The Underlying Principles of Human Metabolism
We eat food. We expend energy doing exercise, sleeping, just being. What happens to the food between it entering out mouths and its being used for energy? That’s what metabolic regulation (at least, so far as this book is concerned) is all about.
In order to cover the periods when we are not eating, we need to store metabolic fuels. We store fuel as fat (triacylglycerol) and as carbohydrate (glycogen). Fat provides considerably more energy per gram stored.
Molecules involved in metabolism differ in an important property: polarity. Polar molecules (those with some degree of electrical charge) mix with water (which is also polar); non-polar molecules, which include most lipids (fatty substances), usually don’t mix with water. This has profound implications for the way they are handled in the body.
Some molecules have both polar and non-polar aspects: they are said to be amphipathic. They can form a bridge between polar and non-polar regions. Amphipathic phospholipid molecules can group together to form membranes, such as cell membranes.
The different organs in the body have their own characteristic patterns of metabolism. Substrates flow between them in the bloodstream (circulation). Larger blood vessels divide into fine vessels (capillaries) within the tissues, so that the distances that molecules have to diffuse to or from the cells are relatively small.
Metabolic Regulation in Perspective
To many students, metabolism sounds a dull subject. It involves learning pathways with intermediates with difficult names and even more difficult formulae. Metabolic regulation may sound even worse. It involves not just remembering the pathways, but remembering what the enzymes are called, what affects them and how. This book is not simply a repetition of the molecular details of metabolic pathways. Rather, it is an at-tempt to put metabolism and metabolic regulation into a physiological context, to help the reader to see the relevance of these subjects. Once their relevance to everyday life becomes apparent, then the details will become easier, and more interesting, to grasp.
This book is written from a human perspective because, as humans, it is natural for us to find our own metabolism interesting – and very important for understanding human health and disease. Nevertheless, many of the principal regulatory mechanisms that are discussed are common to other mammals. Some mammals, such as ruminants, have rather specialized patterns of digestion and absorption of energy; such aspects will not be covered in this book.
readmore : how to boost metabolism
A consideration of metabolic regulation might begin with the question: why is it necessary? An analogy here is with mechanical devices, which require an input of energy, and convert this energy to a different and more useful form. The waterwheel is a simple example.
This device takes the potential energy of water in a reservoir – the mill-pond – and converts it into mechanical energy which can be used for turning machinery, for instance, to grind corn. As long as the water flows, its energy is extracted, and useful work is done.
If the water stops, the wheel stops. A motor vehicle has a different pattern of energy intake and energy output (Figure 1.1). Energy is taken in very spasmodically – only when the driver stops at a filling station. Energy is converted into useful work (acceleration and motion) with an entirely different pattern. A long journey might be undertaken without any energy intake.
Clearly, the difference from the waterwheel lies in the presence of a storage device – the fuel tank. But the fuel tank alone is not sufficient: there must also be a control mechanism to regulate the flow of energy from the store to the useful-work-producing device (i.e., the engine). In this case, the regulator is in part a human brain deciding when to move, and in part a mechanical system controlling the flow of fuel.
What does this have to do with metabolism? The human body is also a device for taking in energy (chemical energy, in the form of food) and converting it to other forms. Most obviously, this is in the form of physical work, such as lifting heavy objects.
However, it can also be in more subtle forms, such as producing and nurturing offspring. Any activity requires energy. Again, this is most obvious if we think about performing mechanical work: lifting a heavy object from the floor onto a shelf requires conversion of chemical energy (ultimately derived from food) into potential energy of the object.
But even maintaining life involves work: the work of breathing, of pumping blood around the vascular system, of chewing food and digesting it. At a cellular level, there is constant work performed in the pumping of ions across membranes, and the synthesis and breakdown of the chemical constituents of cells.
What is your pattern of energy intake in relation to energy output? For most of us, the majority of energy intake occurs in three relatively short periods during each 24 hours, whereas energy expenditure is largely continuous (the resting metabolism)
The Chemistry of Food – and of Bodies
Energy is taken into the body in the form of food. The components of food may be classified as macronutrients and micronutrients. Macronutrients are those components present in a typical serving in amounts of grams rather than milligrams or less. They are the well-known carbohydrate, fat, and protein. Water is another important component of many foods, although it is not usually considered a nutrient. Micronutrients are vitamins, minerals, and nucleic acids.
Although these micronutrients play vital roles in the metabolism of the macronutrients, they will not be discussed in any detail in this book, which is concerned with the broader aspects of what is often called energy metabolism.
The links between nutrition and energy metabolism are very close. We eat car-bohydrates, fats, and proteins. Within the body these are broken down to smaller components, rearranged, stored, released from stores, and further metabolized, but essentially whether we are discussing food or metabolism the same categories of car-bohydrate, fat, and protein can be distinguished. This is not surprising since our food itself is of organic origin, whether plant or animal.
In order to understand metabolism and metabolic regulation, it is useful to have a clear idea of some of the major chemical properties of these components.
This is not intended as a treatise in physical or organic chemistry but as a starting point for understanding some of the underlying principles of metabolism.
The discussion assumes a basic understanding of the meaning of atoms and molecules, of chemical reactions and catalysis, and some understanding of chemical bonds (particularly the distinction between ionic and covalent bonding).
Some Important Chemical Concepts
Polarity
nderstood through an appreciation of the nature of polarity of molecules. Polarity refers to the distribution of electrical charge over the molecule. A non-polar molecule has a very even distribution of electrical.
charge over its surface and is electrically neutral overall (the negative charge on the electrons is balanced by the positive charge of the nucleus). A polar molecule has an overall charge, or at least an uneven distribution of charge. The most polar small particles are ions – that is, atoms or molecules which have entirely lost or gained one or more electrons.
However, even completely covalently bonded organic molecules may have a sufficiently uneven distribution of electrical charge to affect their behavior. Polarity is not an all-or-none phenomenon; there are gradations, from the polar to the completely non-polar.
Polarity is not difficult to predict in the molecules which are important in bio-chemistry. We will contrast two simple molecules: water and methane.
Their relative molecular masses are similar – 18 for water, 16 for methane – yet their physical properties are very different. Water is a liquid at room temperature, not boiling until 100 ◦ C, whereas methane is a gas (‘natural gas’) which only liquifies when cooled to
– 161 ◦ C. We might imagine that similar molecules of similar size would have the same tendency to move from the liquid to the gas phase, and that they would have similar boiling points. The reason for their different behaviors lies in their relative polarity.
The molecule of methane has the three-dimensional structure shown in Figure 1.3a. The outer electron ‘cloud’ has a very even distribution over the four hydrogen atoms, all of which have an equal tendency to pull electrons their way.
The molecule has no distinct electrical poles – it is non-polar. Because of this very even distribution of electrons, molecules near each other have little tendency to interact. In contrast, in the water molecule (Figure 1.3b) the oxygen atom has a distinct tendency to pull electrons its way, shifting the distribution of the outer electron cloud so that it is more dense over the oxygen atom, and correspondingly less dense elsewhere.
Therefore, the molecule has a rather negatively charged region around the central oxygen atom, and correspondingly positively charged regions around the hydrogen atoms. Thus, it has distinct electrical poles – it is a relatively polar molecule.
It is easy to imagine that water molecules near to each other will interact. Like electrical charges repel each other, unlike charges attract.
This gives water molecules a tendency to line up so that the positive regions of one attract the negative region of an adjacent molecule (Figure 1.3b).
So water molecules, unlike those of methane, tend to ‘stick together’: the energy needed to break them apart and form a gas is much greater than for methane, and hence water is a liquid while methane is a gas.
The latent heat of evaporation of water is 2.5 kJ/g, whereas that of methane is 0.6 kJ/g. Note that the polarity of the water molecule is not as extreme as that of an ion – it is merely a rather uneven distribution of electrons, but enough to affect its properties considerably.
The contrast between water and methane may be extended to larger molecules. Or-ganic compounds composed solely of carbon and hydrogen – for instance, the alkanes or ‘paraffins’ – all have the property of extreme non-polarity: the chemical (covalent) bond between carbon and hydrogen atoms leads to a very even distribution of elec-trons, and the molecules have little interaction with each other.
A result is that polar molecules, such as those of water, and non-polar molecules, such as those of alkanes, do not mix well: the water molecules tend to bond to each other and to exclude the non-polar molecules, which can themselves pack together very closely because of the lack of interaction between them. In fact, there is an additional form of direct attraction.
between non-polar molecules, the van der Waals forces. Random fluctuations in the density of the electron cloud surrounding a molecule lead to minor, transient degrees of polarity; these induce an opposite change in a neighboring molecule, with the result that there is a transient attraction between them.
These are very weak attractions, how-ever, and the effect of the exclusion by water is considerably stronger. The non-polar molecules are said to be hydrophobic (water fearing or water hating).
A strong contrast is provided by an inorganic ionic compound such as sodium chloride. The sodium and chlorine atoms in sodium chloride are completely ionized under almost all conditions. They pack very regularly in crystals in a cubic form.
The strength of their attraction for each other means that considerable energy is needed to disrupt this regular packing – sodium chloride does not melt until heated above 800 ◦ C. And yet it dissolves very readily in water – that is, the individual ions become separated from their close packing arrangement rather as they would on melting.
Why? Because the water molecules, by virtue of their polarity, are able to come between the ions and reduce their attraction for each other. In fact, each of the charged sodium and chloride ions will become surrounded by a ‘shell’” of water molecules, shielding it from the
attraction or repulsion of other ions. Sodium chloride is said to be hydrophilic – water loving. The terms polar and hydrophilic are for the most part interchangeable. Similarly, the terms non-polar and hydrophobic are virtually synonymous.
Ionic compounds, the extreme examples of polarity, are not confined to inorganic chemistry. Organic molecules may include ionized groups.
These may be almost en-tirely ionized under normal conditions – for instance, the esters of orthophosphoric acid (‘phosphate groups’), as in the compounds AMP, ADP, and ATP, in metabo-lites such as glucose 6-phosphate, and in phospholipids.
Most of the organic acids involved in intermediary metabolism, such as lactic acid, pyruvic acid, and the long-chain carboxylic acids (fatty acids), are also largely ionized at physiological hydrogen ion concentrations . Thus, generation of lactic acid during exercise raises the hydrogen ion concentration (the acidity) both within the cells where it is produced, and generally within the body, since it is released into the bloodstream.
As stated earlier, polarity is not difficult to predict in organic molecules. It relies upon the fact that certain atoms always have electronegative (electron withdrawing) properties in comparison with hydrogen. The most important of these atoms biochem-ically are those of oxygen, phosphorus, and nitrogen. Therefore, certain functional groups based around these atoms have polar properties.
These include the hydroxyl group (—OH), the amino group (—NH2), and the orthophosphate group (—OPO32− ). Compounds containing these groups will have polar properties, whereas those con-taining just carbon and hydrogen will have much less polarity.
The presence of an electronegative atom does not always give polarity to a molecule – if it is part of a chain and balanced by a similar atom this property may be lost. For instance, the ester link in a triacylglycerol molecule (discussed below) contains two oxygen atoms but has no polar properties.
Examples of relatively polar (and thus water-soluble) compounds which will be frequent in this book are sugars (with many —OH groups), organic acids such as lactic acid (with a COO− group), and most other small metabolites. Most amino acids also fall into this category (with their amino and carboxyl groups), although some fall into the amphipathic (‘mixed’) category discussed below.
Another important point about polarity in organic molecules is that within one molecule there may be both polar and non-polar regions. They are called amphipathic compounds. This category includes phospholipids and long-chain fatty acids .
Cell membranes are made up of a double layer of phospholipids, interspersed with specific proteins such as transporter molecules, ion channels and hormone receptors, and molecules of the sterol, cholesterol . The phospholipid bilayer presents its polar faces – the polar ‘heads’ of the phospholipid molecules – to the aqueous external environment and to the aqueous internal environment; within the thickness of the membrane is a non-polar, hydrophobic region.
The physicochemical nature of such a membrane means that, in general, molecules cannot diffuse freely across it: non-polar molecules would not cross the outer, polar face and polar molecules would not cross the inner, hydrophobic region. Means by which molecules move through membranes are discussed in Chapter 2 .
The long-chain fatty acids fall into the amphipathic category – they have a long, non-polar hydrocarbon tail but a more polar carboxylic group head (—COO− ).
acid, —COO− ). Cholesterol (through its —OH group) may become esterified to a long-chain fatty acid, forming a cholesteryl ester (e.g., cholesteryl oleate, Figure 1.6). The cholesteryl esters are extremely non-polar compounds.
This fact will be impor-tant when we consider the metabolism of cholesterol in Chapter 10. The long-chain fatty acids may also become esterified with glycerol, forming triacylglycerols (Fig-ure 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 mam-malian metabolism – the use of triacylglycerol as the major form for storage of excess energy.
Another compound with mixed properties is cholesterol ; its ring sys-tem is very non-polar, but its hydroxyl group gives it some polar properties.
However, the long-chain fatty acids and cholesterol may lose their polar aspects completely when they join in ester links. An ester is a compound formed by the condensation (elimi-nation of a molecule of water) of an alcohol (—OH) and an acid (e.g., a carboxylic acid, —COO− ). Cholesterol (through its —OH group) may become esterified to a long-chain fatty acid, forming a cholesteryl ester (e.g., cholesteryl oleate, Figure 1.6). The cholesteryl esters are extremely non-polar compounds.
This fact will be impor-tant when we consider the metabolism of cholesterol in . The long-chain fatty acids may also become esterified with glycerol, forming triacylglycerols . 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 mam-malian metabolism – the use of triacylglycerol as the major form for storage of excess energy.
Another compound with mixed properties is cholesterol ; its ring sys-tem is very non-polar, but its hydroxyl group gives it some polar properties.
However, the long-chain fatty acids and cholesterol may lose their polar aspects completely when they join in ester links. An ester is a compound formed by the condensation (elimi-nation of a molecule of water) of an alcohol (—OH) and an acid .
Among amino acids, the branched-chain amino acids, leucine, isoleucine, and va-line, 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:
acid, —COO− ). Cholesterol (through its —OH group) may become esterified to a long-chain fatty acid, forming a cholesteryl ester the cholesteryl esters are extremely non-polar compounds. This fact will be impor-tant when we consider the metabolism of cholesterol in .
The long-chain fatty acids may also become esterified with glycerol, forming triacylglycerols . 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 mam-malian metabolism – the use of triacylglycerol as the major form for storage of excess energy.
Another compound with mixed properties is cholesterol ; its ring sys-tem is very non-polar, but its hydroxyl group gives it some polar properties.
However, the long-chain fatty acids and cholesterol may lose their polar aspects completely when they join in ester links. An ester is a compound formed by the condensation (elimi-nation of a molecule of water) of an alcohol (—OH) and an acid (e.g., a carboxylic acid, —COO− ). Cholesterol (through its —OH group) may become esterified to a long-chain fatty acid, forming a cholesteryl ester (e.g., cholesteryl oleate, .
The cholesteryl esters are extremely non-polar compounds. This fact will be impor-tant when we consider the metabolism of cholesterol in Chapter 10. The long-chain fatty acids may also become esterified with glycerol, forming triacylglycerols .
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 mam-malian metabolism – the use of triacylglycerol as the major form for storage of excess energy.
Another compound with mixed properties is cholesterol; its ring sys-tem is very non-polar, but its hydroxyl group gives it some polar properties.
However, the long-chain fatty acids and cholesterol may lose their polar aspects completely when they join in ester links. An ester is a compound formed by the condensation (elimi-nation of a molecule of water) of an alcohol (—OH) and an acid .
Among amino acids, the branched-chain amino acids, leucine, isoleucine, and va-line, 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:
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.
The entry of fats into the circulation must be coordinated with the availabil-ity of the specific carrier mechanisms. In the rare situations in which it arises, uncomplexed fat in the bloodstream may have very adverse consequences.
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 2.2.1.6) 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
The Chemistry of Food – and of Bodies 13
solvent (in this case, water) will tend to pass through the membrane until the concen-trations 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. Sol-vent 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 osmolality are referred to as isotonic; a common laboratory example is isotonic saline containing 9 g of NaCl per liter of water, with a molar concentration of 154 mmol/l. Since this will be fully ionized into Na+ and Cl− ions, its particle concentration is 308 ‘milliparticles’ – sometimes called milliosmoles – per liter. We refer to this as an osmolarity of 308 mmol/l, but it is not 308 mmol NaCl per liter. (Sometimes you may see the term osmolality, which is 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 signaling 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.
The Chemical Characteristics of Macronutrients
Carbohydrates
Simple carbohydrates have the empirical formula Cn(H2O)n; complex carbohydrates have an empirical formula which is similar to this (e.g., Cn(H2O)0.8n).
The name carbohydrate reflects the idea, based on this empirical formula, that these compounds are hydrates of carbon. It is not strictly correct, but illustrates an important point about this group of compounds – the relative abundance of hydrogen and oxygen, in proportions similar to those in water, in their molecules.
From the discussion above, it will be apparent that carbohydrates are mostly relatively polar molecules, miscible with, or soluble in, water.
Carbohydrates in nature include the plant products starch and cellulose and the mammalian storage carbohydrate glycogen, as well as various simple sugars, of which glucose is the most important from the point of view of human metabolism. The main source of carbohydrate we eat is the starch in vegetables such as potatoes, rice, and grains.
The chemical definition of a sugar is that its molecules consist of carbon atoms, each bearing one hydroxyl group (—OH), except that one carbon bears a carbonyl group (==O) rather than a hydroxyl. In solution, the molecule exists in equilibrium between a ‘straight-chain’ form and a ring structure, but as the ring structure pre-dominates sugars are usually shown in this form .
Nevertheless, some of the chemical properties of sugars can only be understood by remembering that the straight-chain form exists. The basic carbohydrate unit is known as a monosaccharide. Monosaccharides may have different numbers of carbon atoms, and the terminology reflects this: thus, a hexose has six carbon atoms in its molecule, a pentose five, and so on.
Pentoses and hexoses are the most important in terms of mammalian metabolism. These sugars also have ‘common names’ which often reflect their natural occurrence. The most abundant in our diet and in our bodies are the hexoses glucose (grape sugar, named from the Greek glykys sweet), fructose (fruit sugar, from the Latin fructus for fruit), and galactose (derived from lactose, milk sugar; from the Greek galaktos, milk), and the pentose ribose, a constituent of nucleic acids (the name comes from the related sugar arabinose, named from Gum arabic).
Complex carbohydrates are built up from the monosaccharides by covalent links between sugar molecules.
The term disaccharide is used for a molecule composed of two monosaccharides (which may or may not be the same), oligosaccharide for a short chain of sugar units, and polysaccharide for longer chains (> 10 units), as found in starch and glycogen.
Disaccharides are abundant in the diet, and again their common names often denote their origin: sucrose (table sugar, named from the French, sucre), which contains glucose and fructose ;
maltose (two glucose molecules) from malt; lactose (galactose and glucose) from milk. The bonds between individual sugar units are relatively strong at normal hydrogen ion concentrations, and sucrose (for instance) does not break down when it is boiled, although it is steadily broken down in acidic solutions such as cola drinks; but there are specific enzymes in the intestine which hydrolyze these bonds to liberate the individual monosaccharides.
Polysaccharides differ from one another in a number of respects: their chain length, and the nature (α- or β -) and position (e.g., ring carbons 1–4, 1–6) of the links between individual sugar units. Cellulose consists mostly of β -1,4 linked glucosyl units; these links give the compound a close-packed structure which is not attacked by mammalian enzymes.
In humans, therefore, cellulose largely passes intact through the small intestine where other carbohydrates are digested and absorbed. It is broken down by some bacterial enzymes. Ruminants have complex alimentary tracts in which large quantities of bacteria reside, enabling the host to obtain energy from cellulose, the main constituent of its diet of grass.
In humans there is some bacterial digestion in the large intestine . Starch and the small amount of glycogen in the diet are readily digested .
The structure of glycogen is illustrated in Figure 1.8. It is a branched polysaccha-ride. Most of the links between sugar units are of the α-1,4 variety but after every 9–10 residues there is an α-1,6 link, creating a branch. Branching makes the molecules more soluble, and also creates more ‘ends’ where the enzymes of glycogen synthesis and breakdown operate. Glycogen is stored within cells, not simply free in solution but
in organized structures which may be seen as granules on electron microscopy. Each glycogen molecule is synthesized on a protein backbone, or primer, glycogenin. Carbo-hydrate chains branch out from glycogenin to give a relatively compact molecule called proglycogen.
The glycogen molecules that participate in normal cellular metabolism are considerably bigger , typically with molecular weights of several mil-lion. The enzymes of glycogen metabolism are intimately linked with the glycogen granules.
The carbohydrates share the property of relatively high polarity. Cellulose is not strictly water soluble because of the tight packing between its chains, but even cel-lulose can be made to mix with water (as in paper pulp or wallpaper paste).
The polysaccharides tend to make ‘pasty’ mixtures with water, whereas the small oligo-, di-, and monosaccharides are completely soluble. These characteristics have im-portant consequences for the metabolism of carbohydrates, some of which are as follows:
Glucose and other monosaccharides circulate freely in the blood and interstitial fluid, but their entry into cells is facilitated by specific carrier proteins.
Perhaps because of the need for a specific transporter for glucose to cross cell membranes (thus making its entry into cells susceptible to regulation), glucose is an important fuel for many tissues, and an obligatory fuel for some. Carbohydrate cannot be synthesized from the more abundant store of fat within the body. The body must therefore maintain a store of carbohydrate.
Because of the water-soluble nature of sugars, this store will be liable to os-motic influences: it cannot, therefore, be in the form of simple sugars or even oligosaccharides, because of the osmotic problem this would cause to the cells.
This is overcome by the synthesis of the macromolecule glycogen, so that the osmotic effect is reduced by a factor of many thousand compared with monosac-charides. The synthesis of such a polymer from glucose, and its breakdown, are brought about by enzyme systems which are themselves regulated, thus giving the opportunity for precise control of the availability of glucose.
Glycogen in an aqueous environment (as in cells) is highly hydrated; in fact, it is always associated with about three times its own weight of water. Thus, storage of energy in the form of glycogen carries a large weight penalty .
Fats
Just as there are many different sugars and carbohydrates built from them, so there are a variety of types of fat. The term fat comes from Anglo-Saxon and is related to the filling of a container or vat. The term lipid, from Greek, is more useful in chemical discussions since ‘fat’ can have so many shades of meaning. Lipid materials are those substances which can be extracted from tissues in organic solvents such as petroleum or chloroform. This immediately distinguishes them from the largely water-soluble carbohydrates.
Among lipids there are a number of groups . The most prevalent, in terms of amount, are the triacylglycerols or triglycerides, referred to in older literature.
as ‘neutral fat’ since they have no acidic or basic properties. These compounds consist of three individual fatty acids, each linked by an ester bond to a molecule of glycerol. As discussed above, the triacylglycerols are very non-polar, hydrophobic compounds.
The phospholipids are another important group of lipids – constituents of membranes and also of the lipoprotein particles which will be discussed in Chapter 10. Steroids – compounds with the same nucleus as cholesterol (Figure 1.6) – form yet another important group and will be considered in later chapters, steroid hormones in Chapter 6 and cholesterol metabolism .
Fatty acids are the building blocks of lipids, analogous to the monosaccharides. The fatty acids important in metabolism are mostly unbranched, long-chain (12 car-bon atoms or more) carboxylic acids with an even number of carbon atoms.
They may contain no double bonds, in which case they are referred to as saturated fatty acids, one double bond (mono-unsaturated fatty acids), or several double bonds – the polyunsaturated fatty acids. Many individual fatty acids are named, like monosaccha-rides, according to the source from which they were first isolated. Thus, lauric acid (C12, saturated) comes from the laurel tree, myristic acid (C14, saturated) from the Myristica or nutmeg genus, palmitic acid (C16, saturated) from palm oil, and stearic acid (C18, saturated) from suet (Greek steatos). Oleic acid (C18, mono-unsaturated) comes from the olive (from Latin: olea, olive, or oleum, oil). Linoleic acid (C18 with two double bonds) is a polyunsaturated acid common in certain vegetable oils; it is obtained from linseed (from the Latin linum for flax and oleum for oil).
The fatty acids mostly found in the diet have some common characteristics. They are composed of even numbers of carbon atoms, and the most abundant have 16 or 18 carbon atoms. There are three major series or families of fatty acids, grouped according to the distribution of their double bonds .
Differences in the metabolism of the different fatty acids are not very important from the point of view of their roles as fuels for energy metabolism. When considering the release, transport and uptake of fatty acids the term non-esterified fatty acids will therefore be used without reference to particular molecular species. In a later section some differences in their effects on the serum cholesterol concentration and propensity to heart disease will be discussed.
It will be seen from Figures 1.4 and 1.9 that saturated fatty acids, such as palmitic (16:0), have a natural tendency to fit together in nice orderly arrays.
The unsaturated fatty acids, on the other hand, have less regular shapes . This is reflected in the melting points of the corresponding triacylglycerols – saturated fats, such as beef suet with a high content of stearic acid (18:0), are relatively solid at room temperature, whereas unsaturated fats, such as olive oil, are liquid.
This feature may have an important role in metabolic regulation, although its exact significance is not yet clear. We know that cell membranes with a high content of unsaturated fatty acids in their phospholipids are more ‘fluid’ than those with more saturated fatty acids.
This may make them better able to regulate metabolic processes – for instance, muscle cells with a higher content of unsaturated fatty acids in their membranes respond better to the hormone insulin, probably because the response involves the movement of proteins (insulin receptors, glucose transporters) within the plane of the membrane (discussed in Box 2.4, p. 48), and this occurs faster if the membrane is more fluid.
Proteins
Proteins are chains of amino acids linked through peptide bonds. Individual proteins are distinguished by the number and order of amino acids in the chain – the sequence, or primary structure. Within its normal environment, the chain of amino acids will assume a folded, three-dimensional shape, representing the secondary structure (local folding into α-helix and β -sheet) and tertiary structure (folding of the complete chain on itself). Two or more such folded peptide chains may then aggregate (quaternary structure) to form a complete enzyme or other functional protein.
In terms of energy metabolism, the first aspect we shall consider is not how this beautiful and complex arrangement is brought about; we shall consider how it is destroyed.
Protein in food is usually denatured (its higher-order structures disrupted) by cooking or other treatment, and then within the intestinal tract the disrupted chains are broken down to short lengths of amino acids before absorption into the bloodstream.
Within the bloodstream and within tissues we shall be concerned with the transport and distribution of individual amino acids. These are mostly sufficiently water soluble to circulate freely in the aqueous environment of the plasma.
Only tryptophan is sufficiently hydrophobic to require a transporter; it is bound loosely (like the non-esterified fatty acids) to albumin. Amino acids, not surprisingly, do not cross cell membranes by simple diffusion; there are specific transporters, carrying particular groups of amino acids.
Protein is often considered as the structural material of the body, although it should not be thought of as the only structural material; it can only assume this function because of the complex arrangements of other cellular constituents, especially phospholipids forming cell membranes. Nevertheless, apart from water, protein is the largest single component in terms of mass of most tissues.1 Within the body, the Two important exceptions are mature white adipose tissue, in which triacylglycerol is the major constituent by weight, and the brain, of which 50–60% of dry weight is lipid (mostly phospholipid).
majority of protein is present in the skeletal muscles, mainly because of their sheer weight (around 40% of the body weight) but also because each muscle cell is well packed with the proteins (actin and myosin) which constitute the contractile apparatus.
But it is important to remember that most proteins act in an aqueous environment and are, therefore, associated with water. This is relevant if we consider the body’s protein reserves as a form of stored chemical energy. Since protein is associated with water, it suffers the same drawback as a form of energy storage as does glycogen;
with every gram of protein are associated about three grams of water. It is not an energy-dense storage medium. Further, although protein undoubtedly represents a large source of energy that is drawn upon during starvation, it should be remembered that there is, in animals, no specific storage form of protein; all proteins have some function other than storage of energy.
Thus, utilization of protein as an energy source involves loss of the substance of the body. In evolutionary terms we might expect that this will be minimized (i.e., the use of the specific storage compounds glycogen and triacylglycerol will be favored) and, as we shall see in later chapters, this is exactly the case.
Blood, Blood Plasma and Serum
The blood itself is an aqueous environment, consisting of the liquid plasma – a solu-tion of salts, small organic molecules such as glucose and amino acids, and a variety of peptides and proteins – and the blood cells, mostly red blood cells (erythrocytes).
The erythrocyte membrane is permeable to, or has carriers for, some molecules but not others. Glucose, for instance, partially equilibrates across the erythrocyte mem-brane. Its concentration is somewhat lower inside the cell than outside, since the erythrocyte uses some for glycolysis and transport across the cell membrane must be somewhat limiting for this process.
But nevertheless, glucose and some amino acids are carried around both in blood cells and in the plasma. On the other hand, lipid molecules are excluded from red blood cells and carried in the plasma. On the whole, the term ‘in the plasma’ will be used for those substances confined to that compart-ment, and ‘in the blood’ or ‘in the bloodstream’ for those which are carried in both compartments.
If blood is allowed to clot and then centrifuged, a yellow fluid can be removed: this is serum. It is like plasma but lacks the protein fibrinogen, which is used in the clotting process. Serum is often collected from patients for measurement of the concentration of cholesterol or triacylglycerol, mainly because it is convenient to let the blood clot.
The term ‘serum cholesterol,’ for instance, then simply refers to the concentration of cholesterol in the serum; it would be almost exactly the same as the plasma cholesterol concentration.
Lymph and Lymphatics
The interstitial fluid is formed by filtration of the blood plasma through the endothe-lium (vessel lining), as described earlier.
Some of the fluid which leaves the bloodstream in this way will naturally find its way back to the blood vessels, but some is drained away from tissues in another series of vessels, the lymphatics. These are for the most part smaller than blood vessels.
The fluid within them, the lymph, resembles an ultra-filtrate of plasma – that is, it is like plasma but without red blood cells and without some of the larger proteins of plasma. The lymphatic vessels merge and form larger vessels and eventually discharge their contents into the bloodstream. We shall be con-cerned with one particular branch of the lymphatic system – that which drains the walls of the small intestine.
The products of fat digestion enter these lymphatic vessels, which collect together and form a duct running up the back of the chest, known as the thoracic duct. The thoracic duct discharges its contents into the bloodstream in the upper chest. The lymphatic system also plays an important role in defense against infection, but this immunological role is beyond the scope of this book.
source : www.semanticscholar.org
