Lipids

We will now start with our discussion of another family of very important biological molecules, the lipids. As opposed to amino acids, which are mainly used in the synthesis of proteins, lipids have a wide variety of roles and uses in the organism. They are more chemically diverse than other biochemical groups, and therefore are used for a wider variety of roles, and they do not form polymeric structures, as amino acids, saccharides, and nucleic acids do. The common motif in all lipids is that they are largely hydrophobic and insoluble in water. Lipids are involved in three main roles in living organisms:

- As you all know, organisms use lipids known as fats and oils for fuel storage. These are mainly tryacylglycerols. Waxes (such as bee-wax) function both as energy storage as well as impermeable coatings against water.

- Other types of lipids, the phospholipids and sterols, are crucial for the formation of biological membranes, and therefore have structural function.

- Finally, certain lipids are used as enzymes coofactors, in light abosrption, electron transport, intracellular messenging (hormones). We will start our discussion of lipid nomenclature and structure with storage lipids.

Lipids are highly reduced organic molecules - That means, we will find almost everything in lipids as '-CH₂-'. We will have only a few of the carbons in lipid molecules in higher oxidation state (as -CH=CH-, or COOH). This means that they can be used very efficiently to generate energy by oxidation, in the same way that the gas you use in your car (which is composed of highly reduced hydrocarbons) is used in energy generation. In general, complete oxidation of these molecules from CO2 and H2O gives out a lot more energy than with more oxidized molecules, like a sugar (C_n(H2O)_n).

Fatty Acids

The simplest lipids are fatty acids, which relativelly long carbon chains (4 to 36 carbons long) capped with a carboxylic acid. The alkyl side chain can be completely reduced (or saturated - no double bonds, all '-CH₂-'), and some will have unsaturations (will have double bonds, '-CH=CH-' units). In some cases, we can have three membered rings in place of the double bonds (cyclopropane rings). The alkyl side chains of fatty acids are mainly unbranched (that is, nothing comes out of the chain):

One thing you will notice is that the number of carbons in fatty acids is almost always even (multiples of two). This is because lipids are synthetized using acetate units (CH₃-COOH) as building blocks (by, you guessed it, fatty acid synthases, FAS).

What about naming these things? The systematic names can be used. Therefore, a fatty acid with 14 carbons will be n-tetradecanoic acid, one with 16 n-hexadecanoic acid, one with 18 n-octadecanoic acid, and so on. The 'n' comes from being 'normal', i.e., completely linear. The name is almost always 'something-decanoic': the 'something' part is the number of carbons above 10, and the 'decanoic' part is the 10 other carbons. The common names, which are impossible to remember unless you work with them in a day-to-day basis, usually refer to a plant or animal in which they are found in abundance. i.e., n-dodecanoic acid is found in laurel plants, and is called lauric acid. In other cases, they are derived from a greek word that refers to their 'looks'. n-octadecanoid acid is called stearic acid, because stear in greek means hard, and this means that it is a 'hard fat'.

In the same way that their lenghts are usually multiples of two, the position of the double bonds is regular. The possition will usually be between carbons 9 and 10, and then between 12 and 13, and then between 15 and 16. We will never find conjugated double bonds in fatty acids - If a fatty acid has two or three double bonds they will be separated by a methylene unit ('-CH₂-'). Furthermore, the double bonds in fatty acids will almost always be cis. These has important implications on the structure that the molecules can adopt, and how tightly they can be next to each other.

Finally, we can abreviate their names by the following convention. We write two numbers separated by a colon. The first one is the number of carbons in the chain, the second one the number of double bonds, followed by a D and the carbons where the double bond is location in parenthesis. So, n-hexadecanoic acid (palmitic acid) is abreviated 16:0. A fatty acid with 18 carbons, with a double bond between carbons 9 and 10 and 12 and 13 would be 18:2(D^9,12). The common name here would be a-linoleic acid.

From their chemical composition we can see that fatty acids will be highly hydrophobic molecules. Only the carboxylic acid part (which is ionized at pH 7) will be 'soluble' in water. The rest will not. Therefore, fatty acids (and lipids in general) will be very insoluble in water. The longer they are and the more double bonds they have the less soluble they will be. This means that free fatty acids cannot move around the body easily. In order to circulate in blood, fatty acids need to be bound to a carrier protein, serum albumin.

Physical properties such as the melting point of fatty acids (and lipids) will depend on their chemical structure. The only forces keeping fatty acids together are hydrophobic (van der Waals) interactions. In fully saturated fatty acids, the alkyl chains will be in the most energetically favourable conformation when completelly extended, because all the bonds will be staggered. Therefore, if you look at a bunch of saturated fatty acid molecules, they will all line up nicelly, and there will be numerous interactions between the alkyl chains:

These collections of small but additive hydrophobic forces will make the melting points of these fatty acids (and lipids containing saturated fatty acids) to be relativelly high, and they are therefore greasy solids at room temperature. If we have mixtures of saturated and unsaturated fatty acids, the cis double bonds will bend some of the alkyl chains, and the number of interactions between chains from different fatty acids are a lot less - There will be a lot more 'holes'. This has the effect of lowering the melting temperature of these types of fatty acids and the molecules thay form. For example, they will be liquids at room temperature (see below).

Although we can find fatty acids in solution complexed to carrier proteins, it is a lot more likely to find them as carboxylic acid derivatives, either esters or amides. Since we removed the carboxylic acid when we esterify or amidate, these will be even less soluble in water. We will now start discussing some of these fatty acid derivatives, the tryacylglycerols, which are one of the most abundant forms in which we will find energy storage fatty acids.

Triacylglycerols

In these molecules, three fatty acid molecules are esterified with a triol, glycerol:

We can have different types. In some, all the fatty acids are the same, and these are called simple triacylglycerols. They are named according to the fatty acid: tripalmitin, tristearin, etc., etc. We can also find different fatty acids clinging to the glycerol, and in this case we call them mixed triacylglycerols:

As we said before, when we esterify fatty acids they become even more hydrophobic. Therefore, they will agreggate in the cytosol, forming tiny oil-like droplets of 'energy' storage. In vertebrates, there are specialized cells called adipocites which are filled up with triacylglycerol droplets. These cells are used both for energy storage and form body fat (that thing you exercise long and hard to get rid off), as well as thermal insulation.

As we mentioned before, triacylglycerols are highly reduced, and therefore hold more energy per gram than sugars or glycogen. This comparison did not take into account their 'solvation' - Since they are highly hydrophobic, triacylglycerols will have very little water associated to them - They will be bundled up, almost devoid of any water. Sugars (glycogen) are a lot more polar, and will have more water associated. Therefore, in the cytosol, one molecule of polysaccharide may weigh a lot more due to the water, and therefore we get even less energy per gram of glycogen than with lipids. Finally, there is plenly fat when compared with glycogen in the body. The ammount of glycogen in the body we have will only 'power' us for a day. On the other hand, 10 Kg of fat can give us an energy supply that will last for almost a month. We have to keep in mind, however, that it is a lot easier to burn sugars than lipids, and therefore we need sugars for short 'burst' of exercise.

We eat a lot of triacylglycerols with many foods (oils and fat). These are complex mixtures of simple and mixed triacylglycerols. Animal fat is composed mainly of triacylglycerols with saturated fatty acids, and are greasy solids at room temeperature. Vegetable oils, on the other hand, are composed pricipally by unsaturated fatty acids, and are liquid at room temeprature.

Saponification

When we treat tricaylglycerols with a strong aqueous base, such as NaOH or KOH, we will hydrolyse then, and get the salt of the fatty acid:

These compounds are called soaps, and as you all know they have the ability of disolving grease in water. This is because being salts, one endy will be in solution in water, while the other end will interact with fat molecules (triacylglycerols). In these disperssions, the salt end of the molecule will lie in contact with water, while the other end will pack together, forming micelles.

Waxes

There are a number of fatty acids that instead of being esterified with glycerol, are esterified with relativelly long chain alcohols. These compounds, which are highly hydrophobic and have melting temperatures higher than faty acids or triaclyglycerols, are called waxes:

Waxes can be used (and are used) as energy storage in some organisms (plankton). However, the main use of waxes is as a water resistant coating. Bees use beeswax both to glue their hives together (because they have high melting points and are 'solid'), and to avoid water to get in the hive and disolve the honey.

Waxes are used mainly as protective coating in order to avoid water. They are therefore used in the cosmetic industry quite a bit to make oinments, lotions, and polishes. In certain plants, waxes prevent evaporation of water and protect against different bugs (they are bitter and some are toxic).

Structural lipids

Another very important role of lipids is their participation in the 'creation' of biological membranes. Double layers of lipids make membranes that prevent the passage of water and polar substances into (or out of) different vesicles and cells. As we know by now, membrane lipids are amphiphatic: they have a polar (charged) side pointing towards the aqueous solution, and a hydrophobic inner core that is tightly packed together.

There are three main groups of lipids that form part of membranes: glycerophospholipids, sphingolipids, and sterols. In all of them, we have a non-polar hydrophobic side, and a polar side. In glycerophospholipids, the hydrophobic part is formed by two fatty acid chains. In sphingolipids, we have a single fatty acid joined to a fatty amine, sphingosine. Sterols are characterized by a rigid skeleton formed by four fused rings (a triterpene). These parts are the non-polar 'tails'. The polar parts, or 'heads', can be as small as hydroxyl (-OH), or as big as choline, a tertiary amine.

Glycerophospholipids

Glycerophospholipids (or phosphoglycerides, or phospholipids for short) are composed of a molecule of glycerol, esterified with two fatty acids on carbons C1 and C2, and on the third hydroxyl (carbon C3) we have a highly polar group joined through a phosphodiester bond. The phosphate is negativelly charged, and the group attached to the phosphate may also be charged:

All phopshoglycerides are derivatives of phosphatidic acids, in which the group attached to the phosphate is a hydrogen (-P-OH). In some cases, we can have an ether linkage instead of an ester linkage at C1, and the ether linkage can be saturated or insaturated:

The phospholipids of the heart have high content of altky ethers. Although their function is obscure, they may be there to avoid degradation by phospholipases (see below).

Sphingolipids

Sphingolipids are the second largest group of lipids in membranes. They also have polar heads and hydrophobic tails, but instead of having two fatty acids attached to a glycerol molecule, they have only one fatty acid attached to a molecule of sphingosine, which is an amino alcohol:

Sphingosine is homologous to glycerol, as it has the same number of polar groups (-OH, -NH₂, -OH vs -OH, -OH, -OH). The fatty acid is attached through an amide bond, not an ester bond:

Depending on the 'X' substituent of the head group, we will have sphingoyelins, glycsphingolipids and cerebrosides, and gangliosides:

- Sphingomyelins have charged head groups, with phophocholine or phosphoetanolamine. Sphingomyelins look a lot like phosphatydilcholine, both chemically and structurally, as they have similar groups placed in similar locations. Their 3D structure is also similar. They are the main component of the membrane of the myelin sheath of neurones, therefore their name.

- Glycosphingolipids are neutral, and have polar but uncharged head groups, formed by one to six sugars, and do not contain phosphate. These molecules are usually found in the outer face of membranes. One particular type of glycosphingolipids are cerebrosides, which have a single sugar (glucose or galactose).

- Gangliosides bear very complex polysaccharides in the C1 hydroxyl, and one ot the saccharides is N-acetylneuraminic acid, or sialic acid, which has a negative charge at pH 7. Gangliosides, as we will see next time, are involved in molecular recognition.

Prepared by Guillermo Moyna, 1999.