Chapter Eighteen Metabolism.

Chapter Eighteen Metabolism

EXAM 3 RESULTS High = 106 Median = 82 Average = 77
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The Final Exam The final exam will be held: Wednesday March 14, 2007
In this room There will be 75 questions. The exam will cover all the material in the course, but with somewhat greater emphasis on Chapter 18 than on the other chapters. Copyright © Houghton Mifflin Company. All rights reserved.

“Metabolism” refers to the very large number of chemical reactions that occur in living organisms

Types of Metabolic Reactions
Thousands of different reactions occur in our cells: we shall only study a small number of these reactions. We use food for energy and also to build up our body parts. Over 40 years an average adult processes 6 tons of food and 10,000 gallons of water. Metabolic reactions are of two general types: catabolic (breaking down) and anabolic (building up/synthesizing). Copyright © Houghton Mifflin Company. All rights reserved.

Catabolic reactions (breaking down chemicals) usually release energy
Anabolic reactions (synthesizing substances) generally consume energy. A metabolic pathway refers to a series of reactions intended to convert one substance into another. The path may be linear or cyclic. Linear: A → B → C → D Cyclic: A → B ↑ ↓ D ← C Copyright © Houghton Mifflin Company. All rights reserved.

The Structures of Cells
■ Bacteria are “prokaryotic” organisms and their cells lack a nucleus. ■ All higher organisms have “eukaryotic” cells that have a nucleus. Schematic of a eukaryotic cell Mitochondria are the main energy-producing organelles Copyright © Houghton Mifflin Company. All rights reserved.

ATP is the “energy currency” of the cell
Hydrolysis of ATP releases energy and inorganic phosphate (Pi) Copyright © Houghton Mifflin Company. All rights reserved.

Hydrolysis of ATP releases energy
Breaking the phosphate-phosphate bonds releases energy: Copyright © Houghton Mifflin Company. All rights reserved.

Three Important Coenzymes
Flavin Adenine Dinucleotide = FAD Ribitol is a reduced form of ribose Flavin is a three-ring structure The key idea is that FAD can be readily oxidized and reduced: Copyright © Houghton Mifflin Company. All rights reserved.

Nicotinamide Adenine Dinucleotide = NAD
NAD has the same sort of structure as FAD Nicotinamide is a single-ring heterocyclic compound NAD also can be oxidized and reduced: Copyright © Houghton Mifflin Company. All rights reserved.

Coenzyme A CoA transfers acetyl groups O ║ acetyl group = CH3-C --

Biochemical Energy Production
Four Stages: Stage 1: Digestion begins in the mouth and continues in the stomach and small intestine. (Proteins, lipids, polysaccharides are broken down into their subunits: amino acids, fatty acids, sugars.) Stage 2: The small molecules are broken down further, mainly into acetyl groups joined to CoA, i.e., as acetyl CoA.. Stage 3: The citric acid cycle occurs in the mitochondria. Acetyl CoA is taken in, yielding energy, NADH and FADH2, and CO2. Stage 4: Electron transport and oxidative phosphorylation occur, also in the mitochondria. NADH2 and FADH2 supply H+s and electrons. ATP is produced. O2 from breathing is converted to H2O. Copyright © Houghton Mifflin Company. All rights reserved.

The four stages of energy production

■ Breakdown of foods to smaller compounds
■ Further breakdown to two-carbon units bonded to CoA, as acetyl CoA ■ Acetyl CoA is oxidized to produce CO2 and NADH and FADH2 ■ Production of ATP is aided by NADH and FADH2, taking up O2 Copyright © Houghton Mifflin Company. All rights reserved.

Overview of the Citric Acid Cycle
In Stage 1 of digestion the ingested foods (carbohydrates, fats, and proteins) were broken down into their smaller parts (sugars, fatty acids, etc.). In Stage 2 these compounds were further broken down to 2-carbons acetyl units bonded to CoA. These units now enter the CA Cycle, one at a time. The Citric Acid Cycle (CAC) is Stage 3. In a series of eight steps (1) two CO2 molecules will be released, (2) a molecule of CoA-SH will be regenerated, (3) three NADHs and one FADH2 will be generated (from NAD+ and FAD), and (4) one high-energy compound (GTP) will be created. We will examine the eight steps in order to get an idea of how this works. Copyright © Houghton Mifflin Company. All rights reserved.

Other names for the Citric Acid Cycle
Note that the Citric Acid Cycle (CAC) is sometimes called the “Tricarboxylic Acid Cycle” (TCA) (because citric acid has three COO- groups) The CAC is also sometimes called the “Krebs Cycle” in honor of the British biochemist Sir Hans Krebs, who worked out many of the steps in the cycle. Krebs shared the 1953 Nobel Prize for Physiology or Medicine for this work. Copyright © Houghton Mifflin Company. All rights reserved.

This cycle takes place mainly in the mitochondrial matrix

Step 1. Formation of Citrate
Acetyl CoA enters the cycle and combines with the 4-carbon compound oxaloacetate: This hydrolysis step is catalyzed by the enzyme citrate synthase. It yields a 6-carbon compound, citrate, and releases acetyl CoA-SH to be used again. Copyright © Houghton Mifflin Company. All rights reserved.

Steps 2 and 3 Step 2: The citrate is isomerized to isocitrate, under the influence of the enzyme aconitase. Step 3: The enzyme isocitrate dehydrogenase converts isocitrate to α-ketogluterate, converting NAD+ to NADH and releasing a molecule of CO2. Copyright © Houghton Mifflin Company. All rights reserved.

Note that another enzyme is employed.
Step 4 Step 4: The α-ketogluterate is converted to succinyl, generating another NADH and another CO2. CoA-SH enters and attaches to the 4-carbon succinyl. Note that another enzyme is employed. Copyright © Houghton Mifflin Company. All rights reserved.

Note that another enzyme is employed.
Step 5 Step 5: CoA-SH is regenerated, and a new compound, GDP (similar to ADP) is phosphorylated to GTP. Note that another enzyme is employed. Copyright © Houghton Mifflin Company. All rights reserved.

Note that here too, enzymes are employed.
Steps 6, 7, and 8 These steps involve some familiar organic reactions of types that we have seen earlier in the course. Note that here too, enzymes are employed. Copyright © Houghton Mifflin Company. All rights reserved.

Here the enzyme succinate dehydrogenase is used..
Step 6 In this step an alkane is dehydrogenated to form an alkene. The hydrogens go onto FAD to form FADH2: Here the enzyme succinate dehydrogenase is used.. Copyright © Houghton Mifflin Company. All rights reserved.

The enzyme fumerase is used.
Step 7 The fumerate from Step 6 adds a water molecule at its double bond to produce L-malate. The enzyme fumerase is used. Copyright © Houghton Mifflin Company. All rights reserved.

The enzyme malate dehydrogenase is used.
Step 8 The L-malate from Step 7 is oxidized to form oxaloacetate and NADH. Remember, we started the whole cycle when oxaloacetate reacted with acetyl CoA. The enzyme malate dehydrogenase is used. Copyright © Houghton Mifflin Company. All rights reserved.

Summary of the Citric Acid Cycle
We began the cycle with oxaloacetate (a 4-carbon compound) and added acetyl CoA (CH3-C=O-S-CoA).  In going around the cycle a series of eight steps occurred, yielding the following: 2CO2, CoA-SH, 3NADH, 2H+, FADH, and GTP Thus the two carbons of the acetyl have been converted to CO2, a high-energy compound (GTP) has been produced, and the carrier CoA-SH has been released.  Note that at the end the original oxaloacetate has been regenerated to start the cycle again. Different enzymes guided each step. Copyright © Houghton Mifflin Company. All rights reserved.

Further Comments on the Citric Acid Cycle
The “fuel” of the cycle is acetyl CoA, from the breakdown of foodstuffs. The reactions take place mainly in the mitochondrial matrix. Four of the steps involve oxidation or reduction. The oxidizing agents are NAD+ (three times) and FAD (once). Four B vitamins are used in the cycle: riboflavin (in FAD and the α-ketoglutarate complex), nicotinamide (in NAD+), pantothenic acid (in CoA-SH), and thiamin (in the α-ketoglutarate complex). Different enzymes guided each step. Copyright © Houghton Mifflin Company. All rights reserved.

The Electron Transport Chain
We have now gone through three of the four stages of digestion of foodstuffs. The “Electron Transport Chain” and “Oxidative Phosphorylation” comprise the fourth stage. The Electron Transport Chain involves a series of reactions in which electrons and hydrogen ions from NADH and FADH2 are passed along through a chain of carriers, eventually reacting with O2 to form H2O. These reactions take place mainly in enzyme complexes located in the mitochondrial inner membrane. They lead to the production of ATP molecules. Copyright © Houghton Mifflin Company. All rights reserved.

The Essential Details The steps in this chain are rather complicated and we don’t need to know all the details. We should know that electrons are passed along through a chain of intermediate “carriers”: A cytochrome is a heme-containing protein that undergoes reversible oxidation and reduction of its iron atoms: Iron goes between its Fe+3 and Fe+2 states. Copyright © Houghton Mifflin Company. All rights reserved.

Recall the Heme Group The action occurs at the iron atom in the center

The carriers for the Electron Transport Chain are located in the mitochondrial inner membrane
Coenzyme Q and cytochrome c are mobile—they can move between the fixed enzyme complexes. Copyright © Houghton Mifflin Company. All rights reserved.

In the electron Transport Chain Oxidation and Reduction Reactions are Coupled

One component is oxidized and the other is reduced
For example: And among the cytochromes: Copyright © Houghton Mifflin Company. All rights reserved.

A second function of the Electron Transport Chain is to pump protons
Note that it takes energy to pump protons from a region of low concentration to one of high concentration. Copyright © Houghton Mifflin Company. All rights reserved.

The net result of the Electron Transport Chain is that molecular oxygen is reduced to water
O2 + 4H+ + 4e- → 2H2O In the chain carriers first are oxidized (accept electrons) and are then reduced (lose electrons to the next carrier). About 95% of all the oxygen used by cells serves as the final electron acceptor in the ETC. The enzyme complex containing cytochromes a and a3 is called cytochrome oxidase. Its structure includes both iron and copper. Electrons are transferred from copper to iron to oxygen. Copyright © Houghton Mifflin Company. All rights reserved.

Oxidative Phosphorylation
This is the process in which energy released by the ETC is used to make ATP from ADP Pumping the protons to a region of higher H+ concentra-tion creates an electrochemical gradient. This gradient drives a flow of H+ through enzyme complexes called ATP synthases. These complexes catalyze the production of ATP from ADP. Copyright © Houghton Mifflin Company. All rights reserved.

Energy Bookkeeping As a result of all these reactions and shuffling of electrons, ATP is produced. Recall that every acetyl CoA entering the CAC leads to three NADH, one FADH2, and one GTP. When electrons released from these products go through the ETC and oxidative phosphorylation, they help create ATP. Every NADH yields 2.5 ATPs Thus 3x2.5 = 7.5 Every FADH2 yields 1.5 ATPs Thus 1x2.5 = 1.5 Each GTP yields 1 ATP Thus 1x1 = Total = 10.0 Conclusion: Every acetyl CoA that enters the citric acid cycle results in 10 ATPs created. Copyright © Houghton Mifflin Company. All rights reserved.

Glycolysis Glycolysis refers to the metabolic pathway in which glucose (six carbons) is converted to two molecules of pyruvate (3 carbons each). Here we go back to Stage 2 and consider just how acetyl CoA is generated from glucose. (We will not consider how other compounds are converted to acetyl CoA.) There are two steps: Glucose —> 2 pyruvate (glycolysis) Pyruvate —> acetyl CoA This is an anaerobic pathway. (It doesn’t use oxygen.) Copyright © Houghton Mifflin Company. All rights reserved.

Glycolysis (continued)
This is a ten-step process, each step enzyme-catalyzed. In steps 1 and 3 phosphate groups from ATP are attached to the sugars, and in step 6 two more phosphate are attached with the aid of NAD+. In steps 7and 10 ATPs are produced (total = 4) Two ATPs are consumed and four are produced. The net gain from glycolysis is therefore 4-2 = 2 ATPs for each glucose entering the process. Copyright © Houghton Mifflin Company. All rights reserved.

Glucose enters and is phosphorylated in step 1.
A second phosphorylation from ATP in step 3. Two glyceraldehyde 3-phosphates are created. Two ATPs are produced in step 7. Two more ATPs are produced in step 10. Copyright © Houghton Mifflin Company. All rights reserved.

Step 2: Isomerization of the glucose 6-phosphate
Step 3: A second phosphate is attached. Steps 4 and 5: The 6-carbon sugar is converted to two 3-carbon sugars. Step 6: Another phosphate is attached to each 3-carbon compound. Now each one has two (P)s. Step 7: A phosphate is removed from each 3-carbon compound to form an ATP molecule. Copyright © Houghton Mifflin Company. All rights reserved.

Glycolysis (continued)
Step 7 (cont.): The step just shown is an example of substrate-level phosphorylation—direct transfer of a (P) from a compound to ADP to form ATP. (This differs from oxidative phosphorylation, where a free phosphate ion in solution (Pi) is attached to ADP to form ATP.) Step 8: The compound is rearranged (isomerized). Step 9: A water molecule is removed to yield a C=C double bond with the phosphate group attached to it . Step 10: The phosphate group is split off and attached to ADP, thus forming ATP. Copyright © Houghton Mifflin Company. All rights reserved.

Glycolysis: The Net Reaction
The net overall equation for glycolysis is: Glucose + 2 NAD+ + 2 ADP + 2Pi —> 2 Pyruvate + 2 NADH + 2 ATP + 2H+ + 2H2O There is a net gain of two ATPs, and two pyruvates are formed. Copyright © Houghton Mifflin Company. All rights reserved.

Aerobic Conditions: Formation of Acetyl CoA
Under oxygen-rich (aerobic) conditions the reaction of a glucose molecule yields the following: Glucose + 2 ADP + 2 Pi + 4 NAD+ + 2 CoA —> 2 acetyl CoA + 2 CO2 + 2 ATP + 4 NADH+ 4H+ + 2 H2O The acetyl CoAs can now go into the Citric Acid Cycle and the Electron Transport Chain. Copyright © Houghton Mifflin Company. All rights reserved.

Anaerobic Conditions: Reduction to Lactate
In the absence of air, pyruvate is reduced to lactate in humans and many other organisms. Accumulation of lactate in your muscles and blood causes fatigue after strenuous exercise. The net reaction in this case is : Glucose + 2 ADP + 2 Pi —> 2 Lactate + 2 ATP + 2 H2O Anaerobic organisms are energy-poor. Copyright © Houghton Mifflin Company. All rights reserved.

Anaerobic Conditions: Reduction to Ethanol
Some anaerobic organisms—such as yeast—can take a different path and ferment the glucose to ethanol. The overall reaction in this case is: Glucose + 2 ADP + 2 Pi —> 2 Ethanol + 2 ATP + 2 CO2 + 2 H2 This pathway is used in the productionof beer, wine, and other alcoholic drinks. It also causes bread to rise as CO2 bubbles form during the baking process. Copyright © Houghton Mifflin Company. All rights reserved.

Aerobic Conditions: The Overall Story
Here’s the tally for the complete oxidation of one molecule of glucose. Glycolysis (glucose –> 2 pyruvates) 2 ATP Oxidation of 2 Pyruvates 0 ATP Citric Acid Cycle ATP ETC and Ox. Phosphorylation 26 ATP Net yield of ATP = 30 ATP Compare this with the yield of just 2 ATP for anaerobes. Copyright © Houghton Mifflin Company. All rights reserved.

What you absolutely must know from Chapter 18:
￭ First, appreciate that this chapter treats metabolism in great detail, and you don’t need to know every chemical and every reaction. BUT, you do need to understand the general features of metabolism as described below. ￭ Understand that “metabolism” includes tens of thousands of reactions in the human body. We just scratch the surface in our study. ￭ Understand that there are two broad categories of reactions: catabolic (“breaking down”, energy-releasing) and anabolic (“building up”, energy consuming). ￭ Chapter 18 deals entirely with the first category—the breakdown of food stuffs to yield energy. Copyright © Houghton Mifflin Company. All rights reserved.

What you absolutely must know from Chapter 18 (cont.):
￭ Understand the structure of a typical cell (Fig. 18.2), noting especially the ribosomes and the mitochondria. Understand the structure of a mitochondrion (Fig. 18.3). ￭ Understand the structures of AMP, ADP, and ATP. Appreciate that the breaking of the terminal phosphate-phosphate bond of ATP releases a great deal of energy (producing ADP plus Pi). ￭ Understand that there are three key coenzymes needed for our study of food breakdown: FAD, NAD+, and Coenzyme A. Know that the first two act in oxidation-reduction roles, and be able to identify their oxidized and reduced forms. Understand that Coenzyme A carries acetyl groups into the CAC. Know what a “coenzyme” is. ￭ Understand that FAD and NAD+ are dinucleotides. Copyright © Houghton Mifflin Company. All rights reserved.

￭ Understand what an acetyl group is and how it is bonded to CoA. ￭ Understand what happens in each of the four stages of biochemical energy production. Know where each takes place. ￭ Regarding the Citric Acid Cycle: understand (1) where it takes place, (2) that two-carbon units enter the cycle as acetyl CoA units, which combine with oxaloacetate, (3) what ingredients are generated in the cycle (e.g., 2 CO2, 2 ATP, etc.), (4) that there are 8 steps, each guided by a different enzyme, and (5) that CoA is released in step 1 and oxaloacetate is regenerated in the final step. ￭ You don’t need to know the names of every specific enzyme, but you should understand what the major types of enzymes do (e.g., isomerases, dehydrogenases, kinases…) so that you can recognize their actions in examples. Copyright © Houghton Mifflin Company. All rights reserved.

￭ Understand the overall summary of the CAC (page 513), and appreciate that this cycle is sometimes also called the “Tricarboxylic Acid Cycle” or the “Krebs Cycle” (note on page 510). ￭ Understand that steps 6-8 in the CAC involve ordinary organic reactions of types we studied earlier. Be prepared to recognize the type of reaction involved. ￭ Regarding the Electron Transport Chain: understand (1) where it takes place, and (2) that it involves a series of oxidation-reduction reactions in which electrons and hydrogen ions from NADH and FADH2 are passed along, eventually reacting with O2 to produce H2O. ￭ You should know generally what a “heme” group looks like, and what a “cytochrome” is. Copyright © Houghton Mifflin Company. All rights reserved.

￭ Regarding oxidative phosphorylation: understand (1) where it takes place, and (2) that it involves capturing the energy from a flow of protons through enzyme complexes called ATP synthases to produce ATPs. Appreciate that the electrochemical gradient causing the proton flow was generated by enzymes fixed in the mitochondrial cell membraes, which pump protons to regions of higher concentration (see Figs and 18.13). ￭ You should appreciate that ATP is the principal energy-carrying molecule in the cell, and that its hydrolysis is utilized to supply energy for a range of activities such as muscle contraction, nutrient transport, and the synthesis of bodily components. ￭ Appreciate that the “Common Metabolic Pathway” refers to the sum of the reactions that occur in the Citric Acid Cycle, the Electron Transport Chain, and Oxidative Phosphorylation. Copyright © Houghton Mifflin Company. All rights reserved.

￭ Appreciate that most biochemical reactions consist of coupled reactions in which one compound is oxidized while another is reduced. ￭ Understand that “glycolysis” refers to the process in which the sugar glucose (C6) is transformed into two molecules of pyruvate (two C3). Appreciate that this is accomplished in a series of 10 steps, and generates 2 ATPs (net). ￭ Understand that there are three possible metabolic routes for the pyruvate generated in glycolysis: (1) aerobic oxidation via the CAC, ETC, and OP, (2) anaerobic conversion to lactic acid (lactate), or (3) anaerobic fermentation leading to ethanol. ￭ Appreciate that lactic acid is what causes fatigue in muscles and that fermentation is used in making beer, wine and other beverages. Copyright © Houghton Mifflin Company. All rights reserved.

￭ Appreciate the importance of the energy bookkeeping information shown on page 530—that aerobic metabolism of a glucose molecule yields 30 ATPs, whereas anaerobic metabolism yields just 2 ATPs. ￭ Understand that as a result of the above difference only higher (aerobic) organisms are efficient enough to sit around and think and study organic chemistry and biochemistry. ￭ Appreciate that the aerobic metabolism reactions described above constitute “respiration”, taking in O2 to oxidize foodstuffs, thereby capturing energy (as ATPs) and releasing CO2 and H2O. Understand that respiration is just the reverse of photosynthesis, in which green plants take in CO2 and H2O and use energy from the sun to synthesize sugars, releasing O2 in the process. Copyright © Houghton Mifflin Company. All rights reserved.

Do additional problems Review Lecture notes for
To Do List Read chapter 18!! Do additional problems Do practice test T/F Do practice test MC Review Lecture notes for Chapter Eleven Copyright © Houghton Mifflin Company. All rights reserved.

Chapter Eighteen Metabolism.

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