Chapter 9 – Lipids & Biological Membranes

Lipids and Membranes – Comprehensive Study Notes

General Properties of Lipids

  • Lipids are indispensable to every form of life; they perform structural, energy-storage, and signaling roles.
  • Definition: water-insoluble organic compounds that are either purely hydrophobic or amphipathic (possessing discrete polar & non-polar regions).
  • Practical & physiological implication – hydrophobicity drives self-assembly into bilayers, droplets, micelles, etc.; without this property, membranes and energy-dense fat stores could not exist.

9.1 Structural & Functional Diversity

  • Four highest-level families (Fig 9.1):
    • Fatty-acid–derived lipids (fatty acids, triacylglycerols, glycerophospholipids, sphingolipids, waxes, eicosanoids).
    • Phospholipids (glycerophospholipids + sphingomyelins).
    • Glycosphingolipids (ceramides, cerebrosides, gangliosides).
    • Isoprenoids (terpenes, steroids, lipid-soluble vitamins).
  • Mnemonic for students: “Fatty PhySIs” → Fatty-acid, Phospho-, Sphingo-, Isoprenoid.

9.2 Fatty Acids (FA)

  • Core formula R−COOH\mathrm{R{-}COOH} where R = hydrocarbon chain.
  • Variable features:
    1. Chain length (usually 12–2012\text{–}20 C, even numbered due to acetate biosynthetic units).
    2. Degree of unsaturation.
    3. Position/configuration of C=C bonds (typically cis).
  • IUPAC numbering – carboxyl C is C!!1\mathbf{C!!_1}; common nomenclature uses Greek letters (α,β,γ…\alpha,\beta,\gamma\dots); the terminal methyl carbon is ω\omega.
  • pKₐ ≈ 4.54.5 → deprotonated & esterified at physiological pH.
  • Shorthand: 20:4 Δ5,8,11,1420{:}4\,\Delta^{5,8,11,14} (arachidonate). Interpretation → 20 carbons, 4 cis double bonds beginning at C-5.
  • Saturation terminology:
    • Saturated – no C=C.
    • Monounsaturated – one C=C.
    • Polyunsaturated – ≥2\ge 2 C=C.
  • Physical outcome: cis double bonds introduce kinks → lower melting pt (e.g., stearate Tm=70 ∘!CT_m=70\,^{\circ}!\mathrm{C} vs. oleate 13 ∘!C13\,^{\circ}!\mathrm{C} vs. linolenate −17 ∘!C-17\,^{\circ}!\mathrm{C}).
  • Bio-context: membrane fluidity, essential FAs (linoleate, linolenate) must be diet-supplied.

9.3 Triacylglycerols (TAGs)

  • Composition: three fatty-acyl esters on glycerol.
  • Yield 2−32{-}3× the metabolic energy of carbohydrates/protein because they are highly reduced & stored anhydrously.
  • Structural note – glycerol is prochiral; when esterified it is stereochemically locked.
  • Human physiology: adipocytes store TAG in large cytosolic droplets; mobilization via hormone-sensitive lipase.
  • Ethical note: overconsumption → obesity; yet TAG storage has been evolutionarily selected for famine survival.

9.4 Glycerophospholipids (GPLs)

  • Most abundant membrane lipids.
  • Backbone: glycerol-3-phosphate.
  • Two acyl chains at C-1 & C-2; phosphate at C-3 linked to an alcohol head group.
  • Principal subclasses (Fig 9.8):
    • Phosphatidyl-ethanolamine (PE).
    • Phosphatidyl-serine (PS) – bears an extra carboxylate → overall negative charge.
    • Phosphatidyl-choline (PC) – zwitterionic at pH 7.
    • Phosphatidyl-inositol (PI) – later key to signaling.
  • Phospholipases (A₁, A₂, C, D) cleave specific bonds → important for remodeling & signaling; e.g., PLA₂ releases arachidonic acid.
Plasmalogens
  • Variant with a vinyl ether at C-1 (not ester!) – common in nerve & muscle (≈23 % of GPL pool).
  • Hypothesized antioxidant & membrane-dynamics roles.

9.5 Sphingolipids

  • Backbone: sphingosine (trans-4-sphingenine).
  • Ceramide = sphingosine + fatty acid (amide at C-2) – metabolic hub.
  • Sphingomyelins – ceramide + phosphocholine → also counted as phospholipids. Abundant in myelin.
  • Glycosphingolipids:
    • Cerebrosides – one sugar (e.g., galactosylcerebroside in brain white matter).
    • Gangliosides – complex oligosaccharide + Neu5Ac\text{Neu5Ac} (N-acetyl-neuraminic acid). >60 forms. GM₂ buildup ⇒ Tay-Sachs (hexosaminidase A deficiency).
  • Clinical aside: sphingolipidoses are inherited lysosomal-storage diseases; demonstrate importance of lipid catabolism.

9.6 Steroids (Isoprenoids)

  • Core system: three 6-C rings (A,B,C) + one 5-C ring (D); nearly planar.
  • Isoprene unit: C<em>5H</em>8\mathrm{C<em>5H</em>8}.
  • Substituent orientation: down = α\alpha, up = β\beta.
  • Representative structures (Fig 9.15):
    • Cholesterol – major animal sterol; modulates membrane fluidity & precursor for steroid hormones/bile salts.
    • Stigmasterol – plant sterol.
    • Ergosterol – fungal/yeast sterol (antifungal drug target).
    • Testosterone – androgenic hormone.
    • Sodium cholate – bile salt aiding lipid digestion.
  • Cholesterol facts:
    • Present in eukaryotic membranes (rare in plants, absent in bacteria/fungi).
    • Hydroxyl at C-3 → amphipathic; esterification (cholesteryl esters) masks polarity, enabling bloodstream transport with lipoproteins (LDL, HDL).
  • Societal impact: hypercholesterolemia → atherosclerosis; statins target HMG-CoA reductase in isoprenoid pathway.

9.7 Other Important Lipids

  • Waxes – long-chain FA esterified to long-chain alcohol; waterproof coatings on leaves, skin, feathers (e.g., myricyl palmitate).
  • Eicosanoids – oxygenated C20C_{20} PUFA derivatives (usually arachidonic acid):
    • Prostaglandins (cyclopentane ring) – inflammation, vasomodulation; aspirin irreversibly inhibits PG H₂ synthase.
    • Thromboxanes – platelet aggregation (TXA₂).
    • Leukotrienes – bronchoconstriction (LT D₄) → asthma targets.
  • Ethical/pharmacological note: NSAIDs, corticosteroids, and leukotriene-modifying drugs alleviate eicosanoid-mediated conditions.

9.8 Biological Membranes – Composition & Function

  • Define cell boundaries & organelles; ~5–10 nm thick.
  • Composite of lipid bilayer + embedded/associated proteins.
  • Functional highlights:
    • Pumps generate ion or proton gradients (ATP synthase relies on ΔpH\Delta pH).
    • Receptors detect extracellular cues.
    • Scaffold for energy conversion (e.g., oxidative phosphorylation, photosynthesis).
Lipid Bilayers (A)
  • Self-assemble due to hydrophobic effect; van der Waals among tails, H-bond/ionic among headgroups.
  • Interior = non-polar; exterior = polar.
  • Flexible & self-sealing, enabling vesicle trafficking.
Fluid Mosaic Model (B)
  • Coined by Singer & Nicolson (1972).
  • Lateral diffusion rapid (µs-ms); transverse flip-flop slow (hrs-days) unless catalyzed by flippases.
  • Composition varies: myelin ≈80 % lipid, inner mitochondrial membrane ≈75 % protein.
  • Experiment: human/mouse cell fusion → fluorescent labeling demonstrated lateral protein diffusion within ~40 min (Fig 9.24).

9.9 Membrane Dynamics

  • Lateral diffusion coefficient D≈10−8 – 10−9 cm2/sD \approx 10^{-8}\,\text{–}\,10^{-9}\,\mathrm{cm^2/s}.
  • Flip-flop energetically unfavorable due to movement of polar head through hydrophobic core.
  • Biological relevance – asymmetry of lipids (e.g., PS on inner leaflet) maintained for apoptosis signaling.

9.10 Classes of Membrane Proteins

  1. Integral (intrinsic) – traverse bilayer; hydrophobic segments (often α\alpha-helices) e.g., bacteriorhodopsin (7-TM).
  2. Peripheral – electrostatic/H-bond interactions with membrane surface or integral proteins; released by pH/ionic-strength change.
  3. Lipid-anchored – covalently attached lipids:
    • N-myristoylation or S-palmitoylation (fatty acyl anchors).
    • Prenylation on Cys (farnesyl, geranylgeranyl).
    • GPI anchors – glycolipid tether on outer leaflet; important for immune & enzymatic proteins.

9.11 Membrane Transport

  • Four mechanisms summarized in Table 9.3:
    • Simple diffusion – no protein, down gradient.
    • Channels/pores – protein passage, down gradient, not saturable.
    • Passive (facilitated) transport – carrier, saturable, down gradient. Types: uniport, symport, antiport.
    • Active transport – against gradient, energy required. Primary (ATP, light) vs. secondary (coupled ion gradient).
  • Example: E. coli lactose permease uses proton motive force (ΔμH+\Delta\mu_H^+) – classic secondary active transport (Fig 9.34).
  • Endocytosis/Exocytosis – vesicular transport for macromolecules; central to neurotransmitter release, LDL uptake.

9.12 Signal Transduction Across Membranes

  • General scheme (Fig 9.37):
    1. Ligand (1° messenger) binds membrane receptor.
    2. Transducer relays signal to effector enzyme.
    3. Effector generates 2° messenger.
    4. 2° messenger modulates cytosolic/nuclear targets → response.
A. G-Protein–Coupled Pathways
  • G-proteins = heterotrimers (αβγ). GDP-bound inactive; GTP-bound active.
  • Intrinsic GTPase activity provides built-in timer (~sec-min).
Adenylyl Cyclase (AC) Pathway
  • Hormone → GPCR → GsG_sα-GTP → AC converts ATP → cAMPcAMP.
  • cAMPcAMP binds regulatory (R) subunits of protein kinase A (PKA), releasing active catalytic subunits → phosphorylation cascade.
  • Termination: phosphodiesterase hydrolyzes cAMP→AMPcAMP \to AMP; caffeine/theophylline inhibit this enzyme, prolonging signaling.
cGMP Signaling
  • Similar concept; produced by guanylyl cyclase (e.g., NO signaling, phototransduction).
B. Inositol-Phospholipid Pathway
  • PLC cleaves PIP₂ → IP₃ + diacylglycerol (DAG).
  • IP₃ opens ER Ca²⁺ channels; DAG with Ca²⁺ activates protein kinase C (PKC).
  • Integration with Ca²⁺/calmodulin networks → multifaceted cellular outcomes (secretion, metabolism, gene expression).
C. Receptor Tyrosine Kinases (RTKs)
  • Single-polypeptide receptors possessing intrinsic kinase domain.
  • Ligand binding → dimerization → trans-autophosphorylation on Tyr residues.
  • Phospho-Tyr sites recruit SH2-domain proteins → Ras/MAPK cascade or PI3K pathway (Fig 9.49: insulin stimulates PI3K → PIP₃ formation).
  • Clinical correlation: RTK overactivity in cancers; targeted therapies (e.g., trastuzumab vs. HER2).

These bullet-point notes capture every key fact, term, example, figure takeaway, and practical/medical connection from Chapter 9. They can be used as a standalone study guide in lieu of the original text.