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Making energy available — cellular respiration

Although products of the digestion of all three food types – carbohydrates, proteins and lipids – all follow some common pathways for energy conversion, one usually attacks this subject by considering carbohydrate digestion, as this allows a linear presentation of the entire sequence – glycolysis, rhe Krebs cycle and chemiosmotic phosphorylation (the electron transport chain). Afterwards, we will consider how the other two types enter into the same processes.

Glucose is the body’s principal fuel supply and is carried by the blood to all cells. In each cell’s mitochondria, glucose is broken down by cellular respiration, a series of reactions which use various enzymes to convert the glucose into water and CO2 and release the energy needed by metabolism. The overall reaction forming the basis of cellular respiration is

C6H12O6 + 6O2 → 6H2O + 6CO2 + energy

i.e.,

glucose + oxygen → water + carbon dioxide + energy

where the energy is principally stored in molecules of ATP, the body’s “energy currency”. ATP serves as a transport agent, carrying the energy from mitochondria to elsewhere in the cells, which need it in order to function.

There are several sets of reactions capable of breaking down glucose to store energy in ATP molecules. The three main ones are

  • glycolysis,
  • the Krebs cycle (or citric-acid cycle or TCA cycle) and
  • oxidative phosphorylation (the electron transport chain).

Each set is called a pathway. Taken in sequence, they together are referred to as cellular respiration. This step-by-step process has two functions:

  1. Ensure energy is released in small, controlled quantities; and
  2. make the activation energy necessary for each step small enough to be adequately lowered by an appropriate enzyme.

Glycolysis

The first pathway, glycolysis, is a series of reactions which take place in the cytoplasm of the cell and convert one glucose molecule into two pyruvate molecules. The overall equation is:1Coenzyme electron carriers NAD and FAD were discussed in the last chapter.

glucose + 2 ATP + 2 NAD+ + 4 ADP + 2 Pi → 2 pyruvate + 4 ATP + 2 NADH + 2 H+

Each step of this pathway (and all the others) is brought about by an enzyme.The following table indicates the steps of glycolysis in some detail.

Step

Input

Output

Enzyme

1

glucose + ATP

glucose-6-phosphate (G6P)

hexokinase (or glucokinase, if in the liver)

2

glucose-6-phosphate

fructose-6-phosphate (P6P)

glucose-6-phosphate polymerase

3

fructose-6-phosphate + ATP

fructose-1,6-biphosphate

phosphofructokinase

4

fructose-1,6-biphosphate (split)

glyceraldehyde-3-phosphate + dihydroxyacetone phosphate

aldelase

5

dihydroxyacetone phosphate

glyceraldehyde-3-phosphate

triosephosphate isomerase

End energy-consuming, start of energy-yielding phase: Glucose now converted into two glyceraldehyde-3-phosphate

6

2 glyceraldehyde-3-phosphate + 2 Pi + 2 NAD+

2 1,3-biphosphoglycerate + 2 NADH

glyceraldehyde-3-phosphate dehydrogenase

7

2 1,3-biphosphoglycerate + 2 ADP (dephosphorylation)

2 3-phosphoglycerate + 2 ATP

phosphoglycerate kinase

8

2 3-phosphoglycerate

2 2- phosphoglycerate

phosphoglycerate mutase

9

2 2- phosphoglycerate

2 phosphoenolpyruvate (PEP)

enolase

10

2 phosphoenolpyruvate + 2 ADP + 2H+ (dephosphorylation)

2 pyruvate + 2 ATP

pyruvate kinase

Step (6) is important for two reasons. First, it is the one where the Pi necessary to convert ADP into ATP comes into the action. After step (6), the Pi is no longer free and the conversion is now energetically favorable and takes place in the step (7). A similar step produces another pair of ATP molecules in step (10). Step (6) also includes the reduction of NAD+, whereby it collects electrons which it will carry to oxidative phosphorylation..

The glycolysis pathway is used by almost every organism on Earth, including prokaryotes, so it must have evolved very early in the history of life.

 

Glycolysis overview, from Openstax College

Glycolysis overview, from Openstax College

Notice that glycolysis does not require oxygen in order to proceed; it is an example of anaerobic respiration.

Ignoring those complex chemical names, the table shows that each step is chaperoned, so to speak, by a different enzyme. It also shows that although the overall process is to convert glucose to pyruvate, it requires two ATP to get started (input column) but produces four (output column), for a net gain of two ATP.

The Krebs cycle

Recall the overall view of cellular respiration:

C6H12O6 + 6O2 → 6H2O + 6CO2 + energy

i.e.,

glucose + oxygen → water + carbon dioxide + energy

The Krebs cycle (or citric acid cycle, or TCA, tricarboxylic acid cycle) takes place within the matrix of a mitochondrion. The pyruvate molecules formed by glycolysis in the cytoplasm of the cell pass into the mitochondrial matrix,but pyruvate can not enter directly into the Krebs cycle. It is first converted by the enzyme pyruvate dehydrogenase as follows:

  • one C and two O atoms are removed as CO2 (decarboxylation);
  • the pyruvate is oxidized and its electrons serve to reduce NAD+ to NADH + H+;
  • finally, coenzyme-A is added to produce acetyl-CoA, which enters the Krebs cycle.

This is shown at the top of the following figure. This step has been referred to variously as the linking step, the grooming step or the bridging step, but I prefer the preparation step – or prep step.

The steps of the Krebs cycle are the following:

  1. The citrate synthase enzyme (always enzymes) joins the 2-carbon acetyl-CoA with a 4-carbon molecule of oxaloacetate to form a 6-carbon molecule, citrate (or citric acid, hence one of the names of the cycle). As it traverses the cycle, this molecule will lose carbon atoms to become once again a 4-carbon oxaloacetate molecule, which can start the cycle over again with the addition of some acetyl-CoA. But along the way, Good Things will be produced.
  2. Another enzyme, aconitase, converts citrate into isocitrate by a “simple” rearrangement of its bonds.
  3. A further enzyme, isocitrate dehydrogenase, oxidizes isocitrate into 5-carbon α‑ketoglutarate.2Gulp! Carbon is released as CO2 and electrons serve to reduce NAD+ to NADH + H+, with a gain of one NADH + H+.
  4. Yet another enzyme α‑ketoglutarate dehydrogenase converts α‑ketoglutarate into 4-carbon succynal CoA. Once again, CO2 is released and oxidized electrons reduce NAD+ to NADH + H+, for a gain of one more NADH + H+.
  5. The enzyme succynal CoA dehydrogenase converts succynal CoA into succinate. This reaction is exergonic and the released energy serves to form GTP, guanosine triphosphate, similar to ATP, which in turn furnishes energy to convert ADP into ATP. A different enzyme would produce ATP directly. That makes a gain of one ATP.
  6. Succinate dehydrogenase converts succinate into fumarate. The oxidized electrons are passed to the electron carrier FAD which is reduced to FADH2, so there is a gain of one FADH2.
  7. Fumarase catalyzes the addition of a water molecule to fumarate to form malate.
  8. Malate dehydrogenase oxidizes malate back to oxaloacetate (back to step 1). The electrons reduce NAD+ to NADH + H+, so one more NADH + H+ is gained.
The Krebs cycle, from OPenstax College

The Krebs cycle, from Openstax College

Note that one glucose molecule makes two pyruvates and so brings about two “turns” of the Krebs cycle. The oxidation steps in one cycle result in a gain of three NADH + H+, one FADH2 and one ATP.

Chemiosmotic theory of oxidative phosphorylation – electron transport chain

The Krebs cycle may be a great advantage over glycolysis in terms of efficiency of ATP production, but the electron transport chain (ETC), where oxidative phosphorylation takes place, has them both beat hollow.3When I first read about it, I was giggling with joy. Oxidative phosphorylation takes the electrons carried by NADH and FADH2 produced in the Krebs cycle and uses them to produce more ATP – much more.

Recall that NAD and FAD are electron carriers, picking up electrons as they are reduced to NADH and FADH2 as follows:

NAD+ + 2e + 2H+ → NADH + H+

and

FAD + 2e + 2H+ →FADH2

and leaving them off as they are oxidized to NAD+ and FAD in the opposite reactions (just invert the arrows).

In the electron transport chain the NADH and FADH2 produced in the Krebs cycle, with the help of two coenzymes, transport electrons to the first of a series of four enzyme complexes in the inner mitochondrion membrane. Each complex is reduced as it receives an electron and oxidized as it passes it on to the next complex, somewhat like a bucket brigade (or a relay race). The electron is passed along because each successive complex is more electronegative (electron loving) than the preceding one. (One also says it goes from a complex of higher reducing potential to a lower one.) The energy produced by the redox reactions at each complex serves to pump protons across the inner mitochondrial membrane into the inter-membrane matrix.

At the end, the electrons are passed to oxygen which uses them to combine with the residual hydrogen to produce water. The left-over re-oxidized NAD+ and FAD can return to glycolysis and the Krebs cycle to pick up more electrons.

Here is the amazing part! The gradually built-up proton gradient becomes sufficiently strong to power an incredible-seeming object in the inner mitochondrion membrane, an enzyme called the ATP synthase. The protons passing through it actually cause it to turn and to power the combination of ADP with phosphate radicals to produce ATP in large quantities. This synthesis of ATP by adding Pi to ADP with the energy from a proton gradient is called chemiosmotic phosphorylation.4Gulp!

In summary, the overall function of the ETC Is to use the energy of electrons from reduced NADH and FADH2 to pump H+ across the inner mitochondrial membrane into the inter-membrane matrix so that the built-up electrical potential can power the synthesis of ATP by ATP synthase.

Look at cellular respiration with the accounting data added as in the following figure The accounting is clear. Oxidative phosphorylation can produce up to 34 ATP molecules per glucose molecule entering the glycolysis pathway, for a total of 36 ATP in cellular respiration. This is where we get most of our energy.

ATP production in cellular respiration, from Openstax College

ATP production in cellular respiration, from Openstax College

The system exists in one form or another in all eukaryotes and serves also in photosynthesis in plants to make the energy necessary for producing glucose.

The process can be broken down into the electron transport chain (ETC), the four complexes on the left in the following figure, and ATP Synthase, the red complex on the right. We will ignore the details of the many redox reactions taking place in each complex.

Oxidative phosphorylation (electron transport chain), author's own work

Oxidative phosphorylation (electron transport chain), author’s own work

Consider the electrons transported to the ETC by one NADH. Note that only complexes 1, 3 and 4 pump protons across the membrane. Complex 1 accepts electrons from NADH, complex 2, from FADH2.

  1. One NADH is oxidized by complex 1 (C1), NADH dehydrogenase, to give up two e and one H+. For each electron, two H+ are pumped from the matrix across the inner membrane. Various reactions take place within the complex, but we will treat it as a black box.
  2. Both e are transferred to ubiquinone (or coenzyme Q), a mobile transfer molecule. CoQ is hydrophobic and so can move about within the membrane, by which means it delivers the e to complex C3, cytochrome b-c1, bypassing complex 2. The e are passed one at a time to cytochrome c (another mobile transfer molecule). For each e accepted by cytochrome c, two more H+ are pumped across the inner membrane. Again, more is taking place than meets the eye.
  3. Cytochrome c moves back and forth along the inner side of the inner membrane and so delivers the e one at a time to complex C4, cytochrome c oxidase. When C4 has received four e, it can use them to reduce an oxygen molecule, which is therefore the last electron acceptor in the chain: The four e, four H+ and the O2 form two water molecules, while four H+ are pumped across the membrane into the inter-membrane space..
  4. As shown in the figure, FADH2 delivers its e directly to complex C2, which does not pump H+. The e are passed to CoQ and then follow the same path as the other e-.
  5. The electric potential brought about by the H+ inside the cell membrane drives them across the membrane through the ATP Synthase, as the membrane itself is impervious to H+. Three H+ are necessary to make one molecule of ATP.

Many such chains exist in every mitochondrion’s inner membrane, so multiple H+ pumps are running all the time, converting glucose and oxygen into energy stored in ATP.

Other energy sources – energy production from metabolic pathways

We have considered glycolysis, the Krebs cycle and the ETC as components of the carbohydrate metabolic pathway. But we can also get energy from lipids and proteins using parts of the same pathway.

Lipids

In a recent episode, we left lipids inside chylomicrons or other lipoproteins in the blood, or in the liver or muscles. In order to use lipids for energy, triglycerides in the liver or muscle are converted by lipolysis to glycerol and fatty acyl CoA. Acyl CoA is then carried by carnitine into the mitochondria of the cells, where, it is converted back to fatty acids, which are degraded by the cyclic process of β-oxidation. Each loop of this process converts a two-carbon segment into acetyl-CoA, shortening the chain by two carbon atoms at each cycle. The acetyl-CoA enters directly into the Krebs cycle of cellular respiration, bypassing the glycolysis stage necessary for glucose. Since the products of the Krebs cycle also feed the electron transport chain, converted lipids can furnish a lot of energy.

Compared to carbohydrates and proteins, triglycerides can furnish more than twice the energy per unit mass. So when glucose levels become inadequate, triglycerides stored in the liver or muscle are hydrolyzed to fatty acids which, again, must be transported through the blood, this time by albumins, globular proteins in the plasma. The rate of conversion and transport of fatty acids is great enough that they can be oxidized to fulfill almost all the body’s energy needs without the need of energy from carbohydrates. Most cells except brain tissue and red blood cells can get their energy from fatty acids – as long as they last.

But some cells need glucose for energy production. Red blood cells have no mitochondira for β-oxidation and fats cannot cross the blood-brain barrier to enter the brain. The brain only represents about 2% of body weight, but it consumes on the order of 20% of metabolic energy, the greater part of which is to maintain electric potentials. So the brain needs energy continuously and quickly, which explains why we tend to black out after only a few seconds lack of oxygen in the blood. If the body’s supply of carbohydrates becomes too low, the liver goes to work, converting stored glycogen back into glucose (glycogenolysis) or synthesizing glucose from lactate, pyruvate, glycerol or amino acids alanine or glutamine (gluconeogenesis). This may happen when eating mostly fats or when fasting,

The liver stores a large quantity of fatty acids, but uses only a small part of these for its own energy requirements. So when carbohydrate stores (including glycogen) are low, great use is made of fats for energy. But, due to lack of intermediary substances, the Krebs cycle slows down. Excess acetyl-CoA accumulates in the liver, where it is combined in pairs to form acetoacetic acid which is then carried by the blood to other cells. Some of it is converted to β-hydroxybutyrate and acetone, large quantities of which can be transported rapidly to cells.5Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same. These two substances plus acetoacetic acid are collectively referred to as ketone bodies and their synthesis from fats is called ketogenesis. On arriving in cells, all three are converted back into acetyl-CoA, which enters the Krebs cycle. This Is interesting because, in such circumstances, the brain may lack energy because fats can not cross the blood-brain barrier to supply it. But ketone bodies can. So the brain goes from glucose input to ketone bodies without ever using fats. In fact, ketone bodies are produced all the time, even in a healthy body. They are not bodies, but water-soluble liquids. They are so named because one of them is acetone.

In brief, fats stored as triglycerides in the liver may be modified to ketone bodies and enter cells where they are transformed into acetyl-CoA and enter the Krebs cycle, including in the brain.

Proteins

Proteins can also contribute to energy production. While some amino acids are used to re-form proteins (biosynthesis via gene expression) which are then used or stored, some remain. Most of these are converted by deamination, removal of amino groups (-NH2) from the acids, a process occuring almost entirely in the liver. Most of the time, the amino group is transferred to α-ketoglutanate, which thereby becomes an amino acid, glutamate. A >C=O group from the α-ketoglutanate replaces the original amino group, converting the amino acid into a keto acid. So the transfer is really transamination. Here is the interesting part. The amino acid alanine is transaminated to pyruvate; aspartate, to oxaloacetate; and almost all the others, to molecules (pyruvate, acetoacetyl CoA, fumarate, succinyl CoA, oxaloacetate and α-ketoglutamate) which figure somewhere in the Krebs cycle. So all our major nutrients wind up sooner or later participating in the Krebs cycle to make ATP.1 The number of ATP molecules obtained from a gram of oxidized protein is slightly less than that from a gram of oxidized glucose.

In order to avoid its poisoning us, ammonia left over from deamination must be removed and this is carried out by the Urea cycle.

Some of the keto acids can be modified to enter the Krebs cycle, like glucose or glucose products, and so are called glucogenic; others form ketone bodies (ketogenesis) and are called ketogenic. So ketone bodies may be the product of lipids or proteins.

Metabolic pathways for ATP synthesis from foods

Excess protein can turn to fat, too. If more protein than can be used for amino acids is consumed, much of the excess is converted and stored as fat or glycogen (gluconeogenesis). From here on, it follows the course of any other fat or glycogen.

Order of use

The preferred order of nutrients for energy is simple: Carbohydrates come first. But even the glycogen stored mainly in the liver can only furnish the body in fuel for maybe a half day. If carbohydrates run out, fats and proteins start to be used, principally fats. Use of fats continues approximately linearly until they run out. At the same time, stored amino acids are converted by gluconeogenesis to glucose. When the easily-accessed amino-acid store is reduced, fat usage increases and some of this is converted to ketone bodies, which can enter the brain and supply energy to it. However, changing from a carbohydrate-rich to a fat diet may require several weeks for brain cells to switch to obtaining up to 75% of their energy from fats (via ketone bodies).

We have seen that excess carbohydrates can be transformed into fat. Although such fats from carbohydrates also can be converted to acetyl-CoA to make energy, they can never be converted back into carbohydrates.

Anaerobic respiration

As its name implies, oxidative phosphorylation is an aerobic pathway, requiring oxygen. The electron transport chain requires oxygen for the penultimate step of adding H+ ions to O2 to make water. In the absence of oxygen, this cannot take place. If oxygen is lacking, energy must be obtained differently.

Glycolysis requires no oxygen other than what is present in the initial reactants and therefore is a form of anaerobic respiration. In case of rapid, intense energy consumption by muscles, the need may be fulfilled by glycolysis, which is much faster than the Krebs cycle, but can furnish energy for only about 15 seconds. Then another energy source must be found.

There is another, much less efficient means of creating energy from pyruvate by anaerobic respiration – fermentation. One sort of fermentation exists within the body; the other, in yeasts (in bread or beer, for instance).

When oxygen is limited, lactic acid fermentation can take place.. Enzymes use electrons from NADH to reduce the pyruvate to lactic acid plus a small amount of energy. In particular, muscle cells can can do this in order to get fast (but relatively little) energy, releasing the lactic acid into the muscles. The oxidized NADH (now NAD+) can now be recycled to glycolysis.

In bread or beer, ethanol fermentation takes place. Enzymes bring about the decarboxylation of pyruvate to acetaldehyde, releasing CO2 which makes the bubbles in beer or bread. Then enzymes use electrons from NADH to reduce acetaldehyde to ethanol. The ethanol evaporates when cooking bread, but is carefully conserved in the making of beer or wine.

Regulation of glucose levels

The liver converts glucose into glycogen and stores that; it can be reconverted whenever the level of blood sugar becomes low. This function is mediated by the hormones insulin and glucagon, both produced by the pancreas but having opposite effects.

Glucose concentration in the blood needs to be within a certain limited range in order to distribute enough energy to the body, but not so much as would harm organs and tissues, especially where blood vessels are tiny, as in the retina, the body’s extremities and the kidneys. Most cells have receptors which bind insulin, causing glucose transporters in the cell membranes to allow more glucose to enter the cell for storage, thereby reducing the glucose level of the blood. Abnormally high glucose levels in the blood are a sign of diabetes, which can be due to inadequate insulin production or to the cells’ not reacting correctly to insulin presence.

If the blood glucose level becomes too low, the pancreas secretes glucagon which stimulates production of glucose from the breakdown of glycogen, from amino acids or from stored triglycerides (lipolysis).

To see how this energy is used, proceed to the chapter on muscles.

Notes   [ + ]

1. Coenzyme electron carriers NAD and FAD were discussed in the last chapter.
2, 4. Gulp!
3. When I first read about it, I was giggling with joy.
5. Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same.

Digestion – energy and metabolic pathways

Our nutriments are composed almost entirely of three types of substances – carbohydrates (glucids, in some countries), proteins and lipids (or fats); the rest consists of small amounts of minerals and vitamins (organic nutrients required in small amounts, but which the organism cannot synthesize). The sequences of biochemical processes which constitute use of these three types of molecules are called metabolic pathways

Sources of ATP, from Openstax College

Sources of ATP, from Openstax College

The very notion of metabolic pathways is somewhat of an idealization, since science is not that simple when we look closely. In fact, as the image shows, the pathways are connected at multiple points. In addition, there are inputs of enzymes and hormones from other organs.

In addition, there are inputs of enzymes and hormones from other organs. The liver is essential in energy regulation and storage and produces bile, which is needed for digestion of fats and lipids. Bile can be stored in the gallbladder to be delivered to the duodenum (the first part of the small intestine) when needed. The pancreas secretes enzymes essential for the digestion of all three food types.

Digestion in the small intestine is similar for all three principal food types. Carbohydrates, fats and proteins are all broken down by hydrolysis, adding a water molecule to separate the long molecules into shorter ones. For a simple disaccharide represented by R’’-R, this can be represented chemically by:

R’’-R’ +H2O → R’’OH + R’H,

where the hydrolysis process indicated by the arrow requires the use of an enzyme.

Basic digestion of the three food types goes like this:

  • Carbohydrates are composed of poly- and monosaccharides. These are reduced by digestion to monosaccharides, which are used for energy or stored in cells, especially liver and muscle cells.
  • Proteins are polypeptide chains of amino acids, which are broken down into the separate amino acids which will be used to make more proteins.
  • Fats are composed mainly of triglycerides, which are separated into fatty acids.

Different enzymes are used in the three case.

The following sections discuss digestion of each type in more detail.1Principal source of information, Guyton and Hall (2011), chaps. 67-69.

Digestion of carbohydrates

Carbohydrates are composed mainly of sucrose, lactose, long-chain starches and cellulose. Cellulose is not digestible and just passes through the body in the form of fibers that nutritionists are so fond of.

Food is first ground by the teeth, which facilitates subsequent digestion. Ptyalin, a digestive enzyme found in saliva, begins hydrolysis. Only about 5% of hydrolysis takes place in the mouth before the food is moved by the tongue into the pharynx (throat). The epiglottis ensures that it moves past the tracheal opening and into the esophagus (a process which sometimes functions less well in older people), through which it descends into the stomach. Hydrolysis continues there until the food becomes mixed with enough gastric secretions that the mounting acidity renders the enzyme inactive. After being kneaded in acidic gastric juice, the resulting pasty chyme passes into the small intestine, which secretes mucus, hormones and digestive enzymes.

By the time food enters the small intestine, 40-50% of carbohydrates have been hydrolyzed, principally to maltose. Further digestion of carbohydrates takes place in the small intestine as pancreatic amylase, an enzyme secreted by the pancreas, breaks them down into maltose or small glucose polymers, large molecules composed of repeated subunits. Different enzymes then split these into their constituent monosaccharides, the simplest forms of carbohydrates, which are soluble and so can cross the intestinal wall to enter the blood stream and be carried to the liver.

  • Maltose from starches is broken down by maltase and a-dextrinase to glucose.
  • Lactose from milk is converted by lactase into glucose and galactose.
  • Sucrose (table sugar) is converted by sucrase into fructose.

The products are therefore glucose (about 80%), fructose and galactose. The last two substances are converted by the liver into glucose, which is therefore the common final form of carbohydrates arriving in cells. It is either used right away for energy, being sent to the glycolytic pathway and thence to the Krebs cycle, or converted to glycogen (by the process of glycogenesis) and stored.

Glycogen is a large polymer of glucose molecules and is an efficient form for storage. Storing glycogen instead of the individual glucose molecules allows more storage without substantial modification of the cell’s osmotic pressure.2Since osmotic pressure depends on the number of molecules in a solvent. See the discussion of osmosis and related possible danger for cells in the section on water. All the body’s cells can store small amounts of glycogen, but the champions are the liver (5-8% of its weight) and the muscles (1-3%).

When the body’s glycogen storage capacity is filled, excess glucose is converted to acetyl-CoA and thence into triglycerides (lipids), which are stored in adipose tissues. Yes, too much sugar turns to fat. Fat contains ~2.5 times the energy of an equal weight of glycogen. So since much more fat than glycogen can be stored in the body, an average person stores around 150 times as much energy in fat as in carbohydrate.

Digestion of proteins

Proteins are partially broken down in the stomach by the enzyme pepsin, important because it is capable of breaking down the protein collagen in the connective tissue of meat. This enzyme prefers a pH of 2.0-3.0, which is maintained by hydrochloric acid secreted at pH 0.8 by gastric glands in the stomach. When the resulting chyme passes into the small intestine, the pancreas excretes sodium bicarbonate to lower the acidity. As in the case of carbohydrates, the pancreas contributes enzymes, pancreatic proteolytic enzymes or proteases, to the small intestine to continue the breakdown of polypeptides into amino acids, although most remain as relatively small di- or tripeptides. Finally, inside the cytosol of enterocytes3Columnar epithelial cells, i.e., cylindrical cells on the intestinal wall, whose large surface area facilitates the transfer of molecules from the intestine. on the intestinal wall, various peptidases break down what is left into single amino acids which then pass into the blood. These are carried to the cells to be used as raw materials for the construction of new proteins in ribosomes. Any remaining peptides may cause serious problems.

In order to prevent proteolytic enzymes from destroying needed bodily proteins, they exist in unactivated precursor forms called zymogens and are only turned on when needed.

Digestion of lipids

Lipids (fats) consist of triglycerides, phospholipids, cholesterol and small quantities of other substances. Lipids are necessary for the formation of cell membranes and for many functions within cells. Like carbohydrates, they can provide energy. Most ingested fats are neutral fats called triglycerides, consisting of a glycerol nucleus attached to the ends of three fatty-acid side chains. Phospholipids are composed of only two fatty acids, attached to a hydrophilic phosphate “head group”.4This subject was discussed in some detail in a preceding section. Cholesterol is not a fat but has chemical properties similar to those of fatty acids and is digested similarly,

Fat digestion occurs mainly in the small intestine. The problem is that fats are not soluble in water. The hydrophobic fat globules are relatively large and must be broken up by emulsification before they can be effectively acted upon by enzymes. First, fat is mixed with bile (bile salts and, especially, lecithin) with polar and non-polar parts. The non-polar parts attach to the fats, leaving their hydrophilic polar parts pointing outwards. When they are agitated, they break up to form an emulsion, a mixture of one normally non-miscible liquid in another (like well-stirred vinaigrette salad dressing, or detergent in dish water). The smaller units of the fat present a much greater surface area than before and so can be attacked by water-soluble pancreatic lipase and split into free fatty acids (FFAs) and monoglycerides (the glycerol and the attached middle fatty acid ).

Again, the products are surrounded by bile salts with their non-polar ends towards the fats and their polar ends pointing outwards into the water. They then form small spheres called micelles, globs of which are water-soluble. The micelles then ferry the FFAs and monoglycerides through the aqueous solution to the epithelial cells. Since these are also fatty, the lipids can diffuse into them, leaving the bile behind behind to form more micelles.

The same processes of hydrolization and ferrying by micelles takes place for phospholipids and cholesterol using different pancreatic lipases.

Inside the intestinal membrane, the FFAs are re-synthesized into triglycerides. The triglycerides cholesterol, phospholipids and some apoprotein B (about 9% phospholipids, 3% cholesterol and 1% apoprotein B) are packaged into tiny (0.08-0.6 microns) phospholipid vesicles called chylomicrons whic  leave the intestinal cells. They are too big for capillaries but can flow via lacteals into the lymphatic system.5See the chapter on the lymphatic system. The chylomicrons transport the fats and cholesterol through the aqueous lymph and then into the venous blood via the thoracic duct. From the blood, they are stored either in the liver or in adipose tissue.

Triglycerides are converted into FFAs and back because triglycerides cannot cross the intestinal cell membranes, but FFAs can. They then enter the lymphatic system. Only small amounts of water-soluble, short-chain fatty acids like butterfat can pass directly from the small intestine into the blood without making a detour through the lymphatic system.

In short, fats are emulsified by bile salts so that they can be broken up by pancreatic lipase into FFAs. FFAs can cross the intestinal membrane and are reconverted to triglycerides. In order for them to be transported in the aqueous lymphatic system, FFAs and cholesterol are enclosed in phospholipid vesicles, called chylomicrons.

In this manner, almost all ingested fats (except short-chain fatty acids) are absorbed from the intestine into the intestinal lymphatic system in chylomicrons. These then are passed through the thoracic duct into venous blood. Several types of tissues, especially skeletal muscles, adipose tissues and heart tissues, synthesize lipoprotein lipase which hydrolyzes the triglycerides from the chylomicrons. The resulting fatty acids are either used for energy or stored in the cells until needed.

After breakup of the chylomicrons and their removal by the liver, most of the lipids left in blood plasma (>95%) are in the form of tiny particles called lipoproteins, partly lipid and partly protein, which are like miniature chylomicrons. The lipoproteins may contain triglycerides, phospholipids, cholesterol or proteins. Like chylomicrons, lipoproteins serve to transport lipids in the blood. Originally, use of a centrifuge to separate their components led to the definition of four classes of lipoproteins, based on their densities

In the body, though, no centrifuge exists to distinguish among the different densities of lipoproteins. Lipoproteins sent out by the liver carry triglycerides and are referred to as VLDLs (very-low density lipoproteins), since triglycerides are lighter than water. As tissues absorb the triglycerides, the lipoproteins become denser, effectively becoming IDLs (intermediate=density) and then LDLs (low-density). LDLs serve essentially to deliver cholesterol to tissues. But HDLs (high-density) are made up of different proteins. Their function is to carry cholesterol away from tissues and back to the liver.1 Hence, the slightly incorrect practice of calling LDLs “bad cholesterol” and HDSs “good cholesterol”.

The fat intake of the world’s peoples is quite variable, being 10-15% in parts of Asia and 35-50% in western countries. Part of this is converted to triglycerides and stored.

Use of fats for energy — energy production from metabolic pathways

Compared to carbohydrates and proteins, triglycerides furnish more than twice the energy per unit mass. So when glucose levels become inadequate, stored triglycerides are hydrolyzed to fatty acids. The rate of conversion and transport of FFAs is great enough that they can be oxidized to fulfill almost all the body’s energy needs without the need of energy from carbohydrates. Most cells except brain tissue and red blood cells can get their energy from fatty acids.

In order to be used for energy, triglycerides are converted by lipolysis to glycerol and fatty acyl CoA, the latter carried by carnitine into the mitochondria of the cells. There, it is converted back to fatty acids, then degraded by the process of beta-oxidation into acetyl-CoA, which enters the Krebs cycle of cellular respiration, the products of which also feed the electron transport chain (explained shortly).

Glycerol is converted directly into a form which can enter the glycolytic pathway (glycolysis, the introductory step to the Krebs cycle).

glycerol → glycero-3-phosphate → glycolytic pathway → energy

The liver stores a large quantity of fatty acids, but uses only a small part of these for its own energy requirements. So when carbohydrate stores (including glycogen) are low, great use is made of fats for energy. But, due to lack of intermediary substances, the Krebs cycle slows down. Excess acetyl-CoA accumulates in the liver where it is combined in pairs to form acetoacetic acid which is then carried by the blood to other cells. Some of it is converted to β-hydroxybutyrate and acetone, large quantities of which can be transported rapidly to cells.6Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same. These two substances plus acetoacetic acid are collectively referred to as ketone bodies and their synthesis from fats is called ketogenesis. On arriving in cells, all three are converted back into acetyl-CoA, which enters the Krebs cycle. This Is interesting because, in such circumstances, the brain will be lacking energy because fats can not cross the blood-brain barrier to supply it. But ketone bodies can. So the brain goes straight from glucose input to ketone bodies without ever using fats.

In brief, fats stored as triglycerides in the liver may be modified to ketone bodies and enter cells where they are transformed into acetyl-CoA and enter the Krebs cycle even in the brain.7See the figure, “The steps of cellular respiration”, in chapter “Making energy available“.

The preferred order of nutrients for energy is simple: Carbohydrates come first. But even the glycogen stored mainly in the liver can only furnish the body in fuel for maybe a half day. If carbohydrates run out, fats and proteins start to be used, principally fats. Use of fats continues approximately linearly until they run out. At the same time, stored amino acids are converted by gluconeogenesis to glucose, which is used. When the easily-accessed amino-acid store is reduced, fat usage increases and some of this is converted to ketone bodies, which can enter the brain and supply energy to it. However, changing from a carbohydrate-rich to a fat diet may require several weeks for brain cells to switch (mostly) to energy from fats.8Guyton and Hall, 2011, p. 824.

Regulation of glucose levels

The liver converts glucose into glycogen and stores that; it can be reconverted whenever the level of blood sugar becomes low. This function is mediated by the hormones insulin and glucagon, both produced by the pancreas but having opposite effects.

Glucose concentration in the blood needs to be within a certain limited range in order to distribute enough energy to the body, but not so much as would harm organs and tissues, especially where blood vessels are tiny, as in the retina, the body’s extremities and the kidneys. Most cells have receptors which bind insulin, causing glucose transporters in the cell membranes to allow more glucose to enter the cell for storage, thereby reducing the glucose level of the blood. Abnormally high glucose levels in the blood are a sign of diabetes, which can be due to inadequate insulin production or to the cells’ not reacting correctly to insulin presence.

If the blood glucose level becomes too low, the pancreas secretes glucagon which stimulates production of glucose from the breakdown of glycogen, from amino acids or from stored triglycerides (lipolysis).

Now all this energy must be made available by the process of cellular respiration.

Notes   [ + ]

1. Principal source of information, Guyton and Hall (2011), chaps. 67-69.
2. Since osmotic pressure depends on the number of molecules in a solvent. See the discussion of osmosis and related possible danger for cells in the section on water.
3. Columnar epithelial cells, i.e., cylindrical cells on the intestinal wall, whose large surface area facilitates the transfer of molecules from the intestine.
4. This subject was discussed in some detail in a preceding section.
5. See the chapter on the lymphatic system.
6. Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same.
7. See the figure, “The steps of cellular respiration”, in chapter “Making energy available“.
8. Guyton and Hall, 2011, p. 824.

Cell structure

Dogs and cats, butterflies and crayfish, lizards and birds, poison ivy and rosebushes and strawberry plants are all organisms. Organisms are composed of organ systems (digestive, circulatory or immune systems, to mention three examples). These systems are in turn composed of organs, which are composed of tissues which are composed of cells. The cell is where the action is!

The definition of life usually includes the requirement that whatever lives is capable of viable reproduction, which makes it subject to evolution. All life is composed of cells and they reproduce.

There are two kinds of cells, which have already been mentioned in the geology (!) chapter:

  • Eukaryotic contain structures called organelles, many of which are not found in prokaryotic cells. One such organelle is the nucleus, which houses the DNA.
  • Prokaryotic cells are usually smaller. They do not contain nuclei, so their DNA is floating around in the cytoplasm. They do contain ribosomes to carry out protein synthesis.

Cells come in a huge variety of shapes and functions. They are the basis of all living beings. Whether they are nerve cells, muscle cells, skin cells, bone cells or any other kind of cells; whether they come from humans or cats or grasshoppers or oak trees or bacteria, they all are based on common features like a membrane filled with cytoplasm, DNA or RNA along with ribosomes for reproduction, and the fabrication by cellular respiration of ATP for energy. This fact seems to represent a certain indication of the common origin of all life.

Plasma membrane

As we saw in the discussion of water, lipid bilayers, in this case, phospholipid bilayers, can form membranes. All cells are surrounded and protected by such membranes, also called plasma membranes. The membrane contains various proteins which serve to pass substances across the membrane, to identify it or to fulfill other functions. (More on that shortly.) This view of the cell membrane, as a mosaic of elements, is called the fluid mosaic model.

Everything inside the cell except the nucleus is the cytoplasm, including the cytosol, the jelly-like fluid in which other structures float, the organelles, including the nucleus, the mitochondria, and other structures.

Structure of cell membrane, by “LadyofHats” via Wikimedia Commons

Structure of cell membrane, by “LadyofHats” via Wikimedia Commons

The membrane is capable of forming pockets called vesicles. They can form on the inside of the cell membrane and surround material, then close and reopen on the outside in order to eject the material stored in them. In the other direction, they may form around external material and carry it into the cell.

The cell nucleus

The nucleus holds the DNA, normally wrapped with other proteins into strings of chromatin. Chromosomes are only constituted when needed to facilitate reproduction. The nucleus is surrounded by its own double membrane. The nucleolus within the nucleus serves to synthesize ribosomes, which in turn are sites for synthesis of proteins. The greater the number of proteins produced by a cell, the larger its nucleolus.

Figure_03_03_01a_new

Typical animal (a) cell, from Openstax College

Mitochondria

Mitochondria are where the final products of digestion, mainly glucose, are converted into ATP, the body’s “energy currency”, which transports energy to whatever metabolic process may need it. A mitochondrion has both an external and an internal membrane. ATP is produced by processes taking place along the inner membrane. The interior of the mitochondrion is called the matrix. Cellular respiration (energy production) will be discussed in detail in the chapter on anatomy and physiology.

According to symbiogenesis, or endosymbiotic theory, mitochondria originally were prokaryotic bacteria which moved into other cells and formed a symbiotic relation with them. Similarly, choroplasts are prokaryotic bacteria which have moved into plant cells. Mitochondria still have their own DNA, independent of that in the cell nucleus, although they have abandoned or given up much of their original DNA.

The current model of eukaryotic evolution starts with an anaerobic eukaryote which absorbed an aerobic bacterium which later became a mitochondrion. Subsequently, some of these now aerobic eukaryotes absorbed photosynthetic bacteria, probably cyanobacteria, which became chloroplasts. The latter eukaryotes formed plants, whereas those which did not absorb the photosynthetic bacterium became animals.

Mitonchondrion structure, by "Kelvinsong" via Ma href="https://commons.wikimedia.org/wiki/File:Mitochondrion_structure.svg"

Mitonchondrion structure, by “Kelvinsong” via Wikimedia Commons

 

Ribosomes

Ribosomes are where proteins are built following instructions contained in DNA; the instructions are transmitted to the ribosome in the form of messenger RNA, mRNA, about which more later. Ribosomes consist of two subunits, large and small, both of which are constructed in the nucleolus from ribosomal RNA (~75%) and proteins.

Endomembrane system

The endomembrane system has been referred to as the “post office” of the cell, as its components produce, package and export certain cell products, such as proteins or lipids. It has several components.

  • Endoplasmic reticulum — This is actually an extension of the membrane of the nucleus outwards to form folds. The rough ER is studded with ribosomes, to make proteins. The smooth ER is not and produces lipids.
  • Golgi apparatus – This serves to dispatch the various products to their final destinations.
  • Lysosomes – These “garbage-collection” modules contain enzymes which can break down and digest molecules and even cells. In the process of phagocytosis, for example, macrophages, a type of white blood cell and part of the immune system, gobble up pathogens and then deliver them to lysosomes for destruction. They do not exist in plant cells.
  • Peroxisomes – These also contain enzymes for decomposing various molecules by transferring hydrogen to oxygen to produce hydrogen peroxide, H2O2. In the liver, they break down ethanol (alcohol from alcoholic beverages).

“Form follows function”, in biology. Cells which produce large amounts of proteins have voluminous endoplasmic reticulums and those which secrete much have large amounts of Golgi bodies. Those, like muscles, which need great amounts of energy contain many mitochondria.

Cytoskeleton

Proteins of the cytoskeleton support the cell and give it shape. They are of three varieties.

Microtubules are made of the protein tubulum and provide structure, like scaffolding, which allows the cell to resist compression. They also form something like a railroad track for RNA to flow along during protein synthesis, rather than letting it float loose in the cytoplasm.

Microtubules make up two important structures:

  • flagella, the tail-iike appendages existing in humans only on sperm, and which allow them to move about;
  • cilia, fine, hair-like structures which wave continuously and move such things as waste in the respiratory system or egg cells in fallopian tubes.

Microtubules form the centrioles, the principal part of centrosomes, which play an essential role in chromosome splitting during reproduction (explained later in this chapter).

Microfilaments are made of actin. They are thinner than microtubules and form chains responsible for muscle contraction with the cooperation of myosins. (See the section on muscles.)

Microtubules and microfilaments are like cables and work with motor proteins which pull themselves along the cable. A family of motor proteins, kinesins, attach to vesicles carrying, for instance, RNA and crawl along the microtubules similarly to the way myosin crawls along actin in muscle cells.

Since motor proteins move themselves along the support structure of the cell, they are probably evolved forms of the cytoskeleton of bacteria.1This was only observed in the mid-1990s. Lane (2009), 167. Bacteria can be motile in their way too, since they change by adding on elements at one end and leaving them off at the other, effectively moving and generating force. The evolution of motility was an essential step in the spread of plants and – especially – animals some 250-or-more million years ago.

Intermediate filaments are made of keratin and serve, like microtubules, for maintaining cell shape, but, contrary to microtubules, they resist tension which tries to pull apart the cells.

In addition to the support they receive from the cytoskeleton, many animal cells have an extracellular matrix of connective tissue composed of long proteins like collagen which help support the cell and bind cells together. Plants have cell walls composed of a reinforcing layer of cellulose.

Plant cells

Plant cells differ from animal cells in that they have cell walls outside the cell membrane, and contain a central vacuole and chloroplasts.

Typical animal (a) and plant (b) cells, from Openstax College

Typical plant (b) cell, from Openstax College

The cell wall is a stiff outer layer which supports and protects the plant. The large central vacuole contains liquid which exerts pressure to maintain the plant’s standing position, just like air in a balloon makes the balloon stiff. The liquid also stores proteins.

The chloroplasts are where photosynthesis takes place. Like mitochondria, they contain their own simple form of DNA as well as ribosomes, because, like mitochondria, they originated as bacteria which moved into another cell, felt at home and stayed.

The structure of chloroplasts and their use of energy from sunlight to convert CO2 and H2O into sugar will be presented in the next chapter.

Viruses

Viruses are not cells because they do not contain all the good things described above. A virus consists of a protective protein coat called a capsid, which contains the viral DNA or RNA (but not both). It may also be surrounded by an envelope which closely resembles a cell membrane – because the virus has stolen it from a cell and adapted it to its own nefarious ends — a virus in cell’s clothing. Viruses have no ribosomes or other organelles to synthesize proteins, so they are dependent for reproduction on normal cells which they invade, substituting their own genetic material for that of the cell and then letting the cell do the job of protein synthesis – but using the virus’s recipe. Real Trojan horses!

Electrochemical considerations – the action potential

Cells are surrounded by a membrane composed of a phospholipid bilayer arranged in such a way that the membrane surfaces are hydrophilic and the interior hydrophobic. No charged ion, hydrophilic molecule or very large molecule can traverse the membrane. But the cell needs to receive nutriments, expel waste, receive hormonal messages, and so on, so the membrane must not be completely impermeable.

Membrane channels

In order to allow the necessary passage of chemicals, the cell membrane is studded with proteins which control the passage of such objects.

  1. Ion channels are passageways through the cell wall which allow ions to pass naturally in a direction tending to equalize their electrochemical or concentration gradients inside and outside the cell. Such channels may be ion-specific (for instance, allowing only K+ ions to pass), charge-specific (allowing either negative or positive ions, but not both) or size-specific. Some ion channels are leakage channels, opening randomly.
  2. Gated ion channels allow ions through the channel on occurrence of some event. This might be the arrival, for instance, of an electric potential (voltage-gated ion channel) or a specific chemical substance (ligand-gated channel). Voltage-gated channels are essential to the formation of action potentials.
  3. Ion pumps, especially the sodium-potassium (Na-K) pump and the calcium pump, run all the time in most animal cells, using energy from ATP to pump ions across the membrane against their concentration or electrostatic gradient.

The concentration of chemical substances inside and outside the cell generally are not the same and this is crucial to their functioning.

Membrane potentials

It all starts with a pump, the sodium-potassium (Na-K) or ATPase pump. This object is powered by ATP to flip back and forth between two states. In one state, it pumps Na+ ions out of the cell; in the other, it pumps K+ ions into the cell. Soon, a concentration gradient is established for each ion, tending to pull the Na+ back into the cell and to push the K+ out.

The pump does more than that, because for every two K+ ion it pulls into the cell, it pushes three Na+ out. The result is the establishment an electrostatic potential across the cell membrane. Because the extra positive charges outside attract any negative charges inside, they tend to be concentrated close to the membrane surfaces, so the membrane forms an electrical capacitance.

Sodium-pottasium pump, from Wikimedia Commons

Sodium-pottasium pump, from Wikimedia Commons

So the result of the pump is triple:

  • a Na+ concentration gradient tending to pull Na+ back into the cell;
  • a K+ concentration gradient tending to push K+ out;
  • an electric potential across the membrane due to the greater number of positive ions outside the cell.

Note that there are also lots of large anions, such as phosphate or negatively charged proteins, inside the cell. Ion channels for K+ tend to leak K+. The K+ tends to follow its concentration gradient out of the cell, but this leaves behind a more negative interior, which attracts it back toward the interior.  Eventually, an equilibrium state is reached where the outward pressure due to the concentration gradient balances the inward pressure due to the electrostatic gradient. Measurements show that the interior has a potential of -92 mv (relative to the exterior). The cell is said to be polarized. In this state, opening an ion channel would allow positive ions to flow into the cell, depolarizing it.

If we start over and do the same thing, but open a Na+ channel, Na+ rushes into the cell, bringing up the cell’s potential until equilibrium is reached between the concentration and electrostatic forces, this time at a potential of +62 mV. So each ion has an equilibrium potential which is a function of the concentration difference across the cell membrane. The membrane potential of the cell as a whole depends on the concentration differences of all the ions inside and outside the cell. A very small change in ionic concentration can bring about a much greater change in membrane potential.

Since both K+ and Na+ leakage channels exist, but the Na+ channels leak much more slowly than the K+, the result is to increase somewhat the Na+ concentration within the cell and hence raise the potential a little to around -70 mv.2Some authors say -65 mv.

Enter the third type of channel, the gated ion channel. This may be of various types depending on the ion allowed to pass and on the circumstances which gate it, i.e., which initiate the passage. The latter property may be of different types:

  • mechanically-gated, subject to pressure, for instance, on the surface of the skin or on auditory cilla in the ear;
  • temperature-gated;
  • voltage-gated, i.e., to charged ions;
  • ligand-gated, i.e., sensitive to certain molecules (taste, smell, neurons);
  • photosensitive (retina).

The action potential

Consider a nerve or muscle cell at rest, with a membrane potential of around -70 mV, so the cell is polarized. Suppose something happens which causes the membrane potential to increase (i.e., to become less negative). This could be due to entry of ions through a ligand-gated channel (as in neurons) or a mechanically-gated channel (as in a somatosensory channel) or simply due to K+ leakage (as in a pacemaker cell of the heart). If the increase is small, nothing happens. But if it becomes sufficient to bring the potential up to the threshold value of -55 mV, then a voltage-gated Na+ channel opens, allowing Na+ to come rushing into the cell, quickly raising the potential to a positive value and depolarizing the cell. When the potential reaches 30 mV, the voltage-gated Na+ channels close but voltage-gated K+ channels open and K+ starts rushing out of the cell, bringing the potential back down (positive charges are leaving the cell) and repolarizing it.

Action potential, from Wikimedia Commons

Action potential, from Wikimedia Commons

In muscles, release of the neurotransmitter acetylcholine (ACh) by motor nerves opens ligand-gated channels which allow the cell to depolarize to the threshold for voltage-gated sodium channels, which in turn cause an action potential which eventually opens another channel which allows Ca++ into the cell. The Ca++ binds to troponin in the muscle fiber and unlocks it, so that myosin heads can “walk” along the thin filament and contract the muscle.

The heart is special in that it initiates its own action potentials in a repeated, periodic way. The cycle is initiated not by a ligand-gated channel, but mostly by leakage channels which allow some Na+ to enter the heart, gradually raising the membrane potential from about -60 mV to -40 mV. This is the threshold value for a gated channel to open, allowing depolarization of the cell. However, because of the leakage, only slow Na+–Ca++ channels are opened, which explains the relatively slow rise of the potential. After about 100-150 milliseconds, the  Na+–Ca++ channels close and K+ channels open. As K+ rushes out of the cell, the potential redescends to a bit under its initial resting value. Then the K+ channels also close and the cycle starts over. So the heart beats all by itself due to the membrane potential of the cardiac muscle cells, the slow leakage of Na+ and the voltage-gated Na+–Ca++ and K+ channels.

Continue reading about DNA expression and protein synthesis.

Notes   [ + ]

1. This was only observed in the mid-1990s. Lane (2009), 167.
2. Some authors say -65 mv.