Lipid molecules that make up membranes

Cell membranes are built mostly from lipids that have two personalities at once: one end likes water and the rest does not. This topic is about the molecules themselves: their parts, their shorthand and the bonds that hold them together. How these molecules gather into sheets and how those sheets behave is the subject of the next topic, so here we only describe each molecule and its shape.

Fatty acyl chains

Almost every membrane lipid except cholesterol carries one or more fatty acyl chains. A fatty acid is a carboxylic acid head attached to an unbranched hydrocarbon chain. Chains in cells nearly always have an even number of carbons, most often between 14 and 24, because they are built two carbons at a time. Once the carboxyl group is joined to another molecule through an ester or an amide, the piece is called an acyl chain.

A chain with no carbon-carbon double bonds is saturated: every carbon holds as many hydrogens as it can. A chain with one or more double bonds is unsaturated. Naturally occurring double bonds are mostly cis, meaning the two chain segments leave the double bond on the same side. Because a double bond cannot rotate, each cis double bond puts a fixed bend in the chain. A saturated chain, by contrast, can adopt a long, nearly straight zigzag.

Shorthand notation

Chains are written as carbons:double bonds. So 18:0 is an eighteen-carbon chain with no double bonds. Two numbering systems locate the double bonds:

• Delta numbering counts from the carboxyl carbon, which is C1. The symbol $\Delta^9$ means a double bond between C9 and C10.
• Omega (n-) numbering counts from the methyl end, where the last carbon is omega-1. A chain belongs to the omega-$x$ family when the double bond nearest the methyl end begins at carbon $x$ counted from that end. If the last double bond in delta numbering begins at carbon $d$ and the chain has $N$ carbons, then $x = N - d$.

Melting point and chain contact

Free fatty acids pack against each other through London dispersion forces, a type of van der Waals attraction. Each pair of neighboring CH2 groups contributes a small attraction, and the total grows with the length of chain that lies side by side. Two trends follow:

• Longer chains have more contact, so the melting point rises with chain length.
• A cis double bond bends the chain, so neighbors can no longer lie flat against one another along the whole length. Contact drops, and the melting point falls with each added cis double bond.

For C18 acids the melting points are roughly 70 degrees C for stearic acid (18:0), about 13 degrees C for oleic acid (18:1), and a few degrees below zero for linoleic acid (18:2). The values are approximate, but the order is what matters.

Worked example: reading shorthand

Problem. Translate 18:0, 18:1 cis-delta-9, 18:2 cis-delta-9,12 and 20:4 cis-delta-5,8,11,14 into structures. Give the omega class of the last two. Then rank the three C18 acids by melting point and explain.

Solution.

1. 18:0 is a straight chain of 18 carbons, C1 being the carboxyl carbon, with no double bonds (stearic acid).
2. 18:1 cis-delta-9 has one cis double bond between C9 and C10, so one bend near the middle of the chain (oleic acid).
3. 18:2 cis-delta-9,12 has cis double bonds at C9=C10 and C12=C13, so two bends (linoleic acid).
4. 20:4 cis-delta-5,8,11,14 has four cis double bonds, starting at C5, C8, C11 and C14, each separated by one CH2 carbon (arachidonic acid).
5. Omega class of 18:2: the last double bond begins at C12, so $x = 18 - 12 = 6$. It is an omega-6 fatty acid.
6. Omega class of 20:4: the last double bond begins at C14, so $x = 20 - 14 = 6$. It is also omega-6.
7. Melting points: the three share a length, so the number of cis bends decides. Zero bends gives the best contact and the highest melting point, so 18:0 is highest, then 18:1, then 18:2 lowest.

Glycerophospholipids

The most abundant membrane lipids are glycerophospholipids. Their backbone is glycerol 3-phosphate, a three-carbon alcohol with a phosphate on carbon 3.

• Carbon 1 and carbon 2 each carry a fatty acyl chain joined by an ester bond. Carbon 1 usually holds a saturated chain and carbon 2 an unsaturated one.
• Carbon 3 carries the phosphate.

The simplest member, with just a free phosphate on carbon 3, is phosphatidic acid. It is the parent from which the others are made. When an alcohol is joined to the phosphate through a second ester bond, the result is a phosphodiester, and the attached alcohol is the head group. Common ones include:

PC and PE are zwitterions: they carry one positive and one negative charge, so they are neutral overall. PS and PI are net negative. A small group of ether-linked lipids has the chain at carbon 1 joined to glycerol through an ether bond instead of an ester.

Worked example: net charge of head groups

Problem. Estimate the net charge of PC, PE and PS near pH 7. Use approximate pKa values.

Solution. The pKa values below are approximate.

1. The phosphodiester has a pKa of about 1 to 2, far below 7, so it is deprotonated and contributes $-1$ in PC, PE, PS and PI. (Phosphatidic acid has a phosphomonoester instead, whose charge depends on its second ionization.)
2. PC: choline is a quaternary ammonium with no proton to lose, so it is $+1$ at any pH. Net charge: $-1 + 1 = 0$.
3. PE: the ethanolamine amino group has a pKa of about 10 when free, well above 7, so it is protonated: $+1$. Net charge: $-1 + 1 = 0$.
4. PS: phosphate contributes $-1$. The serine carboxyl group has a pKa near 2 to 4, so it is deprotonated: $-1$. The serine amino group is protonated: $+1$. Net charge: $-1 - 1 + 1 = -1$.
5. PI follows the same logic as step 1: the phosphodiester is $-1$ and the inositol hydroxyls are uncharged, so the net charge is $-1$.

Sphingolipids

Sphingolipids are built on sphingosine, a long-chain amino alcohol with 18 carbons. It has hydroxyl and amino groups near one end and a double bond in the chain. Sphingosine already contains a hydrocarbon tail, so it supplies one of the two tails of the finished lipid.

When a fatty acid is joined to the amino group of sphingosine through an amide bond (not an ester), the product is ceramide. Ceramide has two nonpolar tails and a small polar region, and it is the parent of the other sphingolipids. The terminal hydroxyl of ceramide is where head groups attach:

• Sphingomyelin: ceramide with a phosphocholine attached. It is a phospholipid, yet it contains no glycerol. Its head group looks like that of PC, so it is net neutral.
• Cerebrosides: ceramide with a single sugar, such as glucose or galactose. They have no phosphate and are neutral.
• Gangliosides: ceramide with an oligosaccharide that includes one or more units of sialic acid. Sialic acid carries a carboxylate, so gangliosides are negatively charged.

Cerebrosides and gangliosides are glycosphingolipids. In a cell membrane their sugars always face the cell exterior, never the cytosol. The next topics explain why that arrangement exists.

Sterols

Cholesterol is the main membrane sterol in animal cells. It has 27 carbons arranged as follows:

• Four fused rings: three six-membered rings and one five-membered ring, forming a rigid, flat plate.
• A single hydroxyl group at C3, the only polar feature, which acts as a very small polar head.
• A short branched hydrocarbon tail at the opposite end of the ring system.

In a membrane, cholesterol lies parallel to the acyl chains of neighboring lipids, with its hydroxyl at the interface where polar head groups sit and the rigid ring system alongside the chains. Cholesterol also changes how fluid a membrane is, which the next topic covers.

Amphipathic shape

Every membrane lipid is amphipathic, meaning it has both a polar region and a nonpolar region:

Rough molecular shape matters later. A phospholipid with two tails and a head group of similar width is shaped like a cylinder. A lysophospholipid, which has lost one tail, has a head wider than its single tail and is shaped like a cone. How shape influences structure is left to the next topic.

Where enzymes cut a phospholipid

Phospholipases hydrolyze specific bonds in glycerophospholipids. The letter names the bond.

When phospholipase C acts on a phosphoinositide such as PIP2, the two products are diacylglycerol and inositol trisphosphate. Both act as messenger molecules, a topic for the signaling material later.

Worked example: phospholipase products

Problem. A PC molecule is treated separately with phospholipases A2, C and D. List what each releases. A different sample contains diacylglycerol plus phosphocholine. Which enzyme made it?

Solution.

1. A2 cuts the C2 ester. It releases a free fatty acid, and the remaining molecule is a lysophosphatidylcholine that still has its C1 chain.
2. C cuts between glycerol C3 and the phosphate. It releases phosphocholine (phosphate with choline attached), and the glycerol portion left behind is diacylglycerol.
3. D cuts between the phosphate and choline. It releases free choline, and the remaining lipid is phosphatidic acid.
4. A sample with diacylglycerol plus phosphocholine matches step 2, so the enzyme was phospholipase C. Phospholipase D would give phosphatidic acid and choline instead.

Putting the classes together

The four families share a plan: a small backbone, nonpolar tails, and a polar region. Glycerol holds two ester-linked chains. Sphingosine already contains one tail and takes a second through an amide. Cholesterol replaces the chains with a ring system. Telling these backbones and linkages apart, and knowing which bond each enzyme cleaves, covers most of what is asked about membrane lipid structure.