Lipids II - Structural lipids wrap-up

Last time we talked about storage lipids (fatty acids and triacylglicerides) and structural lipids (phosphoglycerides and sphingolipids). Today we will wrap up sctructural lipids with a discussion of some of the functions of sphingolipids and sterols, and we will then talk about the third class of lipids, those with specific biological functions.

Roles of sphingolipids in molecular recognition

As we said before, sphingolipids are located in the outer layers of the membrane, and their head groups are therefore more likely to poke into the fluid surrounding the cell. They are therefore ideal sites of molecular recognition. Glycosphingolipids are the determinants of blood types. Depending on the oligosaccharide clinging from C1, we have the O, A, and B blood types:

Gangliosides are also used in molecular recognition. Several toxins (proteins) bind specifically to the saccharides from gangliosides in the outer layers of the cell membrane. The syntheis and degradation of these sphingolipids is tightly regulated, because their precense or absence determines that different signals are passed or not from cell to cell, and the messages we may want to pass may change according to the situation.

Phospholipases

Having mentioned that some of the lipids in the membrane need to be degraded under different conditions, we will mention by whom they are degraded. Yesterday we said in class that the hydrolysis of membrane phospholipds is in charge of phospholipases. There is a specific phospholipase for each bond of the phosphoglycerides. Phospholipases of type A cleave of one of the two fatty acid chains. Lysophospholipases remove the remaining fatty acid ('lyso' means that one of the fatty acid chains is gone already).

Since they are used in the regeneration of the membrane, the action of phospholipases is regulated. In some particular cases, the action of phospholipases on phosphoglycerides which have inositol as the polar head release inositol phosphates into the cytosol, which are used in intracellular signaling. As we will see below, phospholipase A₂ (which cleaves the second fatty acid, in C2) releases arachidonic acid, which is then used in the biosynthesis of several hormones.

Phospholipases carried in venoms from different species (snakes, scorpions, spiders) act without regulation, and have the effect of generating soaps (saponified fatty acids) in the membrane, which in turn 'dissolve' the membrane. A neat picture of phospholipase A₂ from the cobra venom is here as a CHIME file.

Sterols

The last class of structural lipids are sterols, which are present in most eukaryotic cells. These molecules are characterized by the presence of a steroid nucleus, which is composed of four fused rings - They belong to a class of natural products called terpenes. As all terpenes, they are made up form the five carbon unit isoprene:

The steroid ring is not planar, but flattened in a way that it extends as much as possible. All the rings as in as much of a chair conformation as possible. There is no rotation possible around bonds in the rings, which makes sterols pretty rigid, except for the chain ar C17. The main sterol found in the membranes of eukaryotic cells is cholesterol (avobe). The polar head in this lipids is the hydroxyl in carbon C3. The lenght of sterols is comparable to that of 16 carbon fatty acids, and therefore they can intercalate nicelly with other triglycerides in membranes.

In addition to alter the physical properties of the mebrane, sterols are precursors of several hormones (sex hormones, see below), as well as of bile acids, in which the C17 chain is oxydized and polar. These serve as detergents in the intestine during digestion of fats.

Lipid aggregation

As we said many many times already, lipids are very hydrophobic molecules. However, they are amphipatic -  they have one non-polar tail, and a polar head. Therefore, when placed in water they will try to aggregate with themselves as much as possible. This will maximize hydrophobic interactions between the faty acid chains, and will also maximize the entropy of the water surrounding them (remember the hydrophobic effect was an effect from the solvent). There are different ways in which lipids can aggregate:

- Fatty acids or phospholipids with a single fatty acid chain are wedgy, and therefore they will arrange themselves in a way that places the fatty acid chains together, and the polar groups pointing towards the solvent. They are round particles, because the wedgy molecules close up on themselves. This arrangement is known as a micelle:

- Phospholipdis with two fatty acid chains, sphingolipids, and sterols are more cylindrical and can therefore form long layers. However, a single layer would leave one hydrophobic side exposed to water. Therefore, two layer comes together to form bilayers, which as you know, are the way membranes are made. In these bilayers, the polar heads point towards the solvent, and the fatty acid chains are in the inside:

- Short chunks of bilayers can come together to form relativelly small enclosed spheres with two layers. These are called liposomes, and have a small cavity inside in which the polar heads of the lipids reside. In this cavity we can have water, and water-soluble molecules. Liposomes have been used as formulation for polar molecules that don't trave well through the cell membranes

Other lipids

Apart from storage and structural lipids, which have passive roles, we have many lipid molecules wich have specific activities. These include steroids, and more generally, compounds derived from isoprene units. On the whole, they are responsible for transmission of intra- and intrecellular signals, electron transport, light transduction, fixation of calcium, and other function, either acting alone (as hormones) or as prosthetic groups in enzymes.

Steroids

Most steroids hormones, which can be considered derivatives of cholesterol, are male and female sex hormones found in the adrenal cortex. They are produced in one tissue and transported through the bloodstream to other tissues, and there they trigger the the expression of different genes (which afterewards start making different proteins not expressed until that point). The receptors for these hormons have very high affinities, and therefore very small concentrations (10^-9 M) are needed to trigger their message.

Among the things that they regulate are glucose metabolism and salt excretion.

Eicosanoids

Eicosanoids (eikosi is 20 in greek - 20 carbons) are generated by the action of phospholipases on triglycerides in which one of the fatty acids is arachidonic acid. Although the products obtained from arachidonic acid have hormone-like activity, they are not hormones because they are not transported from one tissue to another. They act intracellularly.

These compounds are involved in a number of functions: reproductive; inflamation, pain, and fever associated with disease, formation of blood clots, and regulation of blood pressure; and gastric acid secretion.

There are three classes of eicosanoids: Prostaglandins, thromboxanes, and leukotrienes:

- Prostaglandins regulate the synthesis of the cellular messenger cyclic AMP (cyclic adenosin monophosphate - cAMP). Since cAMP is involved in many cellular processes, prostaglandins affect many cellular functions. Some prostaglandins regulate muscle contraction during labor. Other elevate body temperature (they produce fever), and cause inflamation and pain.

- Thromboxanes are involved in the formation of blood clots, and the reduction of blood flow to the site of a blood clot.

- Finally, leukotrienes are responsible for the contration of the smoth muscle lining the airways - Excess of leukotrienes results in, for example, asthmatic atacks, as well as allergic reaction resulting from bee stings, penicillin, etc.

Vitamins A, D, E, and K

These compounds are all lipisoluble (meaning that they dissolve in lipids and non-polar organic solvents), and are not made by higher organisms. Therefore, we need ot get them in our diet, otherwise a wide variety of ugly things can happen to us.

Vitamin A (retinol) is essential to vision. We actually eat precursors of vitamin A, carotenoids, which we chop up into vitamin A enzymatically. After enzymatic oxidation of the acohol in retinol to an aldehyde, a trans double bond is isomerized to a cis double bond. These molecules, since they have many conjugated double bonds, absorb visible light. This causes the isomerization of the cis double bond back to trans. The conformational change associated with this isomerization is picked up by proteins, which transmit a signal to the brain that says 'Hey, you are seeing something...'

Vitamin D (7-dehydrocholesterol) is a derivative of cholesterol. UV radiation causes the generation of Vitamin D₃, which is crucial in calcium and phosphate metabolism. Further transformation of Vitamin D₃ into 1,25-dihydroxylcholecalciferol is required, because this molecule act as an hormone which regulated calcium intake in the intestine, and therefore regulates the deposition of calcium and phosphate in the bones. That is why it is important to catch some rays...

Vitamin E is actually a familly of compounds called tocopherols. They are antioxidant compounds (actually, they oxidize themselves before other things get oxidized). They capture very reactive species, such as oxygen radicals, and prevent the oxidation of, among other things, fatty acids. Lack of vitamin E causes the degradation of membranes and all the bad things that this brings about.

Vitamin K is a cofactor required for normal blod cloting. This cofactor is needed in the formation of prothrombin, and protease that is required to convert fibrinogen into fibrin. Fibrin is the protein participatin in the formation of blood clots.

The molecule warfarin serves as an anticoagulant, because it is a competitive inhibitor of prothrombin formation. It bind to the same receptor that bind vitamin K (can you tell why?). Warfarin therefore causes internal bleeding, and was used as a rat poison (nice way to kill a rat...). It is also used (in less lethat doses) to help people for which blood cloting can be risky, such as surgical patients and people with thrombosis.

Finally, we have carrier molecules. Ubiquinone (whose name means 'found everywere') and plastoquinone are electron carriers that work in the production of ATP in the mithochondria and chloroplasts, respectivelly. The two molecules are oxidized or reduced, taking in the process two electrons or two protons - These are the electrons or protons that they carry around. What gets oxidized/reduced in these molecules is the quinone part (the ring with two conjugated carbonyls).

The dolichols are molecules that attach to sugars and help in the synthesis of polysaccharides from sugar monomers. These molecules are very hydrophobic (up to 22 isoprenoid units), and therefore are buried in the membranes, where the sugar transfer reaction needed for the synthsis of polysaccharides occur.

Next class (after the exam) we will start with membranes...

Prepared by Guillermo Moyna, 1999.