27.3 Phospholipids

Phospholipid Structure and Function

Phospholipids are the primary structural components of cell membranes. Their dual nature, with a water-loving head and water-hating tails, drives them to spontaneously assemble into bilayers that separate the inside of a cell from its surroundings. Understanding their chemistry explains how membranes form, stay fluid, and control what passes through.

Structure of Phospholipids

Phospholipids are amphipathic, meaning one part of the molecule is polar and another part is nonpolar. This single property explains almost everything about how they behave.

• The hydrophilic head contains a phosphate group bonded to a variable polar molecule. Common head groups include choline, ethanolamine, serine, and inositol. The choice of head group determines the phospholipid's identity and biological role.
• The hydrophobic tails consist of two fatty acid chains. These can be saturated (like palmitic acid, with no double bonds) or unsaturated (like oleic acid, with one or more $cis$ double bonds that introduce kinks in the chain).

The central scaffold is a glycerol backbone, a three-carbon molecule with three hydroxyl groups:

• Positions 1 and 2: fatty acids are attached via ester bonds (one bond at each position).
• Position 3: the phosphate group is esterified here, and the polar head group is in turn bonded to the phosphate.

This arrangement puts the two nonpolar tails on one end and the charged phosphate-head group on the other, which is what makes the molecule amphipathic.

Glycerophospholipids vs. Sphingomyelins

Not all phospholipids share the same backbone. The two major classes differ in their core structure.

Glycerophospholipids are the most abundant phospholipids in cell membranes. They use the glycerol backbone described above, with two fatty acid ester linkages and a phosphorylated head group. Named varieties differ only in their head group:

• Phosphatidylcholine (PC): most common in the outer leaflet of animal cell membranes
• Phosphatidylethanolamine (PE): concentrated in the inner leaflet
• Phosphatidylserine (PS): normally restricted to the inner leaflet; its exposure on the outer surface signals apoptosis
• Phosphatidylinositol (PI): plays a key role in cell signaling when phosphorylated

Sphingomyelins replace the glycerol backbone with sphingosine, an 18-carbon amino alcohol that already contains a long unsaturated hydrocarbon chain. The structural differences from glycerophospholipids:

1. A single fatty acid attaches to sphingosine's amino group through an amide bond (not an ester bond). This fatty acid plus the sphingosine backbone together form a unit called ceramide.
2. A phosphocholine group is esterified to the terminal hydroxyl of sphingosine, giving sphingomyelin its polar head.

Because sphingosine itself contributes one hydrocarbon chain and the amide-linked fatty acid contributes the other, sphingomyelins still have two hydrophobic tails, just like glycerophospholipids. Sphingomyelins are especially abundant in the myelin sheath that insulates nerve cells.

Phospholipids in Cell Membranes

Phospholipids spontaneously form bilayers in water because of the hydrophobic effect. The nonpolar tails are driven away from water, clustering together in the interior, while the polar heads face the aqueous environment on both sides.

The resulting phospholipid bilayer has several critical properties:

• It acts as a barrier between intracellular and extracellular environments.
• The hydrophobic core blocks the passage of polar and charged molecules such as ions, glucose, and most proteins.
• Small, nonpolar molecules like $O_2$, $CO_2$, and steroid hormones can diffuse through freely.
• Larger or polar molecules need transport proteins (ion channels, carrier proteins, pumps) to cross.

This makes the bilayer selectively permeable, which is the foundation of how cells control their internal chemistry.

Membrane fluidity depends on lipid composition:

1. Unsaturated fatty acids increase fluidity. Their $cis$ double bonds create kinks that prevent tight packing of the tails.
2. Shorter fatty acid chains also increase fluidity because they have weaker van der Waals interactions with neighboring chains.
3. Cholesterol acts as a fluidity buffer. It intercalates between phospholipids, restricting their movement at high temperatures (reducing fluidity) but preventing tight packing at low temperatures (maintaining fluidity). This produces what's called a liquid-ordered state.

Membrane Dynamics and Organization

Beyond simple bilayers, phospholipids participate in more complex membrane behaviors:

• In aqueous solution, phospholipids can also form micelles (single-layer spheres with tails pointing inward). Whether micelles or bilayers form depends on the shape of the phospholipid. Two-tailed phospholipids favor bilayers; single-chain lipids favor micelles.
• Lipid rafts are specialized microdomains within the membrane that are enriched in cholesterol and sphingolipids. These thicker, more ordered patches help organize membrane proteins involved in signaling.
• Membrane curvature is influenced by phospholipid shape. Cone-shaped lipids promote curvature, which matters during processes like vesicle budding and cell division.
• Phospholipid asymmetry is actively maintained. The inner and outer leaflets of the bilayer have different phospholipid compositions (for example, PS is kept on the inner leaflet). Enzymes called flippases, floppases, and scramblases control the movement of phospholipids between leaflets, preventing the spontaneous "flip-flop" that would otherwise be extremely slow due to the energy cost of dragging a polar head through the hydrophobic core.