A survey of intermediary metabolism

The cardboard box models described in chapters 2 and 3 revealed the relative sizes of cell components. Constructing the models showed how tightly packed cells are. Also, it enabled us to talk about the functions of membranes and the relationships among DNA, RNA, ribosomes and proteins. However, the lentils and gherkins and so on that we put into the boxes were inert. The components of real cells, in contrast, are very active and dynamic. In this chapter we shall start to survey this dynamism.

Everything inside a living cell is continually moving and changing, forming and breaking down. At any instant, many or most of the cell's elementary machines - the protein molecules - are busily engaged in specialised individual activities. The proteins themselves are continually being produced and destroyed ("turned over"). At any instant, each mitochondrion, lysosome and segment of endoplasmic reticulum, every little region in the nucleus and in the cytoplasm, is buzzing with activity, each of its numerous proteins pursuing its appointed task. To describe the cell as a hive of industry would be to understate reality. The cell is a hive of hives of industry.

What sort of industry? Broadly, three kinds of processes are going on:-

  • structures are being assembled and disassembled;
  • chains of chemical reactions are being carried out; and
  • the cell's ingredients, from water and small nutrient molecules to structures as large as mitochondria, are being moved from place to place.

In this chapter we shall focus on the second of these, the chains of chemical reactions, and we shall comment on the assembly and disassembly of structures. In chapter 5 we shall focus on the third class of processes, the cell's internal transport mechanisms.

Cellular metabolism and the complexity of life

The word metabolism was invented by a pioneering cell biologist, Theodor Schwann, in the mid-19th century. Like many words in biology it has Greek roots. Loosely translated it means "transformations of a heap". A cell is a huge cocktail - a heap - of different chemical substances and most of these are continually being transformed into one another.

The chemical reactions taking place in a cell can be grouped in sequences known as pathways. If one reaction converts substance A to substance B, another converts B to C, a third C to D and so on to Y and Z, then we speak of a "pathway" converting A to Z. Each pathway serves one of two main purposes. First, it might liberate energy from the starting material (A) and make it available to the cell. In this case Z must be a smaller and simpler molecule than A and will probably be a waste product; energy is liberated when the other molecules in the pathway are broken down to Z. Second, the pathway might produce a chemical substance that the cell needs for communicating information, building a membrane, replicating the cell, or some other purpose. In this case, Z will be larger and more elaborate than A and the A-to-Z pathway will consume energy. The first type of pathway, the breakdown and energy-liberating sort, is described as catabolic ("down metabolism"). The second, the synthetic sort, is described as anabolic ("up metabolism").

These ideas are simple but they are remote from everyday experience, so let us consider something more familiar. The food you eat is digested in your intestine. Then the products of digestion enter your blood stream and are taken to the various cells in your body4. Inside these cells they are used for producing energy (catabolism) or for manufacturing cell constituents (anabolism). Any nutrients that are surplus to the body's immediate requirements for catabolism and anabolism are put into storage for later use. Our bodies store carbohydrate (glycogen, which is similar to starch, is stored in liver, muscle and certain other cells), and they store fat.

It is easy to see why a growing child, many of whose cells are still actively dividing, needs more food per kilogram of body weight than an adult: she needs it to fuel the considerable energy demands of DNA replication and cell division, as well as to manufacture cell constituents. A cancer victim, who also has actively dividing cells, needs extra fuel for the same reasons but is often too ill to have much appetite. This is why cancer

6 This might seem confusing because in chapter 3 we said that lysosomes digest things inside the (eukaryotic) cell. However, our lysosomes do not digest the food we eat. Our food is fully digested in the intestine, broken down into small nutrient molecules before it gets anywhere near our cells (except the cells lining the intestine). What our lysosomes digest is bacteria, debris from dead cells, and so on that are taken up in endocytotic vesicles. (Single-celled eukaryotes are different in this regard. If you were an amoeba, taking in morsels and digesting them with lysosomes would constitute "eating".)

patients "waste away"; body reserves and healthy tissue, particularly muscle, are broken down to provide nutrients for the cancer cells to keep dividing. Also, it is easy to see that because muscular work burns up energy, physical labour makes you need to eat more. On the other hand if you eat a lot and take little exercise you will grow fat - the excess nutrients will go into storage.

This common knowledge applies to individual cells as well as the whole body. A busy cell, one that is dividing or differentiating or manufacturing hormones for export, needs a lot of energy; so its catabolic pathways are very active. It burns fuel rapidly. A cell that manufactures a hormone must build and maintain the requisite manufacturing and secreting equipment, so the relevant anabolic pathways are active as well. A cell that takes in more nutrients than it needs for its immediate catabolic and anabolic activities converts the excess nutrient into food reserves.

Let us pause to reflect on the sizes of nutrient molecules - the products of food digestion such as glucose - and other molecules involved in metabolism. Recall the "grain of salt" image of a protein molecule in a cell (chapter 3). Proteins are big molecules. If a glucose molecule were magnified to the size of your body, then on the same scale a small protein would be the size of a double-decker bus or a terraced house. On this scale, a prokaryote would be the size of a large city and a eukaryotic cell would be a county. In terms of scale, therefore, a glucose molecule in the middle of a liver cell is like you in the middle of the county of Yorkshire, U. K. But our food produces huge numbers of these tiny molecules. If you eat a meal containing a quarter pound (about 100 grams) of starch - rice, potatoes or bread - and the starch is fully digested to glucose, then the number of glucose molecules produced is around 4400,000,000,000,000,000,000,000. (This is more conveniently written 4 x 1023, which means a 4 followed by 23 zeroes.) Even though the number of cells in your body is vast - you might remember the figure ten million million (1013) - this means there are thousands of millions of glucose molecules per cell. And glucose is only one of many nutrients produced by digestion. It takes the body just one or two hours to process all this material, so an active cell metabolises millions of molecules of glucose (and other nutrients) every second.

These vertiginous sizes, numbers and speeds point to an ineluctable feature of the living state: complexity7. A glucose molecule, broken down

7 "Complexity" is another ambiguous word. In its everyday sense it means the opposite of "simplicity". In modern mathematics it describes a system that borders on the "chaotic" (so sensitive to conditions that it is unpredictable) yet behaves in an ordered and stable way. Both meanings of the word apply in the present context, but for clarity, assume the everyday meaning: the living state is not simple!

by a well-defined catabolic pathway, makes its energy available to the cell. Every reaction step in this pathway (there are about two dozen steps) depends on an enzyme, a protein or a small group of proteins of which the sole purpose is to catalyse that reaction. Every reaction step in every pathway of metabolism depends on a specific, dedicated enzyme. Each enzyme in every pathway - of which there are a great many - is the product of one or more genes. All the enzymes together constitute only a fraction of the proteins that a cell makes; not all proteins are enzymes - some have quite different jobs. Your genome, the totality of your genes, potentially codes for around thirty thousand different proteins, some of which are the enzymes that enable all your metabolic pathways to work.

This huge number of genes, and the corresponding number of proteins, constitutes part of the "mass of information" that is too unwieldy to make a comprehensible distinction between life and non-life (chapter 1). However, the fact of this complexity - the vast array of genes, the enormous variety of proteins, the bewildering network of metabolic pathways - seems to be important in itself. Part of the distinction between living and non-living might be (most biologists would say "is") that a living organism is extraordinarily complex - yet it all hangs, and works, together as an integrated, coherent whole.

Metabolic pathways

Metabolism itself is the current focus of our attention, so let us consider an aspect of metabolism that the mind can grasp: the twenty-four-step pathway of glucose catabolism. The final product of this pathway, the molecule that remains after every last drop of available energy has been squeezed out of the glucose, is carbon dioxide. This is a waste product. We dispose of it through our lungs. A glucose molecule is made up of three sorts of atoms: carbon, hydrogen and oxygen. Carbon dioxide (as the name suggests) is made up of just two sorts of atoms, carbon and oxygen. Hence, during glucose catabolism, the hydrogen atoms have been removed. What happens to them? The mitochondria (remember these are the bacteria-sized structures involved in energy metabolism - the chocolates or cocktail sausages in the box model of chapter 3) turn them into water, which is another waste product. A water molecule, H2O, consists of hydrogen and oxygen atoms. The source of the oxygen is well known: we breathe it in. When the mitochondria combine the hydrogens stolen from the glucose molecule with the oxygen breathed in, they trap the energy released in the form of a molecule known as ATP8.

8 Details of chemistry are not crucial for this book, but just for the record, ATP is short for adenosine 5'-triphosphate: a molecule consisting of adenosine (the base adenine, which is one of the four bases in DNA, attached to a type of sugar called ribose) and a string of

Excreted (kidneys, sweat glands etc.)

Fig. 4-1: glucose catabolism and the formation of ATP.

We have gone into some detail here, partly because this pathway of glucose catabolism is extremely widespread among living organisms, and partly because all catabolic pathways follow a similar general pattern irrespective of the initial nutrient. A molecule containing hydrogen atoms is converted to a waste material containing few or no hydrogens; the stolen hydrogens are dumped, usually (though not always) on to oxygen to form water; and ATP is made in the process. ATP provides the energy that the cell - and the whole organism - needs for synthesising and transporting materials, moving itself or part of itself, assembling structures, replicating, generating heat, sending nerve impulses, doing muscular work, and (if you three phosphate groups. ATP usually makes its energy available by losing its third phosphate; the energy liberated when this happens drives a great number of biological processes including chemical syntheses. When ATP loses the phosphate it turns into ADP (adenosine 5'-diphosphate). During catabolism in the mitochondria, this process is reversed: phosphates are attached to ADP molecules so that ATP is regenerated. Readers who are interested in surprising numbers might wish to reflect on the following. A healthy human body contains about 25 grams of ATP at any instant. However, the total daily amount of ATP synthesised from ADP (and broken down again) is around 10-12 kilograms. The turnover of ATP is very rapid.

Excreted (breathed out)

are a glow-worm or a firefly) producing light. It is the general all-purpose fuel for the activities of life.

This account of catabolism leads directly to three of the seven traditional "defining characteristics" of living organisms: eating, respiring and excreting. These three processes are intimately linked, as the glucose example illustrates. What we eat generates glucose; breathing supplies us with oxygen; excretion disposes of carbon dioxide and water. We introduced another of the traditional properties - reproduction - in chapter 2. The seven traditional properties do not define the living state adequately, but they are not irrelevant. So the fact that four of them have emerged so effortlessly from our discussion suggests that we may be on the right track. The remaining three members of the set (movement, response to stimuli and growth) will emerge during the next few chapters.

Every catabolic pathway involves many steps, though not necessarily twenty-four of them; in other words, between the initial nutrient molecule and the final waste product, there are many intermediates. Some of these intermediates are versatile molecules involved in several different pathways, including anabolic ones. All the products of carbohydrate, fat and protein digestion are converted inside the cell to a pool of inter-convertible intermediates. The intermediates can be either broken down to waste products such as carbon dioxide and water, releasing energy for ATP production, or used to synthesise cell constituents, consuming ATP in the process. Fig. 4-2 shows the connections:-

Products synthesized by the cell

-i water

Cell activities requiring energy

Products synthesized by the cell

-i water

Waste products

Fig. 4-2: an overview of intermediary metabolism, showing how catabolism and anabolism are interconnected.

This diagram does not explicitly mention the storage compounds made from surplus nutrients. However, storage compounds are examples of "products synthesised by the cell". As we mentioned earlier, glucose can be converted to glycogen (animal starch), an important reserve fuel in many types of animal cells. In animals such as humans, excess carbohydrate can also be converted via certain intermediates to fat, which is then stored; some of us are aware of this process from depressing personal experience.

Let us recapitulate. Metabolism forges intimate links between eating, respiring and excreting. The molecules of metabolism are minute compared to protein molecules. They take part in a vastly complex array of chemical processes; complexity seems to be integral to the living state. A metabolic pathway is a sequence of chemical reactions, each dependent on its own specific enzyme (an enzyme is usually a protein or group of proteins). Metabolic pathways can be catabolic (breaking nutrient molecules down to waste products and concomitantly producing ATP, which provides energy for a wide range of life processes) or anabolic (manufacturing new materials from intermediates derived from nutrients). Pathways are not isolated; all metabolic pathways taking place in the same cell are interconnected.

We promise that there will not be so many new ideas in the remainder of this chapter!

Metabolism and cell structure

There is a reciprocal dependence between the components of the cell that we discussed in chapter 3, and the pathways of metabolism that we have introduced in the present chapter. Metabolic pathways depend on cell structure and organisation, and cell structure and organisation depend on metabolism.

In mitochondria, the enzymes necessary for certain stages of catabolism are lined up on the membrane like little workstations along a conveyor belt. The starting material, a metabolic intermediate, is chemically converted by the first enzyme "workstation". The product of this conversion hops directly on to the second enzyme, which is held in an immediately adjacent position; and so on for enzyme after enzyme. This arrangement ensures that the pathway is rapid and efficient. (Changing trains at a succession of railway stations would be like this if the trains ran on schedule and at times - and to places - that suited your needs.) In the endoplasmic reticulum (the membrane system that is concerned with manufacturing processes), similar enzyme arrays ensure the speed and efficiency of anabolic pathways. The molecule being transformed is passed from enzyme to enzyme in the correct sequence and with the minimum of fuss. If the enzymes were not appropriately aligned on the membranes, then speed and efficiency would be lost - perhaps fatally.

The enzymes of some metabolic pathways are not bound to membranes but apparently "free" in the cytoplasm. "Free" is not a literal description, however; they are often linked together in loose assemblies called metabolons, in some cases possibly linked to the cytoskeleton. Individual metabolons are not as durable as membranes but they are another way of organising arrays of enzymes. As in membrane-associated pathways, the molecule being processed is transferred from one enzyme to the next with maximum efficiency. Generally, therefore, the efficiency of cellular metabolism depends on cell structure and organisation.

On the other hand, how are structures such as mitochondrial membranes and endoplasmic reticulum and cytoskeleton and metabolons built and maintained? Their component molecules are - obviously - manufactured by the cell. Their proteins are made by ribosomes, using the instructions on the messenger RNA "photocopy" of the gene. All their other components (lipids and complicated carbohydrates) are made by anabolic pathways. To make or replace any of these components, an anabolic pathway is necessary. All anabolic pathways need ATP, and so does protein synthesis at the ribosomes. So catabolic pathways are necessary as well; there is no other source of ATP. In short: to assemble a cellular structure from its components, or even to disassemble it in a controlled way, metabolites and metabolic pathways are necessary. Cell structure and organisation depend on metabolism.

There is a subtler point: the environment inside a cell can be surprisingly destructive. Chemical derivatives of oxygen can irreversibly alter important molecules, rendering them useless. Therefore, the cell has to protect its molecules against the continual threat of chemical damage. The protective devices that it uses are products of metabolism. Therefore, metabolism is needed to protect and maintain the cell's structures as well as to make, replace, assemble and disassemble them.

Cell structure and organisation are necessary for metabolism and metabolism is necessary for cell structure and organisation. In our view, this absolute and intimate interdependence is part of the essence of "livingness".

Back to Nature

Readers who are interested in wildlife rather than cells or molecules, things that can be seen with the naked eye rather than with sophisticated laboratory equipment, might find this account dissatisfying. However, an understanding of metabolism can help us to appreciate the rural idyll we evoked in chapter 1. Most people know that plants use sunlight to manufacture food (glucose and starch) from carbon dioxide. The process is called photosynthesis. The cell structures involved in photosynthesis are the chloroplasts (the gherkins in the model in chapter 3) Like all metabolic processes, photosynthesis is complicated, but simplified scheme of it looks like this:-

Fig. 4-3: photosynthesis. Note the comparison with Fig. 4-1.

This is almost a double-mirror-image of the scheme of glucose catabolism shown earlier in this chapter. Some of the sunlight energy falling on the green parts of the plant is trapped in the starch. When we eat the plant and digest the starch, our cells catabolise the resulting glucose, making this energy available as ATP, which fuels our life processes. Thus, our body's energy comes indirectly from sunlight. Moreover, the diagram shows that the plant's raw materials, water and carbon dioxide, are the excreted waste products of our catabolism. In return, the plant excretes a waste product, oxygen, that is essential for us. This is typical of the natural world: one organism's waste is another one's food. Ultimately, little is wasted.

The oak tree uses the sun's energy to turn carbon dioxide and water into food. Aphids feed on the sap in the oak's trunk, exploiting this food. The beetle crawling down the trunk eats the aphids. It digests them and metabolises the digestion products to fuel its activities, which include aphid-hunting. If the weasel eats the beetle, it will metabolise the products of digested beetle. When the weasel excretes waste, or dies, various fungi and bacteria in the soil fuel digest weasel excrement or dead weasel. The waste products of these bacteria and fungi include carbon dioxide and water, along with simple nitrogen compounds that the oak can absorb through its roots.

The oak uses these simple compounds to make food for itself - and for aphids. Thus, energy and materials are endlessly recycled among the organisms we see around us (or cannot see because they are microscopic), and the recycling process is solar powered. A collection of different organisms living together in a geographical area and transferring nutrients and energy this way is called an ecosystem. If human industry and commerce were a fraction as efficient as a natural ecosystem at recycling, we would have no serious pollution or resource depletion problems.

The oak, the primrose, the beetle, the weasel and the other living things around us each consist of countless millions of cells. Each cell is specialised to meet one or more of the organism's needs. Each contains intricate structures seething with metabolic activities. Even more remarkably, what we see of life with the unaided eye is the tip of an iceberg; most of the organisms essential to the ecosystem are invisible, but no less wonderful in their workings. As we remarked in chapter 1, knowledge and understanding add to our enchantment. They do not detract from it.

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