids

Sphingolipids are built on a sphingosine backbone (an 18-carbon amino alcohol) rather than glycerol. A fatty acid is attached to the amino group of sphingosine via an amide bond, forming ceramide -- the core structure of all sphingolipids.

• Sphingomyelin: Ceramide + phosphocholine. The only sphingolipid that is a phospholipid. Major component of the myelin sheath surrounding nerve axons.
• Ceramide: Functions as a signaling molecule in apoptosis, cell differentiation, and stress responses.
• Sphingosine-1-phosphate (S1P): Promotes cell survival, proliferation, and angiogenesis -- often opposing the pro-apoptotic effects of ceramide.

Cerebrosides

Cerebrosides consist of ceramide linked to a single monosaccharide -- either glucose (glucocerebrosides) or galactose (galactocerebrosides). Galactocerebrosides are abundant in brain and nervous tissue, comprising a significant fraction of the myelin sheath lipids. Deficiency in the lysosomal enzyme $\beta$-glucocerebrosidase causes Gaucher disease, the most common lipid storage disorder.

Gangliosides

Gangliosides are complex glycolipids containing an oligosaccharide chain with one or more sialic acid (N-acetylneuraminic acid, NANA) residues. They are highly concentrated in nervous tissue (ganglion cells, hence the name) and account for about 6% of brain lipids.

• GM1: Receptor for cholera toxin; deficiency of $\beta$-galactosidase leads to GM1 gangliosidosis
• GM2: Accumulates in Tay-Sachs disease due to deficiency of hexosaminidase A
• Blood group antigens: The ABO blood group system is determined by specific glycolipid (and glycoprotein) carbohydrate structures on erythrocyte surfaces

Ganglioside nomenclature: G = ganglioside, M/D/T/Q = mono/di/tri/quatra-sialic acid, and the number indicates migration order on thin-layer chromatography.

Cholesterol

Cholesterol is a 27-carbon molecule with the molecular formula:

Key structural features include a single hydroxyl group at C-3 (makes it weakly amphipathic), a double bond between C-5 and C-6, an 8-carbon branched hydrocarbon side chain at C-17, and methyl groups at C-10 and C-13.

Cholesterol is an essential component of animal cell membranes (up to $\sim 25$ mol% of the plasma membrane), where it modulates fluidity. It is also the precursor to all steroid hormones, bile acids, and vitamin D.

Cholesterol Derivatives

• Bile acids: Cholate, deoxycholate, chenodeoxycholate -- synthesized in the liver, conjugated with glycine or taurine, emulsify dietary fats in the intestine
• Steroid hormones (C21): Progesterone, cortisol (glucocorticoid), aldosterone (mineralocorticoid)
• Steroid hormones (C19): Testosterone, dihydrotestosterone (androgens)
• Steroid hormones (C18): Estradiol, estrone (estrogens) -- formed by aromatase from androgens
• Vitamin D: 7-Dehydrocholesterol $\xrightarrow{\text{UV light}}$ cholecalciferol (vitamin $\text{D}_3$) $\xrightarrow{\text{liver}}$ 25-OH-$\text{D}_3$ $\xrightarrow{\text{kidney}}$ 1,25-(OH)$_2$-$\text{D}_3$ (calcitriol, active form)

Isoprenoids (Terpenoids)

Isoprenoids are built from repeating 5-carbon isoprene units ($\text{C}_5\text{H}_8$). The biosynthetic precursor is isopentenyl pyrophosphate (IPP), derived from the mevalonate pathway. Biologically important isoprenoids include:

• Ubiquinone (Coenzyme Q): Electron carrier in the mitochondrial electron transport chain; contains a long isoprenoid tail ($\text{CoQ}_{10}$ in humans = 10 isoprene units)
• Dolichol: Long-chain isoprenoid alcohol involved in N-linked glycosylation of proteins in the ER
• Vitamin A (retinol): A diterpene ($\text{C}_{20}$) essential for vision (11-cis-retinal in rhodopsin), cell differentiation, and immune function
• Vitamin K: Required for $\gamma$-carboxylation of glutamate residues in clotting factors (II, VII, IX, X)
• Vitamin E ($\alpha$-tocopherol): Lipid-soluble antioxidant that terminates free-radical chain reactions in membranes

Arachidonic Acid Release

Arachidonic acid is released from membrane phospholipids (typically from the $sn$-2 position of phosphatidylcholine or phosphatidylethanolamine) by the action of phospholipase $\text{A}_2$($\text{PLA}_2$). This is the rate-limiting step in eicosanoid synthesis and is inhibited by corticosteroids (which induce lipocortin/annexin, an inhibitor of $\text{PLA}_2$).

The COX Pathway (Cyclooxygenase)

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandin $\text{H}_2$($\text{PGH}_2$), the common precursor to all prostanoids:

• Prostaglandins ($\text{PGE}_2$, $\text{PGI}_2$): Vasodilation, increased vascular permeability, sensitization of pain receptors, fever (act on hypothalamus)
• Prostacyclin ($\text{PGI}_2$): Produced by endothelial cells; inhibits platelet aggregation, promotes vasodilation
• Thromboxane $\text{A}_2$ ($\text{TXA}_2$): Produced by platelets; promotes platelet aggregation and vasoconstriction -- opposes prostacyclin

COX-1 is constitutive (housekeeping: gastric mucosa protection, renal blood flow, platelet function). COX-2 is inducible (upregulated at sites of inflammation). Aspirin irreversibly acetylates a serine residue in the COX active site. NSAIDs (ibuprofen, naproxen) are reversible COX inhibitors. Low-dose aspirin selectively inhibits platelet COX-1, preventing $\text{TXA}_2$ synthesis.

The LOX Pathway (Lipoxygenase)

Lipoxygenases (5-LOX, 12-LOX, 15-LOX) catalyze the addition of molecular oxygen to arachidonic acid at different positions, producing hydroperoxyeicosatetraenoic acids (HPETEs) and ultimately leukotrienes:

• $\text{LTB}_4$: Potent chemotactic agent for neutrophils
• $\text{LTC}_4$, $\text{LTD}_4$, $\text{LTE}_4$: Cysteinyl leukotrienes -- bronchoconstriction, increased mucus secretion; key mediators of asthma (formerly known as "slow-reacting substance of anaphylaxis", SRS-A)

Leukotriene receptor antagonists (montelukast/Singulair) and 5-LOX inhibitors (zileuton) are used therapeutically to treat asthma.