Metabolism: Understanding the Interactions and Transformations in Living Cells

METABOLISM: UNDERSTANDING THE INTERACTIONS AND TRANSFORMATIONS IN LIVING CELLS

WHAT IS METABOLISM? molecule. The vast majority of chemical Metabolism is all the life-sustaining chemi- reactions that occur in the body are cal reactions that occur in living organisms catalyzed (initiated and accelerated) by and transform one molecule into another enzymes, which are proteins that facilitate one. The chemical reactions may rearrange reactions without themselves being altered atoms within a molecule, add atoms to a so they can perform the same reaction over molecule, or remove atoms from a and over again.

UNDERSTANDING METABOLISM

KEY IDEAS Metabolism is all the life-sustaining chemical reactions that occur in living organisms that convert one molecule into another molecule. Many metabolic processes fall into one of two broad categories, catabolism and anabolism. Catabolism is the breakdown of large molecules into smaller ones, and is generally accompanied by the release of energy. Anabolism is the synthesis of large molecules from smaller ones, requiring an input of energy that is often obtained from the oxidation of fuels that are provided by catabolic reactions. Since digestion occurs within the lumen of the gastrointestinal tract, which is fundamentally still outside the body, digestion is not considered to be metabolism.

How Do Enzymes Work?

Starch 1 Starch binds to Enzymes can catalyze the enzyme. chemical reactions only with speciﬁc compounds that can bind at their active site.

To bind and initiate a reaction, Enzyme active site the shape of this 2 The enzyme breaks the amylase enzyme bond between two Enzyme must exactly glucose molecules. The enzyme can now 4 match that of the act again on another starch molecule. starch molecule.

EnzymesE are proteins that facilitate cchemical reactions without being altered themselves. This enzyme 3 Two starch fragments (amylase) breaks down starch, a long are released. chain of sugar (glucose) molecules. ? Why won’t this enzyme break down lipids or proteins?

POP_14867_met_MET0-MET14_PP2.indd 2 10/24/18 5:50 PM How Do Coenzymes Work? Coenzymes associate with enzymes to form an active complex that is capable of catalyzing a chemical reaction. Some vitamins function as coenzymes.

Coenzyme Substrate (vitamin) binds to enzyme

Enzyme is inactive without the required coenzyme

Inactive enzyme Active enzyme Active enzyme With the substrates and The reaction occurs coenzyme in place, the and the products reaction can proceed. are released. ? Describe the basic function of a coenzyme.

The molecule that an enzyme acts on is ones, and is generally accompanied by the referred to as a substrate, and the modifi ed release of energy. Catabolic processes supply molecule that the reaction yields is called the the fuels that are needed to drive anabolism, product. Many enzymes require small, and they can also provide the substrates organic, nonprotein molecules called needed for a number of anabolic processes. coenzymes to function. Coenzymes bind at a The balance between all anabolic and cata- location on the enzyme known as the active bolic processes over the course of several days site and form an active enzyme, which is only will determine if an individual’s weight will then capable of catalyzing its designated remain stable, or whether he or she will expe- reaction. Vitamins C and K, and all of the B rience a change in body weight. For example, vitamins function as coenzymes. if the total number of catabolic processes Many of the chemical transformations that exceeds that of anabolic processes, an indi- occur within cells require multiple individual vidual’s body weight would decrease, as adi- reactions to be completed in a series. For this pose tissue and muscle mass are lost. reason, cellular metabolism is typically orga- Energy metabolism is the chemical reac- nized into metabolic pathways. Each pathway tions that are involved in storing fuels, or transforms its original substrate into a fi nal breaking them down to provide the energy product or products through a sequence of necessary to drive a variety of chemical reac- linked enzyme-catalyzed reactions. At each step tions and other cellular processes (such as in the pathway the product formed in one reac- active transport and muscle contractions). tion becomes the substrate for the next reaction This energy comes from one of two main fuel in the pathway until the fi nal product is formed. sources: glucose and fatty acids. Both of these Many metabolic processes fall into one of fuels are rich in chemical energy, stored in the two broad categories: anabolism and chemical bonds that hold each molecule catabolism. Anabolism is the synthesis of together. As fuels are slowly metabolized and large molecules from smaller ones, requiring broken down, energy is released and the prod- an input of energy. Common anabolic pro- uct of each reaction contains less energy than cesses are those that synthesize proteins from the starting substrate. This released energy is amino acids, glycogen from glucose, and tri- not in a form the body cells can use; it must glycerides from sources of excess calories be converted into a molecule called adenosine (such as glucose and amino acids). Cell divi- triphosphate (ATP). sion and growth are also anabolic processes. Commonly referred to as the cell’s energy Catabolism, on the other hand, is the currency, ATP stores chemical energy in the breakdown of large molecules into smaller bonds of its three phosphate groups. When

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Adenosine Triphosphate (ATP) is produced during energy metabolism. ATP has a high energy content and is often referred to as the energy currency of cells.

Energy Triphosphate Diphosphate Phosphate

Adenosine P P P Adenosine P P + P

ATP ADP

Energy is released when the bond between the second and third phosphate of ATP is broken. A portion of the released energy can be captured to do work, such as fueling muscle contractions. ADP is then used to reform ATP.

our cells need energy, they typically break the coffee with it. ATP, however, is like bills and bond between the last two phosphates, releas- coins—it’s energy your cells can actually ing the stored energy and forming adenosine spend. The primary metabolic pathways diphosphate (ADP). (The “di” in diphosphate involved in producing ATP are glycolysis, the means “two,” as in two phosphates; the “tri” in citric acid cycle, and the electron transport “triphosphate” refers to its three phosphates.) chain (ETC). You can think of the energy in glucose The reactions of energy metabolism pri- and fat as the value of a gold brick: It’s worth marily occur in two cellular compartments, a lot of money, but you can’t buy a cup of the cytosol and the mitochondria. Recall that cells are surrounded by a cell mem-

The cytoplasm includes brane. Within the cell membrane is an aque- the cytosol and all the ous fl uid called the cytosol, as well as a organelles except the nucleus. number of cellular organelles and other structures. The membrane-enclosed organelles (such as mitochondria, endoplasmic reticulum, and the nucleus) carry out a variety of specialized functions. The cytoplasm includes the cytosol and all the organelles except the nucleus. Glucose oxidation (glycolysis) is the only ATP-producing pathway that occurs in the cytosol. Nucleus All other pathways involved in the produc- Rough tion of ATP occur in mitochondria, which endoplasmic reticulum produce the majority of ATP in most cells. Mitochondria are organelles surrounded by a Mitochondria double-membrane system composed of an

Cell membrane inner and outer membrane. The space that is enclosed by the inner membrane is called the matrix. See the Cellular Respiration illustration on page 7. The majority of the functions Cells are the smallest functional unit of living organisms. This is an example of the most common type of cell (an carried out by mitochondria occur in the Enterocyte) found in the lining of the small intestine. A matrix, and in this location the oxygen few of the cellular organelles are labeled. we breathe is used to generate ATP.

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POP_14867_met_MET0-MET14_PP2.indd 2 10/24/18 5:50 PM The breakdown of glucose

Oxidation-reduction reactions involve the transfer of electrons between compounds and play a vital role in energy metabolism. Compound OXIDATION Compound A A Memory hint: Oxidation is the loss of electrons and As the addition of e− The loss of an electron reduction is the gain of electrons. Because (or a hydrogen atom) is a negative number an oxidation reaction. reduces the sum, electrons do not fl oat around free in solution the addition of a − e negatively charged they are always transferred from one sub- electron reduces stance to another, so that as one substance Compound REDUCTION Compound the substance. B B loses an electron another substance simulta- The gain of an electron (or a hydrogen atom) is neously gains that electron. The substance a reduction reaction. that loses an electron is oxidized and the substance that gains an electron is reduced. Oxidation-Reduction Reaction

OVERVIEW OF ENERGY METABOLISM Compound Compound OXIDIZED As fuels provided by our diet are broken down A A − into smaller and smaller molecules they e undergo a series of oxidation reactions. Energy to produce ATP is extracted from the fuels as e− they are oxidized in what is essentially a con- trolled burn. This gradual breakdown and oxi- Compound Compound REDUCED B B dation of fuels allows us to capture some of the chemical energy in those fuels to do work, Because free electrons are not stable, their removal (oxidation) from one substance such as physical movement, anabolic reac- must be accompanied by their acceptance (reduction) by another substance. tions, and active transport. Coenzymes synthesized from the vitamins Some Coenzymes Participate in niacin and ribofl avin function as electron car- Oxidation-Reduction Reactions riers and are involved in transferring electrons (and/or hydrogen atoms) from one substance AH BH to another in energy metabolism. As fuels are oxidized, high-energy electrons are trans- Compound A is Compound B is oxidized and the Coenzyme reduced and the ferred to these coenzymes. It is the reduction coenzyme is reduced coenzyme is oxidized of coenzymes that conserves much of the H+ e− chemical bond energy that is released during A B the oxidation of our metabolic fuels. The reduced coenzymes shuttle their high-energy Coenzymes synthesized from the vitamins niacin and riboﬂavin are often involved in transferring hydrogen atoms, and/or electrons from one substance to another. electron cargo to the electron transport chain (ETC) in mitochondria where a series of What Are Oxidation-Reduction Reactions? Biological oxidation-reduction reactions are critical to life and are essential electron- carrier molecules are embedded in for energy metabolism. Oxidation-reduction reactions involve the the inner mitochondrial membrane. As elec- transfer of electrons (or hydrogen atoms) between compounds, trons are passed from one molecule to and are vital for the extraction and use of the energy that is supplied by the fuels that are provided in the foods we eat. another, energy is released. This energy can be used to synthesize ATP. See the Overview of Energy Metabolism illustration on page 4. process of glycolysis (or the glycolytic pathway), which does not require oxygen. Glycolysis means to break apart glucose, and THE BREAKDOWN OF GLUCOSE it splits the six-carbon glucose molecule into Glucose Metabolism Begins in the Cytosol two 3-carbon molecules of pyruvate, with a net and Is Completed in Mitochondria gain of two ATP and the production of two All cells in the body are able to use glucose as reduced coenzymes. The fi nal steps in glucose fuel to produce ATP. The fi rst step in glucose oxidation occur in mitochondria. When there oxidation occurs in the cytosol with the is adequate oxygen, pyruvate is transported

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OVERVIEW OF ENERGY METABOLISM

METABOLIC PATHWAYS 2 FUELS 1 1 Fatty acids, glucose, and amino acids are the primary fuels Fatty Amino metabolized to provide Glucose Acids Acids us with the energy we need to do work.

e− Glycolysis 2 The metabolic − e pathways by which the energy provided by Pyruvate these fuels is released and used to produce ATP are glycolysis, the citric acid cycle, and e− the electron transport chain (ETC).

e− 3 Acetyl-CoA 3 Each fuel enters these Citric metabolic pathways at e− Acid dierent stages. Cycle

CO2

4 4 The metabolism of all fuels releases high- High-Energy energy electrons that Electrons are carried to the ETC e− e− by reduced coenzymes NADH is produced during glycolysis, citric acid cycle, and ß-oxidation (NADH and/or FADH2) . FADH2 is produced during the citric acid cycle and ß-oxidation 5 ATP

Coenzyme

5 Fuel metabolism Electron produces ATP that is Carriers used to provide energy required to accomplish Electron the work of moving, Transport synthesizing chemical compounds, and active Chain transport. H2O

into mitochondria, where the aerobic (oxygen- Glycolysis occurs in two phases, an energy dependent) oxidation of pyruvate to carbon investment phase and an energy payoff

dioxide (CO2) and water completes the oxida- phase. During the fi rst phase, glucose is rear- tion of glucose. ranged into fructose, and energy is invested as phosphates from two ATP molecules are Glycolysis—the First Step in Glucose Oxidation transferred to the sugar molecule to make it Glycolysis is a universal process that allows more reactive. The doubly phosphorylated every cell in the body to extract energy from fructose can then be split into two 3-carbon carbohydrates. phosphate-containing molecules.

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Glycolysis is the metabolic pathway by which all cells can produce ATP by breaking down glucose to pyruvate. Glycolysis occurs in the cytosol of the cell and does not require oxygen.

GLYCOLYSIS

Phase 1: C Energy Investment C O

C Glucose C

C C

ATP 1 1 The ﬁrst phase of glycolysis 2 ADP requires an input of energy from ATP, using enzymes to add two phosphate molecules from ATP to glucose. P C O C P C C Fructose 2 2 The phosphorylated sugar (now C C fructose) is then cleaved into two 3-carbon molecules, each with one phosphate.

P C C C C C C P

3 Pi Pi Phase 2: 3 The second phase of glycolysis Energy Payo 4 results in the net production of ATP.

P C C C P P C C C P 4 Enzymes add a phosphate to each of these three-carbon molecules. NAD+ NAD+ This does not use ATP.

5 These three-carbon molecules 5 are then oxidized while two coenzymes NAD+ are reduced. H+ e− H+ e− 6

To ETC NADH NADH To ETC

6 When O2 availability is sucient 2 ADP 2 ADP the reduced coenzymes transfer the hydrogen atoms with their 7 high-energy electrons into mitochondria. 2 ATP 2 ATP

7 In two separate enzymatic reactions, all four phosphates are transferred to ADP to form four C C C C C C molecules of ATP. Pyruvate

Summary: Each molecule of glucose produces two molecules of pyruvate, two reduced coenzymes, and four ATP. Since two ATP were used during the energy investment phase, glycolysis results in the net production of two ATP.

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In the energy payoff phase of glycolysis, reduced coenzymes (three NADH and one

energy is harvested as these phosphorylated FADH2), and a GTP, which is an ATP-like mole- three-carbon molecules are oxidized to form cule that is energetically equivalent to pro- two molecules of pyruvate. During this phase ducing ATP (step 5 in the Cellular Respiration of glycolysis four ATP are produced. Since two illustration). ATP were used during the energy investment The citric acid cycle not only completes phase there is a net yield of two ATP. the oxidation of glucose, it is also the final In addition, two coenzymes (NAD+) are oxidative pathway for fatty acids and amino reduced (to NADH) as they acquire high-energy acids. Fatty acids also enter the citric acid electrons (along with a positively charged cycle as acetyl-CoA, while amino acids enter hydrogen ion). When sufficientoxygen is pres- at several different points along the pathway. ent these high-energy electrons will be transferred to the ETC in mitochondria. Reduced Coenzymes Transfer High-Energy Electrons to the Electron Transport Chain The Bridge Reaction Prepares Pyruvate for At the completion of the citric acid cycle the Complete Oxidation oxidation of glucose has yielded 12 reduced Sufficient oxygen availability also allows pyru- coenzymes: two from glycolysis, two from the vate to enter mitochondria where its oxidation oxidation of two molecules of pyruvate to can be completed. The aerobic oxidation of acetyl-CoA, and eight from the oxidation of

pyruvate is responsible for generating the two molecules of acetyl-CoA to CO2 in the cit- majority of ATP that is derived from glucose ric acid cycle. With the completion of glucose metabolism. However, for pyruvate to enter the oxidation in the citric acid cycle the majority next major pathway of energy metabolism (the of the chemical bond energy originally present citric acid cycle), it must first be transformed is now conserved in the high-energy electrons into a two-carbon molecule in a reaction cata- carried by these reduced coenzymes. lyzed by the enzyme pyruvate dehydrogenase. To use the energy conserved in reduced This is step 3 in the Cellular Respiration illus- coenzymes, they transfer their high-energy tration following. electrons to the ETC embedded in the Coenzyme A attaches to pyruvate, which inner-mitochondrial membrane. As electrons

allows a CO2 to be released. This produces move down the ETC they gradually lose the two-carbon acetyl-coenzyme A molecule energy, which is captured, and can then be (acetyl-CoA) and a reduced coenzyme used to synthesize the majority of ATP that is

(NADH). (The release of CO2 at this step is produced by the metabolism of glucose (steps directly dependent on a coenzyme synthe- 6 and 7 in the Cellular Respiration illustration sized from thiamin. A similar thiamin- following).

dependent CO2-producing reaction also The transfer of electrons from reduced occurs approximately midway through coenzymes to the ETC is also critically import- the citric acid cycle.) ant because it returns the coenzymes to their oxidized form, which allows them to continue The Citric Acid Cycle is the Final Step in participating in the oxidation of metabolic Glucose Oxidation fuels. If the electron transfer did not occur The final step in the oxidation of glucose reduced coenzymes would accumulate, and involves entry of acetyl-CoA into the mito- oxidized coenzymes would become depleted. chondrial pathway called the citric acid cycle With an inadequate number of coenzymes (step 4 in the Cellular Respiration illustration available to accept electrons from fuels as they following). This pathway is also commonly are oxidized, oxidation would slow dramati- referred to by two other names: the tricarbox- cally and eventually stop. ylic acid (TCA) cycle and the Krebs cycle (after At the end of the ETC, electrons combine the scientist who first described it). with oxygen and positively charged hydrogen In the citric acid cycle, acetyl-CoA is oxi- ions to form water (step 8 in the Cellular

dized to produce two molecules of CO2, four Respiration illustration following).

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Cellular Respiration is the process by which the energy stored in fuels is transferred to ATP through a series of enzyme-catalyzed reactions. Aerobic respiration requires oxygen and occurs in mitochondria, where fatty acids and pyruvate are broken down to carbon dioxide and water.

CELLULAR RESPIRATION

C C O 1 Glycolysis occurs in the cytosol C Glucose C where glucose is broken down to C C CYTOSOL two molecules of MITOCHONDRIA pyruvate, which produces two ATP and transfers two Glycolysis 2 ATP electrons to − coenzymes. 1 2 e Electron C C C Transport Chain 2 Pyruvate ATP

Ele 7 2 Pyruvate is ctro n ca 6 − transported into rriers e NA mitochondria. DH e− 2 “Co-A” stands for e− coenzyme A, synthesized 8 rs e from the vitamin ri ar c 1 pantothenic acid. n /2 O2 tro H ec D 3 El A + Pyruvate and C C C N E 2 H H O le 2 c fatty acids are Pyruvate CO t 2 ro both broken down CoA n c − a r to acetyl-CoA in e r ie r mitochondria, s releasing one 4 electron for 3 C C CoA pyruvate and two Citric 2 CO2 electrons for MATRIX Acetyl-CoA Acid 5 every acetyl-CoA released during 2 e− Cycle

the breakdown of − NA 4 e fatty acids. D C C C C C C ... C C H a 3 NADH, n Fatty acids d 1 FADH2 F A D H ATP 2 4 The two-carbon “acetyl” portion of acetyl-CoA reacts with a four-carbon molecule that is part of the citric acid cycle, forming the six-carbon molecule citric acid, which gives the cycle its name. Coenzyme A is released in the process. 7 As electrons move down the ETC they lose energy, which is captured and then used to 5 Through a series of reactions the citric acid cycle removes two synthesize the vast majority of the ATP that carbons from citric acid to produce two molecules of carbon is produced during cellular respiration. dioxide, one ATP, and transfers four electrons to coenzymes.

8 At the end of the ETC, electrons combine 6 Coenzymes transfer high-energy electrons to the electron with oxygen and hydrogen to produce water. transport chain (ETC).

? What carries electrons produced during glycolysis, the citric acid cycle, and fatty acid oxidation to the electron transport chain?

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Total Net Yield of ATP from Glucose the attachment of coenzyme A and the Oxidation cutting-off of two carbons at a time (as The complete aerobic oxidation of one acetyl-CoA) from the fatty acid. However, with molecule of glucose produces a total of the release of each acetyl-CoA molecule from 32 molecules of ATP from three different the fatty acid, two coenzymes (one NAD and sources. Glycolysis produces a net yield of two one FAD) are reduced, instead of just one as ATP. Two ATP (GTP) are produced by the citric occurred with pyruvate. Refer to the Cellular acid cycle, and 28 ATP are produced from the Respiration illustration on page 7. energy captured by the transport of electrons For an 18-carbon fatty acid this produces down the ETC. Since both the citric acid cycle nine acetyl-CoA molecules that will be and the ETC are aerobic pathways, 30 of the oxidized by the citric acid cycle. Since one maximum 32 ATP produced by glucose oxida- coenzyme A was attached to the fatty acid tion are produced in an oxygen-dependent when it was activated, and the last reaction manner. of beta-oxidation yields two acetyl-CoA Under some circumstances glycolysis molecules, this requires only eight rounds of produces pyruvate and reduced coenzymes beta-oxidation, producing 16 reduced faster than the aerobic pathways in mitochon- coenzymes. dria can process them. This may occur when glycolysis metabolizes glucose at very rapid Tallying Total ATP Production by Fatty Acid rates to meet high energy demands, or if the Oxidation activity of the ETC is slowed because of limited Recall that each turn of the citric acid cycle oxygen availability. See the Aerobic Versus produces four reduced coenzymes and the Anaerobic Glycolysis illustration on page 9. equivalent of one ATP, so the oxidation of In these circumstances an alternative these nine acetyl-CoA molecules produced means to return reduced coenzymes (NADH) in from an 18-carbon fatty acid will yield nine the cytosol to their oxidized form (NAD+) must ATP and 36 reduced coenzymes. In addition, be used so that glycolysis can continue to pro- 16 coenzymes were reduced during beta- vide ATP. This is accomplished by pyruvate oxidation, so there is a total production of functioning as an alternative hydrogen atom 52 reduced coenzymes. With the transfer of acceptor (both the electron and the positively their high-energy electrons to the ETC the charged hydrogen ion). Reduced coenzymes can reduced coenzymes yield 113 ATP, for a total transfer their hydrogen atom to pyruvate, trans- of 122 ATP produced. After subtracting the forming it to lactate. This quickly regenerates 2 ATP required for the initial activation of the oxidized coenzymes that can then participate fatty acid the final net yield of ATP produced in another round of glycolysis. from an 18-carbon fatty acid is 120 ATP.

FATTY ACID OXIDATION OCCURS IN Fat versus Glucose—ATP Production and THE MITOCHONDRIAL MATRIX Oxygen Consumption Unlike glucose, the oxidation of fatty acids for The oxidation of fatty acids yields more ATP energy occurs completely in mitochondria per carbon atom than is produced from and only in aerobic conditions. Before fatty glucose oxidation. Oxidation of an 18-carbon acids can be transported into the matrix they fatty acid produces a total of 120 ATP, while must be activated by the enzymatic attach- the oxidation of three molecules of glucose ment of coenzyme A, a reaction that requires (with a total of 18 carbons) produces a total of energy input equivalent to that of converting 96 ATP (3 3 32 5 96). two molecules of ATP to ADP. Although the oxidation of fats produces Once fatty acids have been transported into more ATP per carbon than is obtained from the mitochondrial matrix they are oxidized by carbohydrates, it also requires a greater a process called beta-oxidation. Similar to amount of oxygen consumption. The com- what occurred with the mitochondrial plete oxidation of an 18-carbon fatty acid or oxidation of pyruvate, beta-oxidation involves three molecules of glucose both produce

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Aerobic Versus Anaerobic Glycolysis: In aerobic glycolysis reduced coenzymes are oxidized by the electron transport chain, while in anaerobic glycolysis reduced coenzymes are oxidized by converting pyruvate to lactate.

AEROBIC GLYCOLYSIS ANAEROBIC GLYCOLYSIS

C C C O C O

C Glucose C C Glucose C

C C C C + + NAD 3 NAD 7 Glycolysis 2 Glycolysis 4 + − + − 5 H e To mitochondria H e To mitmitochondriaoc and the ETC andand tthehe ETC NADH NADH

H 1 6 O O O

CCC CCC CCC 2 Pyruvate 2 Pyruvate 2 Lactate

1 During glycolysis, two NAD+’s are reduced 4 Under some conditions, such as during intense exercise, or when when they each pick up a hydrogen atom (a oxygen availability is limiting, glycolysis produces NADH faster than hydrogen ion and an electron) as glucose is they can be oxidized back to NAD+ by the ETC in mitochondria. metabolized to pyruvate.

5 The limited capacity of the ETC to oxidize a su cient number of 2 Typically, the reduced coenzymes would be reduced coenzymes (carrying a hydrogen atom) would cause oxidized in the mitochondria as they deliver glycolysis to slow dramatically as the availability of NAD+ the hydrogen atom into mitochondria, with (oxidized coenzymes without a hydrogen atom) decreases. the electron entering the electron transport chain (ETC). 6 To prevent this from occurring, the reduced coenzymes can donate their hydrogen atom to pyruvate to form lactate. 3 This regenerates the oxidized form of the coenzyme that is needed for glycolysis to continue. 7 The reduction of pyruvate to lactate quickly regenerates NAD+, allowing glycolysis to continue at a rapid rate. This is referred to as “anaerobic” glycolysis, even though it often occurs in situations where oxygen is abundant.

What are two ways that the coenzymes reduced during glycolysis can be returned to their oxidized form? ? When rates of glycolysis are very high, how are the vast majority of coenzymes returned to their oxidized form? How would the elimination of mitochondria from skeletal muscle affect both the availability of oxygen in muscle, and its reliance on anaerobic glycolysis for ATP production?

18 CO2 molecules and 18 H2O molecules, con- breathe. In contrast, the three molecules of taining a total of 54 oxygen atoms. Because glucose (with a total of 18 carbons) initially the fatty acid initially contains only two oxy- contain 18 oxygen atoms, so only 36 oxygen

gen atoms this requires an input of 52 oxygen atoms, or 18 molecules of O2, from the air we

atoms, or 26 molecules of O2, from the air we breathe are needed.

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Carbons ATP produced O2 consumed ATP/O 2

Three glucose molecules 18 96 18 5.3

One 18-carbon fatty acid 18 120 26 4.6

An examination of the ratio of ATP pro- phosphate) synthesized from vitamin B6. The duced to oxygen consumed during carbohy- transfer of the amino group allows nonessen- drate and fat oxidation reveals that tial amino acids to be synthesized. It also pre- carbohydrate oxidation produces more ATP vents the release of large quantities of the per molecule of oxygen consumed. amino group, which would accumulate in the body as ammonia and is potentially toxic. KETOGENESIS Instead, the transfer of the amino group When individuals undergo fasting, follow a allows the liver to carefully control the release very-low-carbohydrate diet, or have untreated of the amino group so that the ammonia can type 1 diabetes, a class of compounds called be effectively converted into the less-toxic ketone bodies are synthesized from acetyl- waste product urea. Urea is then transported CoA produced by beta-oxidation in liver in blood to the kidneys where it is filtered and mitochondria. These compounds are beta- then excreted in urine. hydroxybutyrate, acetoacetate, and acetone. Once the amino group has been removed Ketone bodies are produced when insulin con- the remaining carbon skeleton can be used to centrations are very low and the rate of fatty synthesize glucose when blood glucose is low, acid oxidation produces acetyl-CoA faster or fatty acids when excess energy is con- than it can enter the citric acid cycle. sumed. To a lesser degree it can also be The resulting increase in acetyl-CoA metabolized directly as a source of energy. concentrations in liver mitochondria causes When used as a direct energy source the car- two molecules of acetyl-CoA to be joined bon skeletons from various amino acids enter together, which begins the process of ketone the citric acid cycle at several different points body synthesis (also known as ketogenesis). in the cycle where they are oxidized to pro- As will be discussed later, the production of duce reduced coenzymes. As we have seen ketone bodies during a fast is an important with the oxidation of pyruvate and fatty metabolic adaptation, as it provides an alter- acids, the majority of ATP is then produced native energy source for the brain that slows once the high-energy electrons carried by the the catabolism and loss of body proteins. reduced coenzymes are transferred to the ETC. See the Amino Acid Metabolism illustra- AMINO ACID METABOLISM tion on page 11. Amino acids are supplied by our diet as well as by the continual breakdown of body pro- ALCOHOL METABOLISM teins. Although most amino acids in the body Alcohol is readily absorbed into the blood- are used to synthesize proteins, they are also stream through diffusion and then is trans- used to synthesize a variety of other com- ported to the body’s cells and tissues and pounds. In many cases amino acid metabo- dispersed throughout the water-containing lism requires that they first be stripped of portions of the body. Approximately one-fifth their amino group, and the remaining carbon of all alcohol consumed is absorbed through skeleton has several possible fates. the stomach; the rest is absorbed in the small The liver is the major site of amino acid intestine. When consumed in moderate metabolism in the body. In many cases, the amounts, alcohol is metabolized primarily amino group is removed from amino acids in the liver by a two-step process to form and then transferred to other compounds in acetate . In the first step, the enzymealcohol reactions that require a coenzyme (pyridoxal dehydrogenase (ADH) converts alcohol to

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Amino Acid Metabolism Amino acids are metabolized to produce many important compounds. When used as a source of energy or to synthesize glucose or fat, the first step in their metabolism is to remove the amino group and transfer it to another chemical compound in a reaction requiring a coenzyme synthesized from vitamin B6. Amino Acids

Tyr Trp Asn Phe Ala Ile Leu Val Thr His Asp Glu Arg Cys Gln Met Ser Lys Pro Nitrogen from amino Gly Metabolized to produce critical acids is incorporated nitrogen-containing compounds. into urea in the liver. Amino acids and the nitrogen they Nitrogen contain are incorporated into the removed structures of these compounds. Urea Vitamin B6

Carbon Skeleton Once the amino group is removed from amino acids the remaining carbon skeleton has several possible fates.

Urea is excreted Energy Glucose Fat in urine.

Amino acids are used to synthesize glucose only when blood glucose is low, and fat only after eating (in small amounts).

acetaldehyde, which is a highly reactive and of alcohol. However, the activity of this system toxic compound that can damage cellular increases with chronic consumption of high components, including DNA. Acetaldehyde is amounts of alcohol. As a result, alcohol is then converted to acetate by the enzyme metabolized more quickly and alcohol concen- acetaldehyde dehydrogenase (ALDH), and ace- trations in blood do not increase as much as tate then disperses to tissues throughout the they would under normal circumstances, body where it is converted to acetyl- coenzyme which explains why tolerance of alcohol A, which can be used as a source of energy in increases in those who drink frequently. The the liver and elsewhere in the body. With increased speed of alcohol metabolism has a higher levels of alcohol intake, the excessive downside; it also speeds production of the amount of acetyl-coenzyme A that is produced highly toxic acetaldehyde, which increases tis- in the liver results in high levels of fat synthe- sue damage and the risk of cancer. sis that can cause a fatty liver and, eventually, liver damage. Most alcohol is metabolized to FEASTING AND FASTING CYCLE— acetate in the liver, but a small amount can COORDINATING METABOLIC also be metabolized in the stomach by the ADAPTATIONS IN PATHWAYS OF same two-step process. See the Alcohol ENERGY METABOLISM Absorption and Metabolism illustration on We all experience a daily cycle of feasting and page 12. fasting that occurs after we consume our last The microsomal ethanol-oxidizing system meal of the day, fast while we sleep, and then (MEOS), found in the endoplasmic reticulum of break our fast with our fi rst meal the following liver cells, is an alternative means of oxidizing day. This daily cycle of feasting and fasting alcohol (ethanol) to acetaldehyde. Normally requires pathways of energy metabolism to be this system contributes little to the metabolism carefully coordinated. Excess energy provided

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Alcohol Absorption and Metabolism Alcohol is metabolized primarily in the liver where the enzyme alcohol dehydrogenase (ADH) converts alcohol to acetaldehyde. Acetaldehyde is then converted to acetate by acetaldehyde dehydrogenase (ALDH). Acetate can either be metabolized as a source of energy-producing carbon dioxide and water, or it can be used to synthesize fat.

6 A small amount of alcohol is metabolized by the brain.

5 Alcohol that is not removed by the liver circulates throughout the rest of the body. 1 The stomach immediately absorbs approximately 20% of the alcohol Lower body water content in consumed. The women causes blood alcohol presence of food in concentrations to increase the stomach will more quickly than in men of slow alcohol the same body weight. absorption. The majority of The stomach 4 2 alcohol is metabolized metabolizes a Liver in the liver. small amount of Acetate the alcohol that is absorbed there. ALDH Acetaldehyde

ADH Alcohol 3 The small intestine (ethanol) Acetaldehyde is absorbs about highly toxic. It 80% of the causes many of ingested alcohol. the ill eects caused by alcohol Alcohol consumption. absorbed from stomach and small intestine StockLite/Shutterstock ? Why are individuals with high rates of ADH activity and low rates of ALDH activity at low risk of alcohol use disorder?

by meals (feasting) beyond our immediate regulation of the metabolic adaptations that needs must be stored (anabolism) so that occur with feasting and fasting. Insulin is those stores can subsequently be mobilized released when meals containing carbohy- (catabolism) to supply energy when fasting. drates and protein are consumed, and it is the Because pathways of energy storage and mobi- key hormone that stimulates fuel storage. lization work in opposition to each other they Glucagon and epinephrine are released as must be regulated in opposite directions. This blood glucose concentrations drop during a regulation is achieved largely by hormones fast, and they are the key hormones that that control the activities of key enzymes in stimulate fuel mobilization. metabolic pathways to coordinate the metabolic adaptions that accompany periods of Primary Sites of Hormone Action feasting and fasting. Insulin stimulates glycogen synthesis in the Insulin, glucagon, and epinephrine are liver and muscle, and fat synthesis in the liver. the key hormones involved in the short-term It also inhibits the breakdown of glycogen, fat,

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and proteins. The primary site of glucagon As the time following the last evening action is the liver, where it increases glucose meal lengthens blood glucose begins to production by stimulating glycogen break- decrease, causing insulin levels to fall and down and glucose synthesis from noncarbo- glucagon and epinephrine levels to rise. hydrate sources ( gluconeogenesis). Although Glucagon and epinephrine stimulate the liver epinephrine is often associated with the to breakdown glucagon to glucose and release fight-or-flight response, which requires the it into blood. While these hormones also stim- mobilization of fuels to supply energy to con- ulate the liver to synthesize glucose (glucone- tracting muscles, it also has an important ogenesis) from noncarbohydrate sources such role in regulating energy metabolism during as amino acids, this does not occur at high a fast. Like glucagon, epinephrine stimulates rates until liver glycogen has been signifi- glucose production in the liver. It is also the cantly depleted. primary hormone that stimulates the release Epinephrine also activates two lipases in of fatty acids from triglycerides stored in adipose tissue that release fatty acids adipose tissue. (lipolysis) from triglycerides stored there. Fatty acids supply the vast majority of energy Feasting Metabolism—Fuel Storage for most tissues throughout the body while Following a Meal fasting. Insulin stimulates the storage of glucose Extended fast—starvation As the fast con- as glycogen in the liver (and skeletal mus- tinues liver glycogen is depleted after approx- cle if it has been depleted by exercise) after imately 24 hours and all glucose must be meals containing carbohydrates, proteins, supplied by gluconeogenesis in the liver, and fats. Once glycogen stores are replen- which uses primarily the carbon skeletons ished the remaining glucose tends to be from amino acids to synthesize glucose. This oxidized to meet the body’s immediate results in a rapid loss of skeletal muscle mass energy needs. Insulin also stimulates the and high rates of urea production to dispose storage of fatty acids as triglycerides in adi- of the amino groups that have been stripped pose tissue. Generally, little glucose is used from these amino acids. to synthesize fat, as it is more efficient to If a fast is extended and the individual store ingested fat as triglycerides than it is moves into a state of starvation, additional to convert glucose into fatty acids. However, adaptions occur to prolong the life. Key among when carbohydrates are consumed in large these is the preservation of body proteins. excess, insulin stimulates both liver and During a fast, the brain is by far the adipose tissue to convert acetyl-CoA gener- largest consumer of glucose in the body ated from glucose oxidation to be used to because it cannot obtain an appreciable synthesize fatty acids and then store them amount of energy from fat; and the brain in adipose tissue as triglycerides. The pro- may account for as much as 20% of all cess of fatty acid synthesis is called energy used by the body. If an alternative lipogenesis . source of energy for the brain were not available, survival time would be cut dramatically Fasting Metabolism—Fuel Mobilization due to the rapid loss of body proteins to sup- Overnight Fast The principle goals of the ply the amino acids from which to synthe- metabolic adaptations that occur during an size glucose. overnight fast are to mobilize fatty acids Thankfully, the brain can also derive a from triglycerides stored in adipose tissue significant portion of its energy needs from and to maintain blood glucose concentra- ketone bodies produced from fatty acids. tions. Although fatty acids can supply all Once the period of starvation reaches approx- the necessary energy for most tissues, the imately 10 days, ketone bodies supply about brain, red blood cells, and a few other tis- two-thirds of the brain’s total energy needs. sues must have a steady supply of glucose This adaptation allows protein breakdown to function. to slow as fewer amino acids are used for

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gluconeogenesis, and this significantly pro- growth and development. This may be longs survival time during starvation. accomplished by special modified diets, supplements, and medications. For example, INBORN ERRORS OF METABOLISM in the disorder phenylketonuria (PKU) there Inborn errors of metabolism are a group of is a defect in the gene that produces the disorders characterized by a block in a meta- enzyme that breaks down the amino acid bolic pathway. They are caused by mutations phenylalanine. As a result, there is a buildup (or alterations) in the genes that direct the of that amino acid in the body. Individuals production of enzymes and the co-factors for with PKU must limit phenylalanine in the metabolism. A mutation causes a gene to not diet for their lifetime. function at all or function poorly. Most often Another example is maple syrup urine these altered genes are inherited from one or disease in which the body cannot break more parent. down the amino acids leucine, isoleucine, In general, the treatment of these meta- and valine. The urine of people with this bolic disorders is to minimize or eliminate the condition can smell like maple syrup. Long- buildup of toxic metabolites that result from term treatment is a diet that is low in the the block in metabolism while maintaining problematic amino acids.

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