Human Metabolism. Keith N. Frayn

The cholesteryl esters are extremely non-polar compounds. This fact will be important when we consider the metabolism of cholesterol in Chapter 10. The long-chain fatty acids may also become esterified with glycerol, forming triacylglycerols (Figure 1.4). Again, the polar properties of both partners are lost, and a very non-polar molecule is formed. This fact underlies one of the most fundamental aspects of mammalian metabolism – the use of triacylglycerol as the major form for storage of excess energy.

Figure 1.6 Cholesterol and a typical cholesteryl ester (cholesteryl oleate). In the structure of cholesterol, not all atoms are shown (for simplicity); each ‘corner’ represents a carbon atom, or else –CH or –CH₂. Cholesterol itself has amphipathic properties because of its hydroxyl group, but when esterified to a long-chain fatty acid the molecule is very non-polar.

      Among amino acids, the branched-chain amino acids, leucine, isoleucine, and valine, have non-polar side chains and are thus amphipathic. The aromatic amino acids phenylalanine and tyrosine are relatively hydrophobic, and the amino acid tryptophan is so non-polar that it is not carried free in solution in the plasma.

      The concept of the polarity or non-polarity of molecules thus has a number of direct consequences for the aspects of metabolism to be considered in later chapters. Some of these consequences are the following:

      1 Lipid fuels – fatty acids and triacylglycerols – are largely hydrophobic and are not soluble in the blood plasma. There are specific routes for their absorption from the intestine and specific mechanisms by which they are transported in blood.

      2 Carbohydrates are hydrophilic. When carbohydrate is stored in cells it is stored in a hydrated form, in association with water. In contrast, fat is stored as a lipid droplet from which water is excluded. Mainly because of this lack of water, fat stores contain considerably more energy per unit weight of store than do carbohydrate stores.

      3 The entry of lipids into the circulation must be coordinated with the availability of the specific carrier mechanisms. In the rare situations in which it arises, uncomplexed fat in the bloodstream may have very adverse consequences.

      1.2.1.2 Osmosis

      The phenomenon of osmosis underlies some aspects of metabolic strategy – it can be seen as one reason why certain aspects of metabolism and metabolic regulation have evolved in the way that they have. It is outlined only briefly here to highlight its relevance.

Osmosis is the way in which solutions of different concentrations tend to even out when they are in contact with one another via a semipermeable membrane. In solutions, the solvent is the substance in which things dissolve (e.g. water) and the solute the substance which dissolves. A semipermeable membrane allows molecules of solvent to pass through, but not those of solute. Thus, it may allow molecules of water but not those of sugar to pass through. Cell membranes have specific protein channels (aquaporins, discussed in Section 2.2.2.6) to allow water molecules to pass through; they are close approximations to semipermeable membranes.

      If solutions of unequal concentration – for instance, a dilute and a concentrated solution of sugar – are separated by a semipermeable membrane, then molecules of solvent (in this case, water) will tend to pass through the membrane until the concentrations of the solutions have become equal. In order to understand this intuitively, it is necessary to remember that the particles (molecules or ions) of solute are not just moving about freely in the solvent: each is surrounded by molecules of solvent, attracted by virtue of the polarity of the solute particles. (In the case of a non-polar solute in a non-polar solvent, we would have to say that the attraction is by virtue of the non-polarity; it occurs through weaker forces such as the van der Waals.) In the more concentrated solution, the proportion of solvent molecules engaged in such attachment to the solute particles is larger, and there is a net attraction for further solvent molecules to join them, in comparison with the more dilute solution. Solvent molecules will tend to move from one solution to the other until the proportion involved in such interactions with the solute particles is equal.

      The consequence of this in real situations is not usually simply the dilution of a more concentrated solution, and the concentration of a more dilute one, until their concentrations are equal. Usually there are physical constraints. This is simply seen if we imagine a single cell, which has accumulated within it, for instance, amino acid molecules taken up from the outside fluid by a transport mechanism which has made them more concentrated inside than outside. Water will then tend to move into the cell to even out this concentration difference. If water moves into the cell, the cell will increase in volume. Cells can swell so much that they burst under some conditions (usually not encountered in the body, fortunately). For instance, red blood cells placed in water will burst (lyse) from just this effect: the relatively concentrated mixture of dissolved organic molecules within the cell will attract water from outside the cell, increasing the volume of the cell until its membrane can stretch no further and ruptures.

      In the laboratory, we can avoid this by handling cells in solutions which contain solute – usually sodium chloride – at a total concentration of solute particles which matches that found within cells. Solutions which match this osmolarity are referred to as isotonic; a common laboratory example is isotonic saline containing 9g of NaCl per litre of water, with a molar concentration of 154 mmol l⁻¹. Since this will be fully ionised into Na⁺ and Cl⁻ ions, its particle concentration is 308 ‘milliparticles’ – sometimes called milliosmoles – per litre. We refer to this as an osmolarity of 308 mmol l⁻¹, but it is not 308 mmol NaCl per litre. (Sometimes you may see the term osmolality, which is very similar to osmolarity, but measured in mmol per kg solvent.)

      The phenomenon of osmosis has a number of repercussions in metabolism. Most cells have a number of different ‘pumps’ or active transporters in their cell membranes which can be used to regulate intracellular osmolarity, and hence cell size. This process requires energy and is one of the components of basal energy expenditure. It may also be important in metabolic regulation; there is increasing evidence that changes in cell volume are part of a signalling mechanism which brings about changes in the activity of intracellular metabolic pathways. The osmolarity of the plasma is maintained within narrow limits by specific mechanisms within the kidney, regulating the loss of water from the body via changes in the concentration of urine. Most importantly, potential problems posed by osmosis can be seen to underlie the metabolic strategy of fuel storage, as will become apparent in later sections.

      1.2.1.3 Reduction-oxidation

      Metabolic energy in living cells is released by the oxidation of relatively large molecular weight substrates containing substantial amounts of chemically available energy (Gibbs ‘free’ energy, G). This is a form of combustion: energy-rich carbon-containing fuel (metabolic substrate) is ‘burnt’ using oxygen, producing water (H₂O) and carbon dioxide (CO₂) as waste products, in the same way as carbon-based domestic fuel (coal, wood) is burnt on a fire using atmospheric oxygen, and releasing its contained energy, with the same end-products. Clearly in metabolism there is no flame, but that is because the gradual release of the energy is controlled so stringently and incrementally.

The term ‘oxidation’ originally referred to the gain of oxygen in a chemical reaction, and the opposite process, ‘reduction,’ to the loss of oxygen (e.g. when metal oxides are heated, they are ‘reduced’ to pure metal, with the loss of oxygen and a reduction in