Premed · Premed · Biochemistry
Lecture 11: Lipids and Membrane Biochemistry
Biochemistry
Learning Objectives
By the end of this lecture, students will be able to:
- Classify the major types of lipids and describe their structures
- Describe the structure and properties of fatty acids (saturated vs. unsaturated)
- Explain the structure of phospholipids, sphingolipids, and cholesterol
- Describe the fluid mosaic model of biological membranes
- Explain how membrane composition affects fluidity
- Describe the functions of membrane proteins and lipid rafts
Lecture Content
I. Overview and Classification of Lipids
Lipids are a diverse group of biomolecules defined by their hydrophobic or amphipathic nature. They are soluble in organic solvents such as chloroform and methanol but not in water. The major classes include fatty acids (the building blocks of many lipids), triacylglycerols (triglycerides, for energy storage), glycerophospholipids (phospholipids, for membrane structure), sphingolipids (for membrane structure and signaling), steroids (including cholesterol as a membrane component and precursors to hormones), waxes (protective coatings), and eicosanoids (signaling molecules including prostaglandins, thromboxanes, and leukotrienes).
II. Fatty Acids
Fatty acids consist of long hydrocarbon chains with a terminal carboxyl group, typically with even-numbered carbon chains of 14 to 24 carbons (16 and 18 being most common). They are named by the convention carbon number : number of double bonds (with delta positions indicating double bond locations). For example, linoleic acid is designated 18:2 (delta-9,12), meaning 18 carbons with 2 double bonds at carbons 9 and 12.
Saturated fatty acids have no double bonds, are fully saturated with hydrogen, form straight chains that pack tightly, and have higher melting points (solid at room temperature). Examples include palmitic acid (16:0), stearic acid (18:0), and myristic acid (14:0). Unsaturated fatty acids have one or more double bonds in the cis configuration in biological systems. Monounsaturated fatty acids (MUFAs) have one double bond (such as oleic acid, 18:1 delta-9), while polyunsaturated fatty acids (PUFAs) have multiple double bonds (such as linoleic acid, 18:2, and linolenic acid, 18:3). Cis double bonds introduce kinks in the chain that disrupt packing and lower melting points, making these fats liquid at room temperature. Trans fatty acids, produced by partial hydrogenation of vegetable oils, have double bonds in the trans configuration. They behave like saturated fats and are associated with increased cardiovascular disease risk.
Essential fatty acids cannot be synthesized by humans and must be obtained from the diet. These are linoleic acid (omega-6, 18:2 delta-9,12) and alpha-linolenic acid (omega-3, 18:3 delta-9,12,15). The omega designation counts from the methyl end of the chain.
III. Triacylglycerols
Triacylglycerols consist of three fatty acids esterified to glycerol and represent the major form of energy storage in animals, housed in adipose tissue. Because they are highly reduced and anhydrous, they yield more energy per gram than carbohydrates or proteins (approximately 9 kcal/g versus approximately 4 kcal/g). Their hydrophobic nature means they are stored without associated water, unlike glycogen. Simple triacylglycerols contain three identical fatty acids, while mixed triacylglycerols (more common) contain two or three different fatty acids. They are hydrolyzed by lipases during mobilization.
IV. Glycerophospholipids (Phospholipids)
Glycerophospholipids have two fatty acids esterified to glycerol at positions sn-1 and sn-2, with a phosphate group at sn-3 linked to a head group alcohol. They are amphipathic, possessing hydrophobic tails (the fatty acid chains) and a hydrophilic head (the phosphate plus head group). Different head groups yield different phospholipids: choline produces phosphatidylcholine (PC, or lecithin), the most abundant membrane phospholipid; ethanolamine produces phosphatidylethanolamine (PE); serine produces phosphatidylserine (PS), which is normally on the inner leaflet and whose exposure on the outer leaflet signals apoptosis; inositol produces phosphatidylinositol (PI), a precursor for signaling molecules such as IP3, DAG, PIP2, and PIP3; and glycerol leads to phosphatidylglycerol and subsequently to cardiolipin (diphosphatidylglycerol), which is characteristic of the inner mitochondrial membrane. Plasmalogens have an ether linkage at sn-1 instead of an ester and are abundant in the brain and heart. Platelet-activating factor (PAF) is an ether-linked phospholipid involved in inflammation.
V. Sphingolipids
Sphingolipids are built on a sphingosine backbone rather than glycerol. Ceramide, the core of all sphingolipids, consists of sphingosine linked to a fatty acid by an amide bond. Sphingomyelin is ceramide plus phosphocholine and is found in the myelin sheath; it is the only sphingolipid that is also a phospholipid. Glycosphingolipids consist of ceramide plus one or more sugars: cerebrosides have a single sugar (glucose or galactose), globosides have an oligosaccharide without sialic acid, and gangliosides have an oligosaccharide containing sialic acid (such as GM1 and GM2). Gangliosides are abundant in neuronal membranes, and GM2 ganglioside accumulates in Tay-Sachs disease due to hexosaminidase A deficiency.
Sphingolipid storage diseases (sphingolipidoses) are lysosomal enzyme deficiencies that lead to the accumulation of specific sphingolipids. These include Tay-Sachs, Gaucher, Niemann-Pick, Fabry, and Krabbe diseases.
VI. Cholesterol and Steroids
Cholesterol is composed of four fused rings (the steroid nucleus) with a hydroxyl group and a hydrocarbon tail, making it amphipathic. It serves as a major component of animal cell membranes (up to 50% of membrane lipids), where it modulates fluidity by restricting movement at high temperatures and preventing crystallization at low temperatures. Cholesterol is also a precursor for bile acids, steroid hormones (cortisol, aldosterone, testosterone, estradiol, progesterone), and vitamin D. It is not found in prokaryotic membranes and is transported in the blood as part of lipoproteins (LDL, HDL, VLDL).
<image>A comprehensive figure of major lipid structures. Panel A: A saturated fatty acid (palmitate) and an unsaturated fatty acid (oleate) showing the cis double bond kink. Panel B: A triacylglycerol with three different fatty acid chains esterified to glycerol. Panel C: A phosphatidylcholine molecule with the hydrophilic head group (phosphocholine) and hydrophobic tails labeled, shown next to a simplified icon used in membrane diagrams. Panel D: A sphingomyelin molecule built on the sphingosine backbone, with the ceramide portion highlighted. Panel E: Cholesterol structure with the steroid ring system, hydroxyl group, and hydrocarbon tail labeled.</image>
VII. Biological Membranes: The Fluid Mosaic Model
The fluid mosaic model, proposed by Singer and Nicolson in 1972, describes membranes as two-dimensional fluids of lipids with embedded proteins. The lipid bilayer consists of two leaflets of phospholipids with hydrophobic tails facing inward and hydrophilic heads facing outward. It self-assembles in aqueous solution, driven by the hydrophobic effect, and forms a sealed compartment impermeable to most polar and charged molecules.
Membrane asymmetry is maintained by flippases, floppases, and scramblases, with inner and outer leaflets having different lipid compositions. PS and PE are enriched in the inner leaflet, while PC and sphingomyelin are enriched in the outer leaflet. Glycolipids are found exclusively in the outer leaflet, with their sugar moieties facing the extracellular space.
VIII. Membrane Fluidity
Membranes are dynamic, not rigid. Lateral diffusion of lipids is rapid, occurring approximately 10^7 times per second for phospholipids, while transverse diffusion (flip-flop) is very slow (hours to days) without enzymatic assistance. Several factors affect fluidity. Fatty acid chain length determines the extent of van der Waals interactions: shorter chains produce more fluid membranes. The degree of unsaturation is also important: more double bonds create kinks that prevent tight packing, increasing fluidity. Cholesterol has a dual role -- at physiological temperatures it decreases fluidity by filling gaps between phospholipids, while at low temperatures it increases fluidity by preventing tight packing and crystallization. Higher temperature also increases fluidity.
The phase transition temperature (Tm) is the temperature at which the membrane transitions from a gel (ordered) phase to a liquid-crystalline (fluid) phase. Organisms adapt their membrane composition to maintain appropriate fluidity, a process known as homeoviscous adaptation.
IX. Membrane Proteins
Integral (intrinsic) membrane proteins are embedded in the bilayer. Transmembrane proteins span the entire bilayer as single-pass or multi-pass structures and typically have hydrophobic alpha-helical segments of 20 to 25 nonpolar residues. Some use beta-barrels, as seen in porins of bacterial, mitochondrial, and chloroplast outer membranes. Peripheral (extrinsic) membrane proteins associate with the membrane surface via non-covalent interactions and can be removed by high salt or pH changes. Lipid-anchored proteins are covalently attached to a lipid, including GPI (glycosylphosphatidylinositol) anchors on the outer leaflet, palmitoylation and myristoylation through fatty acid anchors, and prenylation (farnesylation, geranylgeranylation) through isoprenoid anchors. Membrane proteins carry out functions including transport, signaling, adhesion, and enzymatic activity.
<image>A detailed cross-section of a biological membrane illustrating the fluid mosaic model. The phospholipid bilayer is shown with integral transmembrane proteins (both single-pass alpha-helical and multi-pass), peripheral proteins on both surfaces, and a GPI-anchored protein on the extracellular face. Cholesterol molecules are shown intercalated between phospholipids. Glycolipids and glycoproteins face outward with sugar chains. The inner leaflet is labeled as enriched in PS/PE and the outer leaflet enriched in PC/sphingomyelin. Lateral diffusion arrows show phospholipid movement within the plane of the membrane.</image>
