Lipids are a broad class of molecules that all share the characteristic that they have at least a portion of them that is hydrophobic. The class of molecules includes fats, oils (and their substituent fatty acids), steroids, fat-soluble vitamins, prostaglandins, glycerophospholipids, and sphingolipids. Interestingly, each of these can be derived from acetyl-CoA.
Arguably, the most important lipids in our cells are the fatty acids, because they are components of all of the other lipids, except some of the steroids and fat-soluble vitamins. Consisting of a carboxyl group linked to a long aliphatic tail, fatty acids are described as either saturated (no double bonds) or unsaturated (one or more double bonds). Fatty acids with more than one double bond are described as polyunsaturated. Increasing the amount of unsaturated fatty acids (and the amount of unsaturation in a given fatty acid) in a fat decreases its melting temperature. This is also a factor in membrane fluidity. If the melting temperature of a fat is decreased sufficiently so that it is a liquid at room temperature, it is referred to as an oil. It is worth noting that organisms like fish, which live in cool environments, have fats with more unsaturation. This is why fish oil is a rich source of polyunsaturated fatty acids.
Figure 3.5.1: Important unsaturated fatty acids.
Biochemically, the double bonds found in fatty acids are predominantly in the cis configuration. So-called trans fats arise as a chemical by-product of partial hydrogenation of vegetable oil (small amounts of trans fats also occur naturally). In humans, consumption of trans fats raises low density lipoprotein (LDL) levels and lowers high density lipoprotein (HDL) levels. Each is thought to contribute to the risk of developing coronary artery disease. The most common fatty acids in our body include palmitate, stearate, oleate, linolenate, linoleate, and arachidonate. Fatty acids are numbered by two completely different schemes. The delta numbering scheme has the carboxyl group as #1, whereas the omega number scheme starts at the other end of the fatty acid with the methyl group as #1. Fatty acids are described as essential if they must be in the diet (can’t be synthesized by the organism). Animals, including humans, cannot synthesize fatty acids with double bonds beyond position delta 9, so linoleic and linolenic acids are considered essential in these organisms.
Figure 3.5.2: Fatty acids.
In animal cells, fats are the primary energy storage forms. They are also known as triacylglycerols, since they consist of a glycerol molecule esterified to three fatty acids. Fats are synthesized by replacing the phosphate on phosphatidic acid with a fatty acid. Fats are stored in the body in specialized cells known as adipocytes. Enzymes known as lipases release fatty acids from fats by hydrolysis reactions. Of the various lipases acting on fat, the one that acts first, triacylglycerol lipase, is regulated hormonally.
Figure 3.5.3: Hydrolysis of fat.
The predominant lipids found in membranes are glycerophospholipids (phosphoglycerides) and sphingolipids. The former are related to fats structurally as both are derived from phosphatidic acid. Phosphatidic acid is a simple glycerophospholipid that is usually converted into phosphatidyl compounds. These are made by esterifying various groups, such as ethanolamine, serine, choline, inositol, and others to the phosphate. All of these compounds form lipid bilayers in aqueous solution, due to the amphiphilic nature of their structure.
Figure 3.5.4: Phosphatic Acid (Left) and Phosphatidyl Ethanolamine (Right)
Though structurally similar to glycerophospholipids, sphingolipids are synthesized completely independently of them, starting with palmitic acid and the amino acid serine. The figure on the right shows the structure of several sphingolipids. LIke the glycerophospholipids, sphingolipids are amphiphilic, but unlike them, they may have simple (in cerebrosides) or complex (in gangliosides) carbohydrates attached at one end. Most sphingolipids, except sphingomyelin, do not contain phosphate.
Figure 3.5.5: The structures of several sphingolipids.
Steroids, such as cholesterol are also found in membranes. Cholesterol, in particular, may play an important role in membrane fluidity. Membranes can be thought of a being more “frozen" or more “fluid." Fluidity is important for cellular membranes. When heated, membranes move from a more “frozen" character to that of a more “fluid" one as the temperature rises. The mid-point of this transition, referred to as the Tm, is influenced by the fatty acid composition of the lipid bilayer compounds. Longer and more saturated fatty acids will favor higher Tm values, whereas unsaturation and short fatty acids will favor lower Tm values. Interestingly, cholesterol does not change the Tm value, but instead widens the transition range between frozen and fluid forms of the membrane.
Figure 3.5.6: Cholesterol
The membrane around cells contains many components, including cholesterol, proteins, glycolipids, glycerophospholipids and sphingolipids. The last two of these will, in water, form what is called a lipid bilayer, which serves as a boundary for the cell that is largely impermeable to the movement of most materials across it. With the notable exceptions of water, carbon dioxide, carbon monoxide, and oxygen, most polar/ionic compounds require transport proteins to help them to efficiently navigate across the bilayer. The orderly movement of these compounds is critical for the cell to be able to 1) get food for energy; 2) export materials; 3) maintain osmotic balance; 4) create gradients for secondary transport; 5) provide electromotive force for nerve signaling; and 6) store energy in electrochemical gradients for ATP production (oxidative phosphorylation or photosynthesis). In some cases, energy is required to move the substances (active transport). In other cases, no external energy is required and they move by diffusion through specific cellular channels.
Figure 3.5.7: Cholesterol in a lipid bilayer.
Figure 3.5.8: Lipid bilayer structure.
The spontaneous ability of these compounds to form lipid bilayers is exploited in the formation of artificial membranous structures called liposomes. Liposomes have some uses in delivering their contents into cells via membrane fusion.
Figure 3.5.9: Liposome, Micelle, and Bilayer Sheet.
Other significant components of cellular membranes include proteins. We can put them into several categories. Integral membrane proteins are embedded in the membrane and project through both sides of the lipid bilayer. Peripheral membrane proteins are embedded in or tightly associated with part of the bilayer, but do not project completely through both sides. Associated membrane proteins are found near membranes, but may not be embedded in them. Their association may arise as a result of interaction with other proteins or molecules in the lipid bilayer. Anchored membrane proteins are not themselves embedded in the lipid bilayer, but instead are attached to a molecule (typically a fatty acid) that is embedded in the membrane.
Figure 3.5.10: Types of membrane proteins.
The geometry of the lipid bilayer is such that is hydrophobic on its interior and hydrophilic on the exterior. Such properties also dictate the amino acid side chains of proteins that interact with the bilayer. For most membrane proteins, the polar amino acids are found where the protein projects through the bilayer (interacting with aqueous/polar substances) and the non-polar amino acids are embedded within the non-polar portion of the bilayer containing the fatty acid tails.
Glycolipids and glycoproteins play important roles in cellular identification. Blood types, for example, differ from each other in the structure of the carbohydrate chains projecting out from the surface of the glycoprotein in their membranes.
Cells have hundreds of membrane proteins and the protein composition of a membrane varies with its function and location. Mitochondrial membranes are among the most densely packed with proteins. The plasma membrane has a large number of integral proteins involved in communicating information across the membrane (signaling) or in transporting materials into the cell.
Materials, such as food and waste must be moved across a cell’s lipid bilayer. There are two means of accomplishing this - passive processes and active processes. Passive processes have as their sole driving force the process of diffusion. In these systems, molecules always move from a higher concentration to a lower concentration. These can occur directly across a membrane (water, oxygen, carbon dioxide, and carbon monoxide) or through special transport proteins (glucose transport proteins of red blood cells, for example). In each case, no cellular energy is expended in the movement of the molecules. On the other hand, active processes require energy to accomplish such transport. A common energy source is ATP (see Na+/K+ ATPase), but many other energy sources are employed. For example, the sodium-glucose transporter uses a sodium gradient as a force for actively transporting glucose into a cell. Thus, it is important to know that not all active transport uses ATP energy. Proteins, such as the sodium-glucose transporter that move two molecules in the same direction across the membrane are called symporters (also called synporters). If the action of a protein in moving ions across a membrane results in a change in charge, the protein is described as electrogenic and if there is no change in charge the protein is described as electro-neutral.
Another important integral membrane protein is the Na+/K+ ATPase (Figure 3.5.11), which transports sodium ions out of the cell and potassium ions into the cell. The protein, which is described as an anti-port (molecules moved in opposite directions across the membrane) uses the energy of ATP to create ion gradients that are important both in maintaining cellular osmotic pressure and (in nerve cells) for creating the ion gradients necessary for signal transmission. The transport system moves three atoms of sodium out of the cell and two atoms of potassium into the cell for each ATP hydrolyzed.
Figure 3.5.11: Sodium-Potassium ATPase.
An interesting integral membrane protein is bacteriorhodopsin. The protein has three identical polypeptide chains, each rotated by 120 degrees relative to the others. Each chain has seven transmembrane alpha helices and contains one molecule of retinal (Vitamin A) buried deep within each cavity (shown in purple in lower figure at left). Vitamin A is light sensitive an isomerizes rapidly between a cis and a trans form in the presence of light. The changing conformation of the vitamin A is used to transport protons through the protein and out of the bacterium, creating a proton gradient across the cell membrane, which is used ultimately to make ATP. It is not too difficult to imagine engineering an organism (say a transparent fish) to contain bacteriorhodopsin in its mitochondrial inner membrane. When light is shone upon it, the bacteriorhodopsin could be used to generate a proton gradient (much like electron transport does) and power oxidative phosphorylation. Such a fish would be partly photosynthetic in that it would be deriving energy from light, but would differ from plants in being unable to assimilate carbon dioxide in a series of “dark reactions."
Figure 3.5.12: Bacteriorhodopsin
Fat Soluble Vitamins
Other lipids of note include the fat-soluble vitamins - A, D, E, and K. Vitamin A comes in three primary chemical forms, retinol (storage in liver), retinal (role in vision), and retinoic acid (roles in growth and development). Vitamin D (cholecalciferol) plays important roles in the intestinal absorption of calcium and phosphate and thus in healthy bones. Derived from ultimately from cholesterol, the compound can be synthesized in a reaction catalyzed by ultraviolet light. Vitamin E (tocopherol) is the vitamin about which the least is known. It consists of a group of eight fat-soluble compounds of which the alpha-isomer has the most biological activity. Vitamin K (the name comes from the German for coagulation vitamin) is essential for blood clotting. It is used as a co-factor for the enzyme that modifies prothrombin to increase its affinity for calcium, allowing it to be positioned closer to the site of a wound.
Figure 3.5.13: Vitamin D
Figure 3.5.14: Top to bottom - Vitamins E, K, and A