CAMPBELL BIOLOGY IN FOCUS © 2014 Pearson Education, Inc. Urry Cain Wasserman Minorsky Jackson Reece Lecture Presentations by Kathleen Fitzpatrick and Nicole Tunbridge Unit 2.4 Cellular Respiration and Fermentation

Overview: Life Is Work ▪Living cells require energy from outside sources ▪Some animals, such as the giraffe, obtain energy by eating plants, and some animals feed on other organisms that eat plants © 2014 Pearson Education, Inc.

▪Energy flows into an ecosystem as sunlight and leaves as heat ▪Photosynthesis generates O 2 and organic molecules, which are used as fuel for cellular respiration ▪Cells use chemical energy stored in organic molecules to regenerate ATP, which powers work © 2014 Pearson Education, Inc.

Figure 7.2 Light energy ECOSYSTEM Photosynthesis in chloroplasts CO 2 + H 2 O Cellular respiration in mitochondria Organic molecules + O 2 ATP ATP powers most cellular work Heat energy

Concept 7.1: Catabolic pathways yield energy by oxidizing organic fuels ▪Several processes are central to cellular respiration and related pathways

Catabolic Pathways and Production of ATP ▪The breakdown of organic molecules is exergonic ▪Fermentation is a partial degradation of sugars that occurs without O 2 ▪Aerobic respiration consumes organic molecules and O 2 and yields ATP ▪Anaerobic respiration is similar to aerobic respiration but consumes compounds other than O 2 © 2014 Pearson Education, Inc.

▪Cellular respiration includes both aerobic and anaerobic respiration but is often used to refer to aerobic respiration ▪Although carbohydrates, fats, and proteins are all consumed as fuel, it is helpful to trace cellular respiration with the sugar glucose C 6 H 12 O O 2 → 6 CO H 2 O + Energy (ATP + heat) © 2014 Pearson Education, Inc.

Redox Reactions: Oxidation and Reduction ▪The transfer of electrons during chemical reactions releases energy stored in organic molecules ▪This released energy is ultimately used to synthesize ATP © 2014 Pearson Education, Inc.

The Principle of Redox ▪Chemical reactions that transfer electrons between reactants are called oxidation-reduction reactions, or redox reactions ▪In oxidation, a substance loses electrons, or is oxidized ▪In reduction, a substance gains electrons, or is reduced (the amount of positive charge is reduced) © 2014 Pearson Education, Inc.

Figure 7.UN01 becomes oxidized (loses electron) becomes reduced (gains electron)

© 2014 Pearson Education, Inc. Figure 7.UN02 becomes oxidized becomes reduced

▪The electron donor is called the reducing agent ▪The electron acceptor is called the oxidizing agent ▪Some redox reactions do not transfer electrons but change the electron sharing in covalent bonds ▪An example is the reaction between methane and O 2 © 2014 Pearson Education, Inc.

Methane combustion as an energy-yielding redox reaction Reactants Products Methane (reducing agent) Oxygen (oxidizing agent) Carbon dioxide Water becomes reduced becomes oxidized

▪Redox reactions that move electrons closer to electronegative atoms, like oxygen, release chemical energy that can be put to work © 2014 Pearson Education, Inc.

Oxidation of Organic Fuel Molecules During Cellular Respiration ▪During cellular respiration, the fuel (such as glucose) is oxidized, and O 2 is reduced ▪Organic molecules with an abundance of hydrogen, like carbohydrates and fats, are excellent fuels ▪As hydrogen (with its electron) is transferred to oxygen, energy is released that can be used in ATP sythesis © 2014 Pearson Education, Inc.

Figure 7.UN03 becomes oxidized becomes reduced

Stepwise Energy Harvest via NAD + and the Electron Transport Chain ▪In cellular respiration, glucose and other organic molecules are broken down in a series of steps ▪Electrons from organic compounds are usually first transferred to NAD +, a coenzyme ▪As an electron acceptor, NAD + functions as an oxidizing agent during cellular respiration ▪Each NADH (the reduced form of NAD + ) represents stored energy that is tapped to synthesize ATP © 2014 Pearson Education, Inc.

Figure 7.4 NAD + Nicotinamide (oxidized form) Nicotinamide (reduced form) Oxidation of NADH Reduction of NAD + Dehydrogenase NADH + 2[H] (from food) 2 e − + 2 H + 2 e − + H + H+H+ H+H+ +

▪NADH passes the electrons to the electron transport chain ▪Unlike an uncontrolled reaction, the electron transport chain passes electrons in a series of steps instead of one explosive reaction ▪O 2 pulls electrons down the chain in an energy- yielding tumble ▪The energy yielded is used to regenerate ATP © 2014 Pearson Education, Inc.

Figure 7.5 Explosive release (a) Uncontrolled reaction (b) Cellular respiration H2OH2O Free energy, G Electron transport chain Controlled release of energy H2OH2O 2 H + 2 e − 2 H e − ATP ½ ½ ½ H 2 +O2O2 O2O2 O2O2 2 H +

The Stages of Cellular Respiration: A Preview ▪Harvesting of energy from glucose has three stages ▪Glycolysis (breaks down glucose into two molecules of pyruvate) ▪Pyruvate oxidation and the citric acid cycle (completes the breakdown of glucose) ▪Oxidative phosphorylation (accounts for most of the ATP synthesis) © 2014 Pearson Education, Inc.

Figure 7.UN05 Glycolysis (color-coded teal throughout the chapter) Pyruvate oxidation and the citric acid cycle (color-coded salmon) 1. Oxidative phosphorylation: electron transport and chemiosmosis (color-coded violet) 2. 3.

© 2014 Pearson Education, Inc. Figure Electrons via NADH Glycolysis GlucosePyruvate CYTOSOL ATP Substrate-level MITOCHONDRION

© 2014 Pearson Education, Inc. Figure Electrons via NADH Glycolysis GlucosePyruvate oxidation Acetyl CoA Citric acid cycle Electrons via NADH and FADH 2 CYTOSOL ATP Substrate-level ATP Substrate-level MITOCHONDRION

© 2014 Pearson Education, Inc. Figure Electrons via NADH Glycolysis GlucosePyruvate oxidation Acetyl CoA Citric acid cycle Electrons via NADH and FADH 2 Oxidative phosphorylation: electron transport and chemiosmosis CYTOSOL ATP Substrate-level ATP Substrate-level MITOCHONDRION ATP Oxidative

▪Oxidative phosphorylation accounts for almost 90% of the ATP generated by cellular respiration and is powered by redox reactions ▪A smaller amount of ATP is formed in glycolysis and the citric acid cycle by substrate-level phosphorylation ▪For each molecule of glucose degraded to CO 2 and water by respiration, the cell makes up to 32 molecules of ATP © 2014 Pearson Education, Inc.

Figure 7.7 Substrate P ADP Product ATP + Enzyme

Concept 7.2: Glycolysis harvests chemical energy by oxidizing glucose to pyruvate ▪Glycolysis (“sugar splitting”) breaks down glucose into two molecules of pyruvate ▪Glycolysis occurs in the cytoplasm and has two major phases ▪Energy investment phase ▪Energy payoff phase ▪Glycolysis occurs whether or not O 2 is present © 2014 Pearson Education, Inc.

Figure 7.UN06 Glycolysis Pyruvate oxidation Citric acid cycle Oxidative phosphorylation ATP

© 2014 Pearson Education, Inc. Figure 7.8 Energy Investment Phase Energy Payoff Phase Net Glucose 2 ADP + 2 P 4 ADP + 4 P 2 NAD e − + 4 H + 4 ATP formed − 2 ATP used 2 ATP 4 ATP used formed 2 NADH + 2 H + 2 Pyruvate + 2 H 2 O 2 NADH + 2 H + 2 ATP

© 2014 Pearson Education, Inc. Figure 7.9a Glycolysis: Energy Investment Phase Glucose ATP ADP Glucose 6-phosphate Phosphogluco- isomerase Hexokinase 1234 ATP ADP Fructose 6-phosphate Phospho- fructokinase Fructose 1,6-bisphosphate Aldolase Isomerase 5 Glyceraldehyde 3-phosphate (G3P) Dihydroxyacetone phosphate (DHAP)

© 2014 Pearson Education, Inc. Figure 7.9aa-3 Glycolysis: Energy Investment Phase Glucose 6-phosphate ADP ATP Hexokinase 1 Fructose 6-phosphate Phosphogluco- isomerase 2

© 2014 Pearson Education, Inc. Figure 7.9ab-3 Glycolysis: Energy Investment Phase Fructose 6-phosphate Phospho- fructokinase 3 Aldolase Isomerase 45 Fructose 1,6-bisphosphate Glyceraldehyde 3-phosphate (G3P) ATP ADP Dihydroxyacetone phosphate (DHAP)

© 2014 Pearson Education, Inc. Figure 7.9b Glycolysis: Energy Payoff Phase 2 NAD + Glyceraldehyde 3-phosphate (G3P) Triose phosphate dehydrogenase H + 2 NADH 2 2 P i 1,3-Bisphospho- glycerate 3-Phospho- glycerate 2-Phospho- glycerate Phosphoenol- pyruvate (PEP) Pyruvate Phospho- glycerokinase Phospho- glyceromutase Enolase Pyruvate kinase 2 ADP ATP 2 H 2 O 2 ATP

© 2014 Pearson Education, Inc. Figure 7.9ba-3 Isomerase Glyceraldehyde 3-phosphate (G3P) Dihydroxyacetone phosphate (DHAP) Glycolysis: Energy Payoff Phase 2 NAD + Triose phosphate dehydrogenas e + 2 H + 2 NADH 2 1,3-Bisphospho- glycerate 3-Phospho- glycerate Phospho- glycerokinase 2 ADP 2 ATP 2 Aldolase P i

© 2014 Pearson Education, Inc. Figure 7.9bb-3 3-Phospho- glycerate Glycolysis: Energy Payoff Phase 2 ATP Phospho- glyceromutase ADP 2 H 2 O 2-Phospho- glycerate Phosphoenol- pyruvate (PEP) Pyruvate EnolasePyruvate kinase

Concept 7.3: After pyruvate is oxidized, the citric acid cycle completes the energy-yielding oxidation of organic molecules ▪In the presence of O 2, pyruvate enters the mitochondrion (in eukaryotic cells), where the oxidation of glucose is completed ▪Before the citric acid cycle can begin, pyruvate must be converted to acetyl coenzyme A (acetyl CoA), which links glycolysis to the citric acid cycle © 2014 Pearson Education, Inc.

Figure 7.UN07 Glycolysis Pyruvate oxidation Citric acid cycle Oxidative phosphorylation ATP

© 2014 Pearson Education, Inc. Figure 7.10a CYTOSOL Pyruvate (from glycolysis, 2 molecules per glucose) CO 2 CoA NAD + NADH MITOCHONDRION CoA Acetyl CoA + H +

© 2014 Pearson Education, Inc. Figure 7.10b Co A Citric acid cycle FADH 2 FAD ADP + P i AT P NAD H 3 NAD H + 2CO 2 Co A Acetyl CoA

▪The citric acid cycle, also called the Krebs cycle, completes the breakdown of pyruvate to CO 2 ▪The cycle oxidizes organic fuel derived from pyruvate, generating 1 ATP, 3 NADH, and 1 FADH 2 per turn © 2014 Pearson Education, Inc.

Figure 7.UN08 Glycolysis Pyruvate oxidation Oxidative phosphorylation ATP Citric acid cycle

© 2014 Pearson Education, Inc. Figure Acetyl CoA Oxaloacetate CoA-SH Citrate H2OH2O Isocitrate Citric acid cycle 2 1

© 2014 Pearson Education, Inc. Figure Acetyl CoA Oxaloacetate Citrate H2OH2O Isocitrate NADH NAD + + H + CO2CO2 α-Ketoglutarate Citric acid cycle 3 1 CoA-SH 2

© 2014 Pearson Education, Inc. Figure Acetyl CoA Oxaloacetate Citrate H2OH2O Isocitrate NADH NAD + + H + CO2CO2 α-Ketoglutarate Citric acid cycle CoA-SH CO2CO2 NAD + NADH + H + Succinyl CoA CoA-SH 2

© 2014 Pearson Education, Inc. Figure Acetyl CoA Oxaloacetate Citrate H2OH2O Isocitrate NADH NAD + + H + CO2CO2 α-Ketoglutarate Citric acid cycle CoA-SH CO2CO2 NAD + NADH + H + ATP formation Succinyl CoA ADP GDP GTP P i ATP Succinate CoA-SH 3 2

© 2014 Pearson Education, Inc. Figure Malate Succinate FAD FADH 2 Fumarate H2OH2O 7 6 Acetyl CoA Oxaloacetate Citrate H2OH2O Isocitrate NADH NAD + + H + CO2CO2 α-Ketoglutarate Citric acid cycle CoA-SH CO2CO2 NAD + NADH + H + ATP formation Succinyl CoA ADP GDP GTP P i ATP CoA-SH 3 2

© 2014 Pearson Education, Inc. Figure NADH NAD + + H + 8 Malate Succinate FAD FADH 2 Fumarate H2OH2O 7 6 Acetyl CoA Oxaloacetate Citrate H2OH2O Isocitrate NADH NAD + + H + CO2CO2 α-Ketoglutarate Citric acid cycle CoA-SH CO2CO2 NAD + NADH + H + ATP formation Succinyl CoA ADP GDP GTP P i ATP CoA-SH 3 2

© 2014 Pearson Education, Inc. Figure 7.11a CoA-SH Acetyl CoA Start: Acetyl CoA adds its two-carbon group to oxaloacetate, producing citrate; this is a highly exergonic reaction. Oxaloacetat e Citrate Isocitrate H2OH2O 1 2

© 2014 Pearson Education, Inc. Figure 7.11b Isocitrate Redox reaction: Isocitrate is oxidized; NAD + is reduced. Redox reaction: After CO 2 release, the resulting four-carbon molecule is oxidized (reducing NAD + ), then made reactive by addition of CoA. CO 2 release α-Ketoglutarate Succinyl CoA NAD + NADH + H + CO2CO2 CO2CO2 CoA-SH NAD + NADH + H + 3 4

© 2014 Pearson Education, Inc. Figure 7.11c CoA-SH Redox reaction: Succinate is oxidized; FAD is reduced. Fumarate Succinate Succinyl CoA ATP formation ATP ADP GDP GTP FAD FADH 2 P i 5 6

© 2014 Pearson Education, Inc. Figure 7.11d Redox reaction: Malate is oxidized; NAD + is reduced. Fumarate Malate Oxaloacetate H2OH2O NAD + + H + NADH 7 8

▪The citric acid cycle has eight steps, each catalyzed by a specific enzyme ▪The acetyl group of acetyl CoA joins the cycle by combining with oxaloacetate, forming citrate ▪The next seven steps decompose the citrate back to oxaloacetate, making the process a cycle ▪The NADH and FADH 2 produced by the cycle relay electrons extracted from food to the electron transport chain © 2014 Pearson Education, Inc.

Concept 7.4: During oxidative phosphorylation, chemiosmosis couples electron transport to ATP synthesis ▪Following glycolysis and the citric acid cycle, NADH and FADH 2 account for most of the energy extracted from food ▪These two electron carriers donate electrons to the electron transport chain, which powers ATP synthesis via oxidative phosphorylation © 2014 Pearson Education, Inc.

The Pathway of Electron Transport ▪The electron transport chain is in the inner membrane (cristae) of the mitochondrion ▪Most of the chain’s components are proteins, which exist in multiprotein complexes ▪The carriers alternate reduced and oxidized states as they accept and donate electrons ▪Electrons drop in free energy as they go down the chain and are finally passed to O 2, forming H 2 O © 2014 Pearson Education, Inc.

Figure 7.UN09 Glycolysis Pyruvate oxidation Citric acid cycle Oxidative phosphorylation: electron transport and chemiosmosis ATP

© 2014 Pearson Education, Inc. Figure 7.12 Multiprotein complexes (originally from NADH or FADH 2 ) Free energy (G) relative to O 2 (kcal/mol) NADH NAD + FADH 2 FAD 2 2 e−e− e−e− FMN Fe S Q I II II I Cyt b Cyt c 1 Fe S Cyt c IV Cyt a Cyt a 3 2 e−e− O2O2 2 H + + ½ H2OH2O

© 2014 Pearson Education, Inc. Figure 7.12a Multiprotein complexes Free energy (G) relative to O 2 (kcal/mol) NADH NAD + FADH 2 FAD 2 2 e−e− e−e− FMN FeS Q I I II I Cyt b Cyt c 1 FeS Cyt c IVIV Cyt a Cyt a 3 2 e−e−

© 2014 Pearson Education, Inc. Figure 7.12b Cyt c 1 Cyt c IVIV Cyt a Cyt a 3 2 e−e− Free energy (G) relative to O 2 (kcal/mol) (originally from NADH or FADH 2 ) 2 H + + ½ O2O2 H2OH2O

▪Electrons are transferred from NADH or FADH 2 to the electron transport chain ▪Electrons are passed through a number of proteins including cytochromes (each with an iron atom) to O 2 ▪The electron transport chain generates no ATP directly ▪It breaks the large free-energy drop from food to O 2 into smaller steps that release energy in manageable amounts © 2014 Pearson Education, Inc.

Chemiosmosis: The Energy-Coupling Mechanism ▪Electron transfer in the electron transport chain causes proteins to pump H + from the mitochondrial matrix to the intermembrane space ▪H + then moves back across the membrane, passing through the protein complex, ATP synthase ▪ATP synthase uses the exergonic flow of H + to drive phosphorylation of ATP ▪This is an example of chemiosmosis, the use of energy in a H + gradient to drive cellular work © 2014 Pearson Education, Inc.

Figure 7.13 INTERMEMBRANE SPACE MITOCHONDRIAL MATRIX Rotor Internal rod Catalytic knob Stator H+H+ ATP ADP P i +

▪The energy stored in a H + gradient across a membrane couples the redox reactions of the electron transport chain to ATP synthesis ▪The H + gradient is referred to as a proton-motive force, emphasizing its capacity to do work © 2014 Pearson Education, Inc.

Figure 7.UN09 Glycolysis Pyruvate oxidation Citric acid cycle Oxidative phosphorylation: electron transport and chemiosmosis ATP

© 2014 Pearson Education, Inc. Figure 7.14 Protein complex of electron carriers H+H+ H+H+ H+H+ H+H+ Q I II II I FADH 2 FAD NAD + NAD H (carrying electrons from food) Electron transport chain Oxidative phosphorylation Chemiosmosis ATP synthase H+H+ ADP + ATP P i H2OH2O 2 H + + ½ O 2 IV Cyt c 1 2

© 2014 Pearson Education, Inc. Figure 7.14a Protein complex of electron carriers H+H+ Q I II II I FADH 2 FA D NAD + NADH (carrying electrons from food) Electron transport chain H2OH2O 2 H + + ½ O 2 Cyt c 1 IVIV H+H+ H+H+

© 2014 Pearson Education, Inc. Figure 7.14b ATP synthase Chemiosmosis 2 H+H+ H+H+ ADP + P i ATP

An Accounting of ATP Production by Cellular Respiration ▪During cellular respiration, most energy flows in the following sequence: glucose → NADH → electron transport chain → proton-motive force → ATP ▪About 34% of the energy in a glucose molecule is transferred to ATP during cellular respiration, making about 32 ATP ▪There are several reasons why the number of ATP molecules is not known exactly © 2014 Pearson Education, Inc.

Figure 7.15 Electron shuttles span membrane CYTOSOL 2 NADH 2 FADH 2 or 2 NADH Glycolysis Glucose 2 Pyruvate oxidation 2 Acetyl CoA Citric acid cycle 6 NADH2 FADH 2 Oxidative phosphorylation: electron transport and chemiosmosis + about 26 or 28 ATP + 2 ATP About 30 or 32 ATP Maximum per glucose: MITOCHONDRION

© 2014 Pearson Education, Inc. Figure 7.15a Electron shuttles span membrane 2 NADH 2 FADH 2 or 2 NADH Glycolysis Glucose 2 Pyruvate + 2 ATP

© 2014 Pearson Education, Inc. Figure 7.15b 2 NADH6 NADH 2 FADH 2 Citric acid cycle Pyruvate oxidation 2 Acetyl CoA + 2 ATP

© 2014 Pearson Education, Inc. Figure 7.15c 2 NADH 6 NADH 2 FADH 2 or Oxidative phosphorylation: electron transport and chemiosmosis + about 26 or 28 ATP

© 2014 Pearson Education, Inc. Figure 7.15d Maximum per glucose: About 30 or 32 ATP

Concept 7.5: Fermentation and anaerobic respiration enable cells to produce ATP without the use of oxygen ▪Most cellular respiration requires O 2 to produce ATP ▪Without O 2, the electron transport chain will cease to operate ▪In that case, glycolysis couples with fermentation or anaerobic respiration to produce ATP © 2014 Pearson Education, Inc.

▪Anaerobic respiration uses an electron transport chain with a final electron acceptor other than O 2, for example, sulfate ▪Fermentation uses substrate-level phosphorylation instead of an electron transport chain to generate ATP © 2014 Pearson Education, Inc.

Types of Fermentation ▪Fermentation consists of glycolysis plus reactions that regenerate NAD +, which can be reused by glycolysis ▪Two common types are alcohol fermentation and lactic acid fermentation © 2014 Pearson Education, Inc.

▪In alcohol fermentation, pyruvate is converted to ethanol in two steps ▪The first step releases CO 2 from pyruvate, and the second step reduces acetaldehyde to ethanol ▪Alcohol fermentation by yeast is used in brewing, winemaking, and baking © 2014 Pearson Education, Inc.

Figure ADP ATP P i Glucose Glycolysis 2 Pyruvate 2 CO 2 2 NADH + 2 H + 2 NAD + 2 Ethanol (a) Alcohol fermentation 2 Acetaldehyde (b) Lactic acid fermentation 2 Lactate 2 NADH + 2 H + 2 NAD + 2 Pyruvate Glycolysis 2 ATP 2 ADP + 2 P i Glucose

▪In lactic acid fermentation, pyruvate is reduced by NADH, forming lactate as an end product, with no release of CO 2 ▪Lactic acid fermentation by some fungi and bacteria is used to make cheese and yogurt ▪Human muscle cells use lactic acid fermentation to generate ATP when O 2 is scarce © 2014 Pearson Education, Inc.

Comparing Fermentation with Anaerobic and Aerobic Respiration ▪All use glycolysis (net ATP = 2) to oxidize glucose and harvest chemical energy of food ▪In all three, NAD + is the oxidizing agent that accepts electrons during glycolysis ▪The processes have different final electron acceptors: an organic molecule (such as pyruvate or acetaldehyde) in fermentation and O 2 in cellular respiration ▪Cellular respiration produces 32 ATP per glucose molecule; fermentation produces 2 ATP per glucose molecule © 2014 Pearson Education, Inc.

▪Obligate anaerobes carry out only fermentation or anaerobic respiration and cannot survive in the presence of O 2 ▪Yeast and many bacteria are facultative anaerobes, meaning that they can survive using either fermentation or cellular respiration ▪In a facultative anaerobe, pyruvate is a fork in the metabolic road that leads to two alternative catabolic routes © 2014 Pearson Education, Inc.

Figure 7.17 Glucose CYTOSOL Glycolysis Pyruvate O 2 present: Aerobic cellular respiration No O 2 present: Fermentation Ethanol, lactate, or other products Acetyl CoA Citric acid cycle MITOCHONDRION

The Evolutionary Significance of Glycolysis ▪Ancient prokaryotes are thought to have used glycolysis long before there was oxygen in the atmosphere ▪Very little O 2 was available in the atmosphere until about 2.7 billion years ago, so early prokaryotes likely used only glycolysis to generate ATP ▪Glycolysis is a very ancient process © 2014 Pearson Education, Inc.

Concept 7.6: Glycolysis and the citric acid cycle connect to many other metabolic pathways ▪Gycolysis and the citric acid cycle are major intersections to various catabolic and anabolic pathways © 2014 Pearson Education, Inc.

The Versatility of Catabolism ▪Catabolic pathways funnel electrons from many kinds of organic molecules into cellular respiration ▪Glycolysis accepts a wide range of carbohydrates ▪Proteins must be digested to amino acids and amino groups must be removed before amino acids can feed glycolysis or the citric acid cycle © 2014 Pearson Education, Inc.

▪Fats are digested to glycerol (used in glycolysis) and fatty acids ▪Fatty acids are broken down by beta oxidation and yield acetyl CoA ▪An oxidized gram of fat produces more than twice as much ATP as an oxidized gram of carbohydrate © 2014 Pearson Education, Inc.

Figure Proteins Amino acids Carbohydrates Sugars Glucose Glycolysis Glyceraldehyde 3- Pyruvate P Acetyl CoA Citric acid cycle NH 3 Fats Glycerol Fatty acids Oxidative phosphorylation

Biosynthesis (Anabolic Pathways) ▪The body uses small molecules to build other substances ▪Some of these small molecules come directly from food; others can be produced during glycolysis or the citric acid cycle © 2014 Pearson Education, Inc.