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Energy and Electrons from Glucose
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The sugar glucose (C6H12O6) is the most common form of energy molecule.
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Cells obtain energy from glucose by the chemical process of oxidation carried out through a series of
metabolic pathways.
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Several principles govern metabolic pathways:
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Metabolic pathways are formed by complex chemical transformations in the cell which occur in a number of
separate reactions.
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Each reaction in the pathway is catalyzed by a specific enzyme.
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Metabolic pathways are similar in all organisms, from bacteria to humans.
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Many metabolic pathways are compartmentalized in eukaryotes, with certain reactions occurring inside an
organelle.
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The operation of each metabolic pathway can be regulated by the activities of key enzymes.
Cells trap free energy while metabolizing glucose
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When burned in a flame, glucose releases heat, carbon dioxide, and water.
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C6H12O6 + 6 O2  6 CO2 + 6 H2O + energy (heat and light).
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The same equation applies for the biological, metabolic use of glucose. This process, however, has many
steps and is carefully controlled.
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About one-third of the energy is collected in ATP.
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G for the complete conversion of glucose is –686 kcal/mol.
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The reaction is therefore highly exergonic, and it drives the endergonic formation of ATP.
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Some kinds of cells metabolize glucose incompletely, and others
completely.
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The incomplete breakdown is called fermentation and is anaerobic (no
oxygen required). Fermentation has steps that are common to all organisms.
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Complete capture of the energy in the hydrocarbon bonds of glucose
requires oxygen.
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The two main metabolic processes for complete use of glucose are glycolysis and cellular respiration.
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Glycolysis is a series of reactions that produce some usable energy and two molecules of a three-carbon sugar
called pyruvate.
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Cellular respiration occurs in aerobic (oxygen-containing) environments. Pyruvate is converted to CO2 and
H2O. The energy from hydrocarbon bonds is used to make ATP molecules.
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If cellular respiration does not occur, then fermentation does.
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Fermentation occurs when the environment is anaerobic (lacking gaseous
oxygen).
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It also occurs in the rare eukaryotic cell with no mitochondria, the
usual location of cellular respiration.
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In fermentation, lactate or ethanol and CO2 are produced, but far less energy is extracted from glucose. (See
Figure 7.1.)
Redox reactions transfer electrons and energy
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Redox reactions transfer the energy of electrons.
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A gain of one or more electrons or hydrogen atoms is called reduction.
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The loss of one or more electrons or hydrogen atoms is called oxidation.
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Whenever one material is reduced, another is oxidized. (See Figure 7.2.)
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To determine whether an organic compound is being oxidized or reduced, look at the carbons in the
compound and note the changes in the number of bonds they have with hydrogen or oxygen.
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If a carbon gains a bond with hydrogen, the compound is reduced.
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If a carbon loses a bond with hydrogen, the compound is oxidized.
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Reaction 1 of the above diagram is oxidation because the changed carbon loses a hydrogen bond (even
though the compound as a whole still has the same amount of hydrogen).
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Reaction 2 is also oxidation because the central carbon in the reactant loses a hydrogen bond (even though
the compound as a whole still has the same amount of hydrogen).
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An oxidizing agent accepts an electron or a hydrogen atom.
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A reducing agent donates an electron or a hydrogen atom.
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During the burning of glucose and the metabolism of glucose, glucose is the reducing agent (and is oxidized),
while oxygen is the oxidizing agent (and itself is reduced).
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The overall G of a biologically related redox reaction is negative.
The coenzyme NAD is a key electron carrier in redox reactions
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The molecule NAD (nicotinamide adenine dinucleotide) is an essential energy carrier in cellular redox
reactions. (See Figure 7.3.)
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NAD exists in an oxidized form, NAD+, and a reduced form, NADH + H+. (See Figure 7.4.)
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NAD+ + 2 H  NADH + H+. This is the reduction reaction and requires an input of energy.
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Oxygen reacts with NADH + H+
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NADH + H+ + 1/2O2  NAD+ + H2O
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The G of this oxidation reaction is –52.4 kcal/mol. (By comparison, the
G of the ATP to ADP reaction is –12 kcal/mol.)
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NAD can be thought of as a packaging agent for free energy.
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Another electron carrier is FAD (flavin adenine dinucleotide).
An Overview: Releasing Energy from Glucose
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Depending on the presence or absence of oxygen, the energy-harvesting processes in cells use different combinations of metabolic pathways. (See Figure 7.5.)
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With oxygen and a means to use it, four major pathways operate:
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Glycolysis splits glucose into two pyruvate molecules.
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Pyruvate oxidation results in acetate, a compound requiring further metabolism.
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The citric acid cycle uses the product of pyruvate oxidation.
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The respiratory chain uses the products of the citric acid cycle and of glycolysis to produce more ATP.
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When no oxygen is available, or the cells are types that are unable to use it, glycolysis occurs followed by a
fermentation reaction that converts the pyruvate molecules. (See Figure 7.6.)
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The locations of these processes in cells are shown in Table 7.1.
Glycolysis: From Glucose to Pyruvate
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Glycolysis can be divided into two stages: energy-investing reactions that use ATP, and energy-harvesting
reactions that produce ATP. (See Figure 7.6.)
The energy-investing reactions of glycolysis require ATP
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Glycolysis converts glucose to pyruvate.
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To get energy out of glucose, energy first must be invested.
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In separate reactions, two ATP molecules are used to make modifications to glucose.
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Phosphates from each ATP are added to the carbon 6 and carbon 1 of the glucose molecule to form fructose
1,6-bisphosphate.
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See Figures 7.6 and 7.7 for the details of this part of glycolysis.
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Note that the enzyme in the first reaction is hexokinase. (All kinases add phosphates.)
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The enzyme aldolase splits the molecule into two three-carbon molecules that then both become
glyceraldehyde 3-phosphate (G3P).
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Up to this point, no energy has been yielded.
The energy-harvesting reactions of glycolysis yield NADH + H+ and ATP
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See Figure 7.6 for the energy-yielding reactions of glycolysis.
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Producing NADH + H+:
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A reaction catalyzed by the enzyme triose phosphate dehydrogenase releases a lot of free energy, more than
100 kcal per mole of glucose.
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The energy is stored rather than lost as heat and is used to make two molecules of NADH + H+, one for each
of the two glyceraldehyde molecules made from the one glucose molecule.
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Producing ATP:
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Two other reactions each yield one ATP per glyceraldehyde or four ATP molecules per glucose molecule.
This part of the pathway is called substrate-level phosphorylation.
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The final product is two three-carbon pyruvate molecules, which still have some reduced carbon bonds.
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Glycolysis is followed by cellular respiration or fermentation, depending on the presence or absence of
oxygen.
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At the end of glycolysis there is a net gain of two ATP molecules and two NADH + H +.
Pyruvate Oxidation
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Pyruvate is oxidized to acetate. This forms the link between glycolysis and cellular respiration.
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Pyruvate oxidation occurs in a multistep reaction catalyzed by an enormous enzyme complex that is attached
to the inner mitochondrial membrane.
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The acetyl group is added to coenzyme A to form acetyl CoA. A molecule of NADH + H + is generated during
this reaction, capturing approximately 50 kcal/mol. (See Figure 7.8.)
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As two pyruvate molecules are generated from each glucose molecule during glycolysis, two NADH + H + per
glucose are generated during this stage of glucose oxidation.
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This reaction requires a series of steps completed by the pyruvate dehydrogenase complex.
The Citric Acid Cycle
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Pyruvate oxidation is the link between glycolysis and the citric acid cycle.
Acetyl CoA is the starting point for the citric acid cycle.
The pathway has eight reactions and occurs in the mitochondrial matrix.
The reaction completely oxidizes the carbons of the acetate.
The citric acid cycle produces two CO2 molecules and reduced carriers
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The products of the citric acid cycle include two molecules of CO2.
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Free energy is captured by NAD+ and FAD+ to generate the reduced form of each; some free energy is also
captured in the synthesis of ATP from ADP.
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The cycle begins when the two carbons from the acetate are added to oxaloacetate, a four-carbon molecule, to
generate citrate, a six-carbon molecule.
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A series of reactions oxidize two carbons from the citrate. With some enzyme-catalyzed molecular
rearrangements, oxaloacetate is formed, and this can be used for the next cycle.
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For each turn of the cycle, three molecules of NADH + H+, one molecule of ATP, and one molecule of
FADH2 are generated. (The FADH2 is another reducing agent, similar to NADH.)
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As two acetate molecules are contributed from each glucose, twice this number of high-energy molecules are
generated per glucose. See Figure 7.9 for a complete accounting.
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Some of the products of the citric acid cycle are starting substrates for other necessary molecules like
nucleotides and amino acids.
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This cycle is maintained in a steady state, as the concentrations of molecules do not change much.
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This complex of reactions is far more efficient at harvesting energy than a single reaction would be.
The Respiratory Chain: Electrons, Protons, and ATP Production
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The respiratory chain, the final component of glucose oxidation, is needed to make use of the generated
reducing agents and the energy they possess.
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By relieving them of their hydrogens (H+ + e–), respiration also replenishes the supply of the oxidized forms:
FAD and NAD+.
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Electrons pass along a series of membrane-associated electron carriers called the respiratory chain or the
electron transport chain.
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The flow of electrons by way of a series of redox reactions causes the active transport of protons across the
inner mitochondrial membrane and into the intermembrane space, creating a proton concentration gradient.
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The protons then diffuse through proton channels down the concentration and electrical gradient back into
the matrix of the mitochondria, creating ATP in the process.
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The entire process of ATP synthesis by electron transport through the respiratory chain is called oxidative
phosphorylation.
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Evolution has produced the lengthy electron transport chain we observe today to control the release of energy
during the oxidation of glucose in a cell.
The respiratory chain transports electrons and releases energy
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ATP is generated because the protons move through a transmembrane protein called ATP synthase. This
enzyme makes ATP from ADP and P i.
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The respiratory chain transports electrons and releases energy.
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Protein complexes are bound to the inner mitochondrial membrane.
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The membrane is highly folded to increase surface area.
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Figure 7.10 shows a functional diagram of the mitochondrial inner membrane.
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NADH + H+ passes its hydrogen atoms to the NADH-Q reductase protein complex. The NADH-Q reductase
passes the hydrogens on to ubiquinone (Q), forming QH2.
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The QH2 passes electrons to cytochrome c reductase, which in turn passes them to cytochrome c. Next to
receive them is cytochrome c oxidase. The cytochrome oxidase passes them on to oxygen.
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Reduced oxygen unites with two hydrogens to form water.
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See Figure 7.11 for a complete review of the respiratory chain.
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This complex series of reactions actually tames the energy release by allowing only small, manageable energy
packets (ATP) to form.
Proton diffusion is coupled to ATP synthesis
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As electrons pass through the respiratory chain, protons are pumped into the intermembrane space against a
concentration and electrical gradient. (See Figure 7.12 and Animated Tutorial 7.1.)
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The potential energy generated is called the proton-motive force.
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The chemiosmotic mechanism for ATP synthesis:
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NADH or FADH2 (reduced forms) yield energy upon oxidation.
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The energy is used to pump protons into the intermembrane space, contributing to the proton-motive force.
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The potential energy from the proton-motive force is harnessed by ATP synthase to synthesize ATP from
ADP.
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Synthesis of ATP from ADP is reversible: Excess ATP can be hydrolyzed to ADP + Pi + free energy.
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Why is this reaction driven toward ATP synthesis and not hydrolysis in mitochondria?
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The synthesized ATP is transported out of the mitochondrial matrix as quickly as it is made.
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The proton gradient is kept high by the pumping of the electron transport chain because of the availability of
fuel molecules such as glucose.
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In mammals, ATP synthase is a multi-protein machine with 16 different polypeptides.
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Two functional parts of the machine are a membrane channel for H+ and a lollipop-shaped portion that
protrudes into the matrix.
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The movement of a proton through the channel causes the physical rotation of the core of the enzyme.
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This pushes the ADP and P i so close together that they bond.
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Figure 7.13 shows the initial experiments that demonstrated the chemiosmotic mechanism. (See also
Animated Tutorial 7.2.)
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Proton diffusion can be used to create only heat when uncoupled from ATP production.
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If a simple proton channel without ATP synthase is added, then the potential energy of the proton-motive
force is transferred to heat energy.
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A protein called thermogenin does just this to generate heat in newborn humans and hibernating animals.
Fermentation: ATP from Glucose, without O2
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ATP.
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When there is an insufficient supply of oxygen, a cell cannot reoxidize cytochrome c.
Then QH2 cannot be oxidized back to Q, and soon all the Q is reduced.
This continues until the entire respiratory chain is reduced.
NAD+ and FAD are not generated from their reduced form.
Pyruvate oxidation stops, due to a lack of NAD+.
Likewise, the citric acid cycle stops, and if the cell has no other way to obtain energy, it dies.
Thus, oxygen at the end of the respiratory chain reaction acts as the ultimate electron acceptor.
Some cells under anaerobic conditions continue glycolysis and fermentation and produce a limited amount of
Some organisms are confined to totally anaerobic environments and use only fermentation.
There are two general metabolic reasons for this:
These organisms lack the molecular machinery for oxidative phosphorylation.
These organisms lack enzymes to detoxify the toxic byproducts of O2, such as hydrogen peroxide.
Some fermenting cells produce lactic acid and some produce alcohol
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In the absence of oxygen or in eukaryotic cells that lack mitochondria, pyruvate builds up as the end-product
of glycolysis, and NAD+ supplies dwindle. Since the supply of NAD+ is limited, NADH + H+ must be converted back
to NAD+.
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The NADH + H+ concentration builds up and an enzyme reduces pyruvate using NADH + H+.
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In lactic acid fermentation, the enzyme lactate dehydrogenase uses the reducing power of NADH + H + to
convert pyruvate into lactate, and NAD+ is replenished in the process. (See Figure 7.14.)
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Lactic acid fermentation occurs in some microorganisms—even in our muscle cells when they are starved for
oxygen.
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Alcohol fermentation involves the use of two enzymes to metabolize pyruvate. (See Figure 7.15.)
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First carbon dioxide is removed from pyruvate, leaving acetaldehyde.
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Then NADH + H+ is used by the second enzyme to convert the acetaldehyde to ethanol.
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Without oxygen, the yield of energy is low.
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Four ATP molecules are generated per glucose molecule, but two had to be
invested.
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The net yield therefore is just two ATP per glucose molecule.
Contrasting Energy Yields
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A total net of 38 ATP molecules can be generated from each glucose molecule in glycolysis followed by
complete aerobic respiration.
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Some animal cells’ inner mitochondrial membranes are impermeable to NADH. To get into the matrix
requires the energy of one ATP for each of the two NADH produced per molecule of glucose. This reduces the yield to
36 ATP molecules. (See Figure 7.16.)
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In contrast, fermentation has a net yield of only 2 ATP molecules from each glucose molecule. (See Figures
7.14 and 7.15.)
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The end products of fermentation (such as lactic acid and ethanol) contain much more unused energy than the
end products of aerobic respiration.
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In aerobic respiration, each NADH + H+ generates three ATP molecules, and each FADH2 generates two
ATP molecules when consumed in the electron transport chain.
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Coupled with glycolysis, aerobic respiration captures 63 percent of the
energy stored in glucose; fermentation captures only 3.5 percent. Aerobic
respiration is 18 times more efficient at harvesting energy from glucose.
Relationships between Metabolic Pathways
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Glucose utilization pathways can yield more than just energy. They are interchanges for diverse biochemical
traffic.
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Intermediate chemicals are generated that are substrates for the synthesis of lipids, amino acids, nucleic acids,
and other biological molecules. (See Figure 7.17.)
Catabolism and anabolism involve interconversions using carbon skeletons
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Catabolic and anabolic pathways intersect around the energy-yielding pathways.
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Catabolic uses of molecules include the following:
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Polysaccharides are hydrolyzed into sugars, which pass on to glycolysis.
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Lipids are converted to fatty acids, which become acetate (and then acetyl CoA), and glycerol, which is
converted to dihydroxyacetone phosphate, an intermediate in glycolysis.
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Proteins are hydrolyzed into amino acids, which feed into glycolysis or the citric acid cycle.
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Anabolic interconversions include the following:
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Gluconeogenesis is the process by which intermediates of glycolysis and the citric acid cycle are used to form
glucose.
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Acetyl CoA can form fatty acids. Amino acids can be polymerized into proteins.
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Common fatty acids have even numbers of carbons because they are formed by adding two-carbon acetyl
CoA “units.”
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The citric acid cycle intermediate -ketoglutarate is the starting point for the synthesis of purines.
Oxaloacetate is a starting point for pyrimidines. (See Figure 7.18.)
Catabolism and anabolism are integrated
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The levels of the products and substrates of energy metabolism are remarkably constant.
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Cells regulate the enzymes of catabolism and anabolism to maintain a balance.
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What happens if inadequate fuel molecules are available?
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Polysaccharides are an intermediate storage form of energy. A typical person has about one day’s worth of
energy stored as the carbohydrate glycogen.
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A typical person has about a week’s worth of needed amino acids stored as protein, and over a month’s worth
of energy stored as fats.
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Fats are compact energy storage molecules because they exclude water and are particularly hydrocarbon-rich.
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If food is withheld, glycogen is used up first, then fats.
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Fats cannot cross the blood–brain barrier. To supply glucose to the brain, glucose must be synthesized by
gluconeogenesis. This requires the use of amino acids.
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Therefore, proteins must be broken down.
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After fats are depleted, proteins alone provide energy.
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At this point important disease-fighting proteins (antibodies) are consumed, and the likeliness of severe
illness increases.
Regulating Energy Pathways
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Metabolic pathways work together to provide cell homeostasis.
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Positive and negative feedback control whether a molecule of glucose is used in anabolic or catabolic
pathways.
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Figures 7.19 and 7.20 diagram allosteric regulation. The amount and balance of products a cell has is
regulated tightly.
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This balance is achieved via allosteric regulation of enzyme activities. Control points use both positive and
negative feedback mechanisms.
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The main control point in glycolysis is the enzyme phosphofructokinase.
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This enzyme is inhibited by ATP and activated by ADP and AMP.
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When ATP is low, phosphofructokinase is active; when ATP is high, it is inactive.
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The main control point of the citric acid cycle is the enzyme isocitrate dehydrogenase.
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This enzyme converts isocitrate to -ketoglutarate.
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NADH + H+ and ATP are inhibitors of this allosteric enzyme.
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NAD+ and ADP are activators of it.
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Accumulation of isocitrate and citrate occurs, but is limited by the inhibitory effects of high ATP and NADH.
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Citrate acts as an additional inhibitor to slow the fructose 6-phosphate reaction of glycolysis.
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The accumulated citrate also switches acetyl CoA to the synthesis of fatty acids.