Metabolism
CHAPTER
21

The book for the first-semester course in human anatomy & physiology described the body’s chemical basis, its cells and tissues, and four of its organ systems. Now we turn our attention to the body’s other seven organ systems. The next system we will investigate is the endocrine system, which secretes chemicals called hormones. All hormones exert their effects by altering the metabolism of specific cells; therefore, to understand the effects of selected hormones, it is necessary to take a closer look at cellular metabolism.

METABOLISM

Metabolism (me-TAB-ō-lizm; “to change”) refers to all chemical reactions in the body and includes anabolism, which builds molecules, and catabolism, which breaks down molecules. Most metabolic activity requires enzymes, which are chemical catalysts made of protein. A catalyst   is a substance that speeds up a chemical reaction without becoming part of the product(s) of that reaction.

Certain enzymes extract energy from food molecules and this energy can drive some of the processes used for the synthesis of adenosine triphosphate (ATP). Most often, cellular work (movement of matter) is accomplished by transferring a phosphate group (PO43-) from ATP to another molecule. When this happens, the ATP experiences dephosphorylation (dē-fos-for-i-LĀ- shun), while the molecule receiving the phosphate experiences phosphorylation. Dephosphorylation or phosphorylation can change a molecule’s shape, resulting in cellular work. Examples of work performed using the energy derived from ATP include the transport of Na + and K+ ions through a Na+ – K+ pump located in the cell membrane and muscle contraction. In some cases, phosphorylation may also increase a molecule’s likelihood of interacting with other molecules. 

Extracting energy from food molecules involves a series of redox (oxidation-reduction) reactions. Oxidation is the removal of an electron (e–) from a substance, whereas, reduction is the addition of an electron to a substance. Recall the acronym, OIL RIG: Oxidation Is Loss, Reduction Is Gain. The oxidized form of a substance contains less energy than the reduced form of that substance. For example, the complete oxidation of a glucose molecule releases energy along with carbon dioxide  (CO2)  and  water.  The  CO2  is a highly oxidized carbon compound that contains less energy than the glucose molecule (C6H12O6). We can summarize oxidation and reduction in a number of different ways:

In equation 1, A+ has one more proton than it has electrons; thus, adding one electron causes the A to become neutral. In equation 2, adding an electron to a neutral substance makes the substance negatively charged. In equation 3, adding an electron to a negatively charged substance causes the substance to have a double negative charge. In equations 4 and 5, the H2 is a proton; therefore, coupling a single electron with a single proton produces a hydrogen atom, while coupling two electrons with two protons produces two hydrogen atoms. Remembering these simple equations will help you understand some of the chemical reactions described in later sections.

PHOSPHORYLATION OF ADP

To make ATP, cells must phosphorylate ADP (adenosine diphosphate), and this process requires energy, which the cells derive from food molecules. While the extraction of energy from food molecules may involve multiple, complicated chemical reactions, the phosphorylation of ADP occurs in only two ways: substrate-level phosphorylation and chemiosmosis (see Figure 21-1).

Substrate-level Phosphorylation

In substrate-level phosphorylation, an enzyme removes a phosphate group from one molecule and donates it to ADP. This is what happens in a skeletal muscle cell during the first few seconds of strenuous activity when molecules of creatine phosphate donate their phosphate groups to ADP molecules. In this chapter, you will learn about two other instances of substrate-level phosphorylation that may occur inside cells.

Figure 21-1. Methods of generating ATP

Figure 21-2. Facilitated diffusion 

Chemiosmosis

In chemiosmosis (ke-mē-os-MŌ-sis), an enzyme attaches an unbound phosphate group to an ADP. The enzyme, which is bound to a membrane, derives the energy for this process from protons diffusing through the enzyme. In eukaryotic cells, chemiosmosis occurs inside mitochondria and requires a steady supply of oxygen gas (O2); for this reason, chemiosmosis also has alternate names, including oxidative phosphorylation, cellular respiration, and aerobic respiration. We will first describe the catabolism of carbohydrates, the main food source from which cells derive energy for the phosphorylation of ADP.

OVERVIEW OF CARBOHYDRATE METABOLISM

Most discussions of ATP synthesis begins with glucose, which is the most common carbohydrate circulating in your blood. While free glucose molecules may exist in the diet, they most often enter the body bound together in long chains called complex carbohydrates (polysaccharides). Let’s first look at how carbohydrates are absorbed into the blood.

Absorption of Monosaccharides

When you eat complex carbohydrates, such as starch (stored in plant cells) or glycogen (stored in animal cells), enzymes in your small intestine break them down into simple sugars, or monosaccharides. These simple sugars, including glucose, fructose, and galactose, are isomers; that is, they all have the same chemical formula (C6H12O6), but have different molecular shapes. Fructose enters mucosal cells lining the inner wall of the intestine through facilitated diffusion (Figure 21-2). Recall facilitated diffusion involves a carrier protein located in the plasma membrane of a cell. Facilitated diffusion is a type of diffusion, in which a substance moves along a gradient from a region of higher concentration into a region of lower concentration. The specific carrier through which fructose enters the mucosal cell is called GLUT-5. After passing through the mucosal cell’s cytoplasm, fructose leaves the cell by facilitated diffusion and then enters the blood. The fructose leaves the cell through either another GLUT-5 or a different carrier called GLUT-2 (mentioned again shortly). The movement of glucose and galactose out of the intestine and into the blood is slightly different from that of fructose and involves two processes: secondary active transport and facilitated diffusion. Like facilitated diffusion, secondary active transport (SAT) involves a carrier protein, but this carrier transports two substances: one along a gradient and the other against a gradient (from low to high concentration). SAT carriers in mucosal cells transport glucose or galactose against a gradient while simultaneously transporting sodium ions (Na+) along a gradient. Recall that Na/K pumps establish a steep concentration gradient for Na+, with the higher concentration being outside the cell (in the ECF). A Na/K pump is an example of a primary active transport (PAT) carrier in that it directly hydrolyzes ATP. With every turn, a Na/K pump transports three Na+ ions out of the cell and transports two K2 ions into the cell (Figure 21-3a).
Secondary active transport of glucose or galactose involves a carrier called the Na2– glucose symporter. Before this carrier can do its job, Na+ must first bind to it. This binding causes the carrier to change shape, which then allows a glucose or galactose molecule to bind to the carrier. The carrier changes shape again and moves both the Na+ and glucose (or galactose) into the mucosal cell. The word symporter is used because both substrates are moving through the carrier in the same direction, and the process is called cotransport. (Later, you will learn about antiporters, which move substrates in opposite directions through SAT called countertransport.) After passing through the mucosal cell, glucose and galactose exit the cell through facilitated diffusion, a process that involves GLUT-2 carriers, which can also transport fructose out of the mucosal cell. For all other body cells, except for a few in the kidneys, glucose passes into cells via facilitated diffusion through GLUT-2 carriers (Figure 21-3b). Except in mucosal and kidney cells, after glucose enters a cell, an enzyme called glucokinase (glū-kō-KĪ-nās) phosphorylates it using ATP as the source of the phosphate group. Glucokinase is sometimes called hexokinase (hek-sō-KĪ-ās), be- cause its substrate (glucose) contains six carbons (hex, six). Phosphorylation converts the glucose into glucose phosphate, which is unable to exit the cell. You might say the phosphorylation of glucose “traps” the glucose inside the cell. In mucosal and kidney cells, glucose passes through the cytoplasm without being phosphorylated. This allows the glucose molecules to pass all the way through the cells and into the blood, where they can travel to other cells in the body. Instead of using glucose as their primary source of energy for ATP synthesis, mucosal and kidney cells most likely use amino acids. In upcoming sections, unless otherwise specified, any reference to a cell refers to one other than a mucosal or kidney cell.

Oxidation of Glucose

A cell must oxidize glucose in a series of reactions instead of all at once. But why is this so? If com- plete oxidation of glucose occurred in one chemical reaction, the amount of heat released would be so great that the cell would burn up. You have witnessed the complete oxidation of carbohydrate molecules in one quick step if you have ever held a marshmallow over a campfire and watched it burst into flames. When the sugars get hot enough, they react with O2 in the atmosphere. This reaction converts the sugars into CO2 and H2O, with a simultaneous release of enough heat to ignite the marshmallow. Obviously, a cell could not tolerate this much energy release all at once. Fortunately, the hydrolysis (oxidation) of glucose inside our cells occurs through a series of reactions that release energy gradually. Two chemical processes associated with carbohydrate catabolism are glycolysis and fermentation, both of which occur in a cell’s cytoplasm. Additional energy can be extracted from carbohydrates inside mitochondria in a process called aerobic respiration. Figure 21-4 provides an overview of these processes.

Figure 21-3 Secondary active transport

Figure 21-4. Overview of glycolysis, fermentation, and cellular respiration

GLYCOLYSIS

Glycolysis (glī-KOL-i-sis; “sugar splitting”) is the initial series of redox reactions that convert glucose, a six-carbon (6C) compound, into two, three-carbon (3C) compounds called pyruvate (PĪ-rū-vāt). Pyruvate is the ionized form of pyruvic acid (pī-RŪ-vik); i.e., it is the anion formed when pyruvic acid dissociates as follows:

Pyruvic acid → H+ + pyruvate-

Since glycolysis does not require oxygen, it is an anaerobic process (an-a-RŌ-bic; an, without; aero, air). Glycolytic enzymes oxidize glucose and some byproducts by breaking carbon-hydrogen (C–H) bonds. Most oxidation reactions remove two hydrogen atoms; i.e., two electrons (2e-) and two protons (2H+ ):

2e–   + 2H+ → 2H

Enzymes that oxidize substrates during glycolysis donate their electron and proton cargo to a coenzyme called nicotinamide adenine dinucleotide (NAD; nik-ō-TIN-a-mīd AD-e-nēn dī-NŪ-klē-o-tīd), which is derived from niacin (vitamin B3). Biochemists denote the oxidized form of this compound NAD+ . By accepting two electrons and two protons, the NAD+ becomes reduced to NADH + H+:

NAD+ + 2e- + 2H+ → NADH + H+

Think of the enzymes that remove electrons and protons from substrates as being like machines that dig up dirt, while the coenyzmes are like dump trucks that receive the dirt. NAD+ is like an “empty” dump truck because an enzyme has not yet given electrons and protons to it. NADH + H+  is like a “full” dump truck because  it has been loaded with donated electrons and protons. While it is most accurate to write the reduced form of NAD+ as NADH + H+, we will simply write it as NADH. In addition to reducing NAD+ to NADH, several reactions in glycolysis perform substrate-level phosphorylation of ADP. In this event, enzymes obtain phosphate groups from glycolysis compounds and transfer them to ADP. Glycolysis makes only a small number of ATP molecules, and this production alone can sustain human life for just a few minutes. Look at Figure 21-5 to see an overview of glycolysis and fermentation, then read the explanations that follow.

Steps of Glycolysis

Glycolysis involves nine steps, resulting in the conversion of one glucose molecule into two pyruvate molecules. You are not expected to memorize these steps; however, you will be asked to associate the names of compounds written in italics with the process of glycolysis. In other words, when you see a list of compounds, you will have to know  which  ones are found in glycolysis and which ones are not. The names of enzymes that perform these steps are provided in a supplemental section at the end of this chapter (you do not need to learn that information).

  1. Glucose is phosphorylated to form glucose phosphate. Ironically, the enzyme that phosphorylates the glucose obtains the phosphate from an ATP In this case, it is necessary to “burn” a few ATPs before glycolysis can make more ATPs.
  2. Glucose-phosphate is rearranged to form fructose-phosphate.   
  3. Fructose-phosphate is phosphorylated to form fructose biphosphate (bī-FOS-fāt). Again, the source of phosphate for this reaction comes from an ATP molecule.
  4. Fructose biphosphate splits into two compounds: dihydroxyacetone phosphate (dī- hī-DROK-sē-AS-e-tōn) and glyceraldehyde 3-phosphate (G3P or PGAL, glih-ser-AL-de- hīd).
  5. The dihydroxyacetone phosphate in step 4 is converted to G3P; thus, one glucose molecule has now been converted to two G3P molecules.

The following steps occur for both molecules of G3P.

  1. G3P is phosphorylated using a free PO 43- and oxidized to form biphosphoglycerate (bī-fos-fō-GLIH-ser-āt). The electrons and protons removed from G3P are donated to NAD+ , reducing it to NADH.
  2. An ATP forms when a phosphate from bi- phosphoglycerate is transferred to ADP (this is substrate-level phosphorylation of ADP). In turn, the biphosphoglycerate becomes phosphoglycerate (fos-fō-GLIH-ser-āt).
  3. Phosphoglycerate becomes phosphoenolpyruvate (fos-fō-FĒ-nol pī-RŪ-vāt) when an enzyme removes a water molecule from it.
  4. An ATP forms when a phosphate from phosphoenol pyruvate is transferred to When this happens, the phosphoenol pyruvate becomes pyruvate.

Although glycolysis generates four molecules of ATP, two ATPs were consumed to get the process started; thus, glycolysis has a net production of two ATPs. The two pyruvate molecules together still contain less energy than the original glucose molecule for three reasons:

  1. Some of the energy is now in NADH
  2. Some of the energy is now in ATP
  3. Some of the energy escapes as heat

Although it is an oxidized form of glucose, pyruvate still contains usable energy, and further oxidizing it inside mitochondria can release that energy.

Figure 21-5. Glycolysis and fermentation

FERMENTATION

Fermentation is a process that a pyruvate molecule experiences when it cannot enter a mitochondrion for further oxidation. So, you might ask, what prevents a mitochondrion from accepting a pyruvate molecule? In order to oxidize each pyruvate formed in glycolysis, a mitochondrion needs three O2 molecules. When the number of O2 molecules inside the mitochondrion drops below the number of pyruvates waiting for oxidation, fermentation occurs. For instance, if ten pyruvates are produced, but only 24 O2 molecules are available in the mitochondrion, then eight pyruvates can be oxidized and two would undergo fermentation.

During fermentation, an enzyme reduces pyruvate by donating to it two electrons and two protons obtained from NADH. Reducing a pyruvate transforms it into a molecule called lactate (LAK-tāt), which is the ionized form of lactic acid. We can summarize fermentation in humans as follows:

Pyruvate + 2e–  + 2H+ → Lactic acid → H+ + Lactate

Fermentation is responsible for making muscles feel tired during a strenuous workout. You may wonder why fermentation would be beneficial if it makes a person’s muscles fatigue. Keep in mind that NADH normally unloads electrons to the mitochondria. However, without an adequate number of O2 molecules to accommodate aerobic respiration, not only are mitochondria unable to accept additional pyruvate molecules, but they are also unable to accept electrons from all the NADH molecules generated during glycolysis. Fermentation, however, provides an alternate “dumping ground” for electrons carried by NADH molecules (“full dump trunks”). After NADH donates electrons to pyruvate, the resulting NAD+ (“empty dump trunk”) can return to glycolysis to pick up more electrons. In this way, the cell can continue to make ATP through glycolysis.

Since fermentation results when the supply of oxygen cannot keep up with the mitochondrial demand for oxygen, a person who is performing fermentation is said to be building up an oxygen debt, also called excess post-exercise oxygen consumption (EPOC). The visible sign of an oxygen debt is a person breathing heavily after intense exercise. This is an attempt to take in additional oxygen molecules above the amount required at rest. The oxygen debt can be formally defined as the amount of additional oxygen required to:

  • Reestablish aerobic respiration to pre-exercise levels
  • Oxidize all lactate molecules
  • Replenish glycogen and creatine phosphate stores

AEROBIC RESPIRATION

When mitochondria contain adequate amounts of O2, all pyruvate molecules produced during glycolysis can enter it to undergo complete oxidation. Mitochondria can then use the released energy to synthesize many more ATPs.

Oxidation of Pyruvate

Aerobic respiration requires that pyruvate pass through a mitochondrion’s outer and inner membranes to enter the matrix (inner compartment). Within the matrix, an enzyme removes one of the pyruvate’s carbon atoms and releases it as carbon dioxide (CO2); this process is called decarboxylation (dē-kar-boks-i-LĀ-shun). After this step, the newly formed compound, which contains only two carbons, becomes

oxidized by the removal of two electrons and two protons that are donated to NAD+ , converting it into NADH. The decarboxylation and oxidation of pyruvate converts the pyruvate into a two- carbon acetyl compound (a-SĒ-tal). Another enzyme binds the acetyl compound to coenzyme A (derived from pantothenic acid, or vitamin B5) to form acetyl CoA. The formation of acetyl CoA is as follows:

Pyruvate + NAD+  + CoA → CO2 + NADH + Acetyl CoA

Figure 21-6. The Krebs cycle

Krebs cycle

Inside the mitochondrial matrix, acetyl CoA undergoes a series of redox reactions, collectively called the Krebs cycle. The Kreb’s cycle is also called the citric acid cycle because citric acid  is the first compound formed in the reactions. Furthermore, due to the structure of citric acid, this cycle is also called the tricarboxylic acid (TCA) cycle (trī-kar-bok-SIL-ik). The word “cycle” implies that the last compound formed in the series of reactions will be the first compound in the series when it repeats. Figure 21-6 illustrates this series of reactions. Like glycolysis, some of the energy released from the Krebs cycle reactions is used in the synthesis of ATP via substrate-level phosphorylation of ADP. Most electrons removed during the Krebs cycle bind to NAD+, reducing it to NADH. In one reaction, electrons (and protons) bind to another coenzyme, called flavin adenine dinucleotide (FAD; FLĀ-vin AD-e-nēn dī-NŪ-klē-ō-tīd), which is derived from riboflavin (vitamin B2). The oxidized form of FAD is written simply, FAD; whereas,  the reduced form is written FADH2. By the end of the Krebs cycle, much of the energy in a glucose molecule has been incorporated into molecules of NADH and FADH2. Look at Figure 21-6. Following are the steps of the Krebs cycle, and each step requires a specific enzyme. The italicized term is the ionized form of the acid, which is enclosed in parentheses. You are not expected to memorize these steps, but you must be able to associate the names of compounds written in italics with the Kreb’s cycle.
  1. Acetyl CoA reacts with oxaloacetate (oks-sa-lō-AS-e-tāt; oxaloacetic acid) and water to form citrate (SI-trāt; citric acid), then coenzyme A is released.
  2. Citrate is rearranged into isocitrate (ī-sō-SI-trāt; isocitric acid).
  3. Isocitrate is oxidized to form α-ketoglutarate (al-fa kē-tō-GLŪ-tar-āt; α-ketoglutaric acid); CO2 is released and NADH forms.
  4. α-ketoglutarate reacts with coenzyme A and undergoes oxidation to form succinyl-CoA (SUK-sin-il); CO2 is released and NADH forms.
  5. Succinyl-CoA reacts with water, releases coenzyme A and undergoes dephosphorylation to form succinate (SUK-si-nāt; succinic acid); the released phosphate is donated to guanosine diphosphate (GDP) to form guanosine triphosphate (GTP). The GTP then donates a phosphate to ADP to form ATP. This is an example of substrate-level phosphorylation of ADP.
  6. Succinate is oxidized to form fumarate (fū-MAR-āt; fumaric acid) and FADH2 forms.
  7. Fumarate reacts with water to form malate (MAL-āt; malic acid).
  8. Malate is oxidized to form oxaloacetate (oxaloacetic acid); NADH forms.

Electron Transport Chain

The energy derived from the Krebs cycle is in electrons, which are passed to other compounds within the mitochondrion. Some of this transferred energy is used in the synthesis of more ATP molecules. After leaving the Krebs cycle, each NADH and FADH2 donates two electrons (2e–) to electron-carrier molecules embedded within the mitochondrion’s inner membrane. The molecules are part of the electron transport chain (ETC), or electron transport system (ETS). Figure 21-7 illustrates the parts of the ETC.

The ETC includes a number of proteins, some of which are coupled together with other compounds to form complexes. There are four complexes in the ETC, and each is identified by a Roman numeral (I, II, III, IV). The FAD that accepts electrons from the Krebs cycle is actually a part of complex II. Following is the pathway followed by the electrons donated to the ETC. You are not expected to memorize these steps, but you must be able to associate the names in boldface with the ETC.

  1. NADH formed in the mitochondrion donates 2e– to flavin mononucleotide (FMN; FLĀ vin mon-ō-NŪ-klē-ō-tīd), located within complex I; the NADH becomes NAD+.
  2. Within complex I, FMN passes the electrons to an iron-sulfur protein (FeS), reducing the ferric iron (Fe3–) to the ferrous form (Fe2+). Passing electrons through complex-I energizes the complex, enabling it to function as a proton pump, which transports two protons (i.e., two hydrogen ions—2H+) from the mitochondrial matrix through the inner membrane and into the intermembrane Meanwhile, 2e– released from the Kreb’s cycle bind to FAD located with complex II, converting the FAD to FADH2. Still within complex II, the FADH2 passes the 2e– to the Fe-S protein, converting the FADH2 back to FAD.
  3. Electrons pass out of complexes I and II and bind to coenzyme Q (also called CoQ or ubiquinone; ū-BIK-wi-nōn), which is not part of any Coenzyme Q passes 2e– to cytochrome b (SĪ-tō-krōm) located within complex III. Still within complex III, cytochrome b passes the electrons to a Fe-S protein, which then passes the electrons to cytochrome c1.
  4. The moving electrons provide energy for complex III to pump 2H+ from the matrix into the intermembrane compartment; thus, complex III functions as an electron-carrier and a proton pump.
  5. The 2e– pass out of complex III and onto cytochrome c, which is not part of any complex.
  6. Cytochrome c passes the 2e– to cytochrome a located within complex IV, which contains iron (Fe) and copper (Cu). Cytochrome a then passes the electrons to cytochrome a3. Like complexes I and III, complex IV also acts as a proton pump, deriving energy from electrons moving through it to pump 2H+ from the matrix into the intermembrane
  7. Electrons pass out of complex IV and onto an oxygen atom, which is derived from molecular oxygen (O2) in the Thus, oxygen is the final electron acceptor in the ETS. When an oxygen atom receives 2e–, it becomes reduced to an oxygen ion (O2) that attracts 2H+ from the matrix. When the reduced oxygen picks up the two protons water forms as follows:

2e– + ½O2 + 2H+ → H2O

Figure 21-7. The electron transport chain

Mitochondrial vs. Cytosolic NADH

Mitochondrial NADH, FADH2, and cytosolic NADH donate their electrons to different parts of the ETC, and thus energize different numbers of proton pumps. Mitochondrial NADH always donates its electrons to complex I. Since these electrons pass along the entire ETC, they can energize all three proton pumps (complexes I, III, and IV). Electrons from FADH2 enter complex III, so they can energize only the last two proton pumps (III and IV). The NADH molecules from glycolysis cannot enter the mitochondrion, but “hand off” their electron cargo to a “shuttle” molecule in the inner membrane of the mitochondrion. In most body cells, a malate-aspartate shuttle (MAL-āt AS-par-tāt) hands off these electrons to complex I, so they can energize all proton pumps in the ETC. Brown fat cells, however, use a glycerol phosphate shuttle (GLI-ser-ol), which passes the electrons to FAD within complex II; consequently, these electrons can energize only the last two proton pumps.

Chemiosmosis Production of ATP

The ETC’s continual pumping of H+ ions into the intermembrane space creates asteep concentration gradient for these ions, which can diffuse back into the matrix through special membrane-bound enzymes called ATP synthases. These enzymes are energized by the protons moving through them and are capable of phosphorylating ADP using “unbound” phosphates obtained from the matrix. This process is called chemiosmosis, so-named because it involves the movement of chemicals (in this case, protons or H+) through a membrane. While osmosis literally means, “push-through process,” think of the protons moving through ATP synthases as being like water moving through a dam and providing energy for the generation of electricity. If O2 molecules are unavailable to accept electrons at the end of the ETC, the ETS will cease to transport electrons. In turn, some of the NADH and FADH2 molecules that have accepted electrons from Kreb cycle reactions will be unable to unload their electron cargo to become NAD+  and FAD. Consequently, fewer Kreb  cycles can occur because there are not enough NAD+ and FAD molecules to accept their electrons. Cyanide is a powerful poison because it binds to the enzyme that transfers electrons from the last ETC compound to oxygen. This binding prevents the enzyme from removing electrons from the ETC, thereby causing the ETC to be overloaded and unable to accept more electrons from NADH and FADH2. Figure 21-4 shows the relationship between glycolysis, fermentation, and aerobic respiration. Theoretically, for each proton pump energized by a pair of electrons, one ATP can be made by the ATP synthase. Therefore, electrons donated to the ETC by one mitochondrial NADH or one cytosolic NADH handing its electrons off to a malate-aspartate shuttle molecule result in the formation of three ATPs. Electrons donated to the ETC by one mitochondrial FADH2 or one cytosolic NADH handing its electrons off to a glycerol-phosphate shuttle molecule result in the formation of two ATPs. The export of ATP from the mitochondrion is coupled to the import of ADP using an antiporter protein in the mitochondrion’s outer membrane.

Theoretical ATP Yield from Glucose

There has been debate over how many ATP molecules are synthesized from the energy derived from one glucose molecule in a typical eukaryotic cell. While the actual number depends on several factors, let’s retrace the steps involved in the complete oxidation of glucose.

ATPs from Glycolysis

Glycolysis uses two ATPs to get started but then makes four ATPs via substrate-level phosphorylation. Therefore, glycolysis generates a net of two ATPs. In addition, glycolysis generates 2 NADHs. Electrons carried by each NADH from glycolysis will drive either two or three proton pumps in the ETS, depending on the particular shuttle system used. In turn, each proton pump moves two protons through the mitochondrion’s inner membrane into the intermembrane space. Each time two protons diffuse back into the mitochondrial matrix through an ATP synthase, one ATP molecule forms. Therefore, glycolysis directly and indirectly yields a net total of 6-8 ATPs.

ATP from the Oxidation of Pyruvate

Oxidation of one glucose molecule yields two py- ruvate molecules, each of which can be oxidized to form an acetyl-CoA. While this reaction does not generate ATP directly, the oxidation of each pyru- vate results in the formation of one NADH. Since these two NADHs are inside the mitochondrion, the electrons from each one will drive three proton pumps, resulting in the formation of 6 ATPs via chemiosmosis.

ATPs from the Kreb’s Cycle

The two acetyl-CoA molecules resulting from the oxidation of two pyruvates enter separate Krebs cycles, and each cycle generates one ATP via substrate-level phosphorylation. Therefore, the two Krebs cycles resulting from the oxidation of one glucose molecule yield two ATPs indirectly. In addition, each Krebs cycle generates electrons that are carried to the ETC by three NADH molecules and one FADH2. Thus, the two Krebs cycles generate electrons for 6 NADH (which yield 18 ATPs indirectly) and 2 FADH2 (which yield 4 ATPs indirectly). For that reason, two Krebs cycles are ultimately responsible for the synthesis of 24 ATPs. Theoretical ATPs/Glucose: (6-8) + 6 + 24 = 36-38 ATPs

Actual ATP Yield from Glucose

The actual number of ATPs synthesized from the energy derived from one glucose molecule is less than the theoretical yield due to several factors.

  1. Some protons “leak” through the mitochondrion’s inner membrane without going through the ATP synthetase; consequently, each mitochondrial NADH yields ~ 5 ATPs, instead of 3, and each FADH2 or cytosolic NADH yields ~1.5 ATPs, instead of 2.
  2. The cell burns ~1 ATP to transport each pyruvate into the mitochondrion.

Therefore, glycolysis, which nets 2 ATPs directly and 2 NADH molecules (each yielding ~3-5 ATPs) probably results in the formation of only 5-7 ATPs. The oxidation of two pyruvates, which forms 2 NADH, yields only about 5 ATPs. Two Kreb cycles yields 2 ATPs, 6 NADH (yielding ~15 ATPs) and 2 FADH2 (yielding ~ 3 ATPs); thus, the total is 28-30 ATPs.

Actual ATPs/Glucose: (5-7) + 5 + 18 = 28-30 ATPs

GLUCOSE STORAGE AND SYNTHESIS

In addition to catabolizing (ka-TAB-ō-līz-ēng) glucose for energy, the body can also store, retrieve, and synthesize glucose. Three processes relate to this capability: glycogenesis, glycogenolysis, and gluconeogenesis.

Glycogenesis

Glycogenesis (glī-kō-JEN-e-sis; glyco, sugar; gen- esis, creation) is an anabolic reaction in which an enzyme, called glycogen synthase, bonds glucose molecules together to form the polysaccharide glycogen. Glycogenesis involves dehydration synthesis and occurs primarily in liver and muscle cells when they contain excess glucose.

Figure 21-8. Glucose storage and retrieval

Glycogenolysis

Glycogenolysis (glī-kō-jen-OL-i-sis) is a catabolic process whereby an enzyme, called glycogen phosphorylase, (fos-FOR-i-lās) breaks apart glycogen to release individual glucose molecules. However, unlike most decomposition reactions that utilize water as a means of breaking bonds (through a process called hydrolysis), glycogen phosphorylase adds a phosphate to glycogen to break bonds between adjacent glucose molecules. Due to this phosphorylation process, each glucose molecule released from glycogen is actually a glucose phosphate, which is able to enter glycolysis.

Most cells can store some glycogen, but liver and muscle cells can store large quantities of it. Unfortunately, the glycogen in muscle cells cannot serve as a source of blood glucose because the resulting glucose phosphates cannot diffuse out of the cell. In contrast, liver cells contain an enzyme called glucose phosphatase (FOS-fa-tās) that can dephosphorylate the glucose phosphate, allowing the phosphate-free glucose to enter the blood. When glucose levels in the blood drop below optimum, certain hormones stimulate liver cells to perform glycogenolysis. Figure 21-8 summarizes glucose storage and retrieval.

Gluconeogenesis

Gluconeogenesis (glū-kō-nē-ō-JEN-i-sis; neo, new) is a process in which the cell uses non- carbohydrate substrates to create glucose. This process occurs in the liver. Substrates that the liver can readily transform into glucose include pyruvate from glycolysis and lactate from fermentation, glycerol (from fats), amino acids, and some compounds from the Kreb’s cycle. The formation of glucose from lactate released from skeletal muscles occurs through a process of reactions known as the Cori cycle. Like glycogenolysis, gluconeogenesis normally occurs when concentrations of glucose in the blood drop below optimum, such as during stress, fight-or-flight activities, and interdigestive periods (between meals). Gluconeogenesis also occurs when the body is utilizing fats as the primary energy source, such as during starvation or if the person has diabetes mellitus.

LIPID METABOLISM

Lipids are not water soluble, but bind to a protein before entering the blood. The protein allows the lipid to circulate in the blood in a more soluble form without clumping together with other lipids. This more water-soluble combination of lipid and protein is a lipoprotein (lī-pō-PRŌ- tēn). As lipoproteins circulate through tissues, cells remove the lipids, using an enzyme called lipoprotein lipase, and then either use the lipids for energy or store them.

Lipogenesis

Lipogenesis (lī-pō-JEN-i-sis) is an anabolic process in which adipocytes (fat cells) and liver cells synthesize and store triglycerides. This process usually occurs during digestive periods immediately following a meal when blood glucose levels are adequate to maintain normal metabolism. More than half of all stored triglycerides are found in the subcutaneous tissue below the dermis (skin). The remainder exists in the genital region, mesentery, and around the kidneys and between skeletal muscles.

Lipolysis

Lipolysis (lī-POL-i-sis) is the process by which cells hydrolyze stored triglycerides to yield glycerol and fatty acids. When there is a lack of carbohydrate, most cells convert glycerol into a compound that will undergo oxidation in glycolysis; however, the liver may convert this compound back to glucose (during gluconeogenesis) and release it into the blood. Cells do not convert fatty acids   to glycolysis compounds or glucose molecules; instead, they hydrolyze fatty acids in a process called beta-oxidation, which occurs inside the mitochondria. During beta-oxidation, an enzyme breaks off two-carbon acetyl fragments from the fatty acid. Each time, the break occurs at the second (or beta) carbon atom. The acetyl CoA, which enters the Kreb’s cycle reactions for further oxidation.

When there is a lack of glucose in the cell, more beta-oxidation of fatty acids occurs. With an excess number of acetyl compounds forming from beta-oxidation accumulates, not all of them can enter the Kreb cycle. The cell then converts the extra acetyl compounds into ketone (KĒ-tōn) compounds. Since most ketones are acidic, this can lead to acidosis when they accumulate in the blood. People with diabetes mellitus have a deficiency of the hormone insulin that helps cells absorb glucose. As a result, most of their cells must utilize lipids as the primary source of energy, which causes excessive ketone production. In severe cases, acetone (a ketone) may be smelled in their breath.

Figure 21-9. The ornithine cycle

PROTEIN METABOLISM

Proteins are the major building blocks in the body and are normally considered a “last resort” energy source, behind carbohydrates and fats. Information about protein synthesis was covered in the first-semester course, and it involves transcription (RNA synthesis in the nucleus) and translation (amino acid sequencing at the ribosomes). Here we will give a brief summary of how amino acids, the building blocks of proteins, are built and how proteins and amino acids are used for energy.

Amino Acid Synthesis

The liver can convert amino acids into other compounds, including other amino acids. The process by which an enzyme converts one amino acid into another amino acid is transamination (trans-am- i-NĀ-shun). In this process, the enzyme removes an amino group from one amino acid and attaches it to a keto (KĒ-tō) acid. The original amino acid becomes a keto acid and the original keto acid becomes an amino acid.

Proteolysis

Proteolysis (prō-tē-OL-i-sis) is the catabolic process by which enzymes hydrolyze proteins to yield amino acids. Other enzymes decompose the amino acids in a process called deamination (dē- am-i-NĀ-shun). During deamination, the enzyme removes the amino group (NH2) from the carbon chain and combines it with a hydrogen atom to form ammonia (NH3). In the liver, several reactions, known as the ornithine cycle (OR-ni-thēn), combine ammonia with carbon dioxide to form urea (ūr-Ē-a) (see Figure 21-9). The urea then enters the blood and later the kidneys remove it and excrete it in urine.

Enzymes can convert deaminated amino acids to either pyruvate or one of the Kreb cycle compounds. If pyruvate forms, it can undergo oxidization in the mitochondrion or it can be reduced to lactic acid or converted to glucose.

INTERCONVERSION OF NUTRIENTS

Liver cells can convert certain nutrients into other nutrients, and these can enter glycolysis and respiration at different steps. In addition, the liver is able to convert some non-carbohydrate substrates into glucose. A summary of these interconversions is shown below:

Carbohydrates←→Glucose←→Pyruvate Carbohydrates←→Organic acids←→Kreb’s cycle Protein ←→ Amino acids ←→ Keto acids ←→ pyruvate Protein ←→ Amino acids ←→ Keto Acids ←→ Kreb’s cycle Protein ←→ Amino acids ←→ Glucose

Triglycerides ←→ Glycerol ←→ Pyruvate

Triglycerides ←→ Glycerol ←→ Glucose

Triglycerides ←→ Fatty acids ←→ Acetyl ←→ Kreb’s cycle

Note that the liver can convert the glycerol component of triglycerides (fats) into glucose but cannot do this with the fatty acid component. Recall that the conversion of non-carbohydrate substrates to glucose is gluconeogenesis.

METABOLIC RATE

Now that you know about some different aspects of nutrient metabolism, we will conclude this chapter with a description of how physiologists measure one’s metabolic rate. Metabolic rate refers to the amount of heat liberated from all anabolic and catabolic reactions in a certain amount of time, and it is usually recorded as Kcal/m2/hr, or kilocalories of heat produced per square meter of body surface area per hour. Physiologists usually measure metabolic rate by one of two methods:
  • Using a calorimeter (kal-ō-RIM-i-ter) that directly measures the amount of heat liberated from the
  • Using a respirometer (res-per-OM-e-ter) that measures the amount of O2 consumed in a given amount of There are approximately 4.8 kcal of heat liberated for each liter of oxygen consumed (i.e., 4.8 Kcal/L). By including the surface area, or some other measure of size, physiologists can compare the metabolic rates of different-size organisms.
Basal Metabolic Rate (BMR) is the amount of energy required to keep a person alive under basal conditions. More specifically, it is the amount of heat produced by all chemical reactions occurring under basal conditions in a given amount of time. Basal conditions means that the person is:
  1. Relaxed
  2. Under no stress
  3. Has had no food for at least 12 hours
  1. Is comfortable—outside temperature~68-80o F
Factors that increase metabolic rate include exercise, stress, certain hormones, food intake, and body temperature. Factors that decrease metabolic rate include outside temperature (within a certain range), height, and weight.

REGULATION OF BODY TEMPERATURE

Higher body temperature increases metabolic rate, and higher metabolic rate can increase body temperature. More specifically, there is a 10% increase in the rate of chemical reactions for every 1oC (2.7oF) rise in cell temperature. The average “core” temperature (deep inside the body) of a healthy human is approximately 37oC (98.6oF.), but temperature in the skin can vary 30oF, depending on the temperature outside the body. At rest, most body heat comes from the liver, heart, brain, and endocrine glands. However, during exercise, contracting skeletal muscles can generate more than 40 times as much heat as all other organs combined. In order to respond to changes in body temperature, the body must be able to detect temperature changes. Thermoreceptors, which respond to changes in temperature, are found in the hypothalamus (the body’s “thermostat”), the skin, and the body’s core. All thermoreceptors send signals (impulses) to the hypothalamus, which can respond in a way to maintain homeostasis.

Response to Low Temperature

When body core temperature drops below normal, the hypothalamus initiates sympathetic activities to increase body heat. The activities include the following heat-promoting mechanisms:

  • Vasoconstriction of skin blood vessels to keep warm blood away from the surface
  • Shivering
  • Increased thyroxine secretion from the thyroid gland
  • Increased piloerection (contraction of arrector pili muscles)
  • In addition to the above physiological reactions, a behavioral response, such as putting on a jacket, getting close toafire, etc. can help retain body heat.

Figure 21-10. The body’s response to core temperature and to outside temperature

Response to High Temperature

Higher body temperature causes the hypothalamus to initiate heat-loss mechanisms, including:

● Vasodilation of skin vessels to allow warm blood to move closer to the surface

● Sweating to allow heat loss through the evaporation of water

● Behavioral responses that promote heat loss include removing clothing, standing in the shade, etc.

Figure 21-10 shows the body’s response to core temperature and to outside temperature.

TOPICS TO KNOW FOR CHAPTER 21

(Nutrient Metabolism)

absorption of monosaccharides
acetyl CoA
acetyl compound
acidosis
adenosine triphosphate
aerobic respiration
amino group
ammonia
anabolism
anaerobic
arginine
ATP
ATP synthases
basal metabolic rate
beta-oxidation
biphosphoglycerate
BMR
C2H12O6
calorimeter
carbon dioxide
catabolism
catalyst
cellular respiration
cellular work
chemiosmosis
citrate
citric acid
citric acid cycle
citrulline
coenzyme A
coenzyme Q
complex carbohydrates
complex I
complex II
complex III
complex IV
copper
CoQ
Cori cycle
creatine phosphate
cyanide
cytochrome a
cytochrome a3
cytochrome b
cytochrome c
cytochrome c1
deamination
decarboxylation
dephosphorylation
dihydroxyacetone phosphate
electron acceptor
electron carrier
electron transport chain
electron transport system
EPOC
ETC
ETS
excess post exercise oxygen consumption
facilitated diffusion
FAD
FADH2
fermentation
Fe-S protein
flavin adenine dinucleotide
flavin mononucleotide
FMN
fructose
fructose biphosphate
fructose-phosphate
fumarate
fumaric acid
G3P
galactose
GDP
glucokinase
gluconeogenesis
glucose
glucose phosphatase
glucose phosphate
glyceraldehyde 3-phosphate
glycerol phosphate shuttle
glycogen
glycogen phosphorylase
glycogen synthase
glycogenesis
glycogenolysis
glycolysis
GTP
guanosine diphosphate
guanosine triphosphate
heat-loss mechanisms
heat-promoting mechanisms
hexokinase
interconversion of nutrients
iron
isocitrate
isocitric acid
isomers
keto acid
ketone
Krebs cycle
lactate
lactic acid
lipid metabolism
lipogenesis
lipolysis
lipoprotein
lipoprotein lipase
malate
malate-aspartate shuttle
malic acid
membrane carrier
metabolic rate
metabolism
mitochondrial vs. cytosolic NADH
molecular oxygen
monosaccharides
NAD
NAD+
NADH
NADH + H+
NH2
NH3
niacin
nicotinamide adenine dinucleotide
O2
ornithine cycle
oxalate
oxaloacelate
oxaloacetic acid
oxidation
oxidation of glucose
oxidation of pyruvate
oxidative phosphorylation
oxygen debt
pantothenic acid
phosphoenol pyruvate
phosphoglycerate
phosphorylation
piloerection
polysaccharide
protein metabolism
proteolysis
proton gradient
proton pump
pyruvate
pyruvic acid
redox reactions
reduction
regulation of body temperature
respirometer
riboflavin
secondary active transport
shuttle system
substrate-level phosphorylation
sulfur
succinate
succinic acid
succinyl-CoA
symporter
TCA cycle
theoretical ATP yield from glucose
thermoreceptor
transamination
transcription
translation
tricarboxylic acid cycle
triglycerides
ubiquinone
unbound phosphate
urea
vasoconstriction
vasodilation
vitamin B2
vitamin B3
vitamin B5
α-ketoglutarate
α-ketoglutaric acid


EOC Questions

EOC Questions