DAT Bootcamp Bio Academy

Chapter 3: Cellular Energy

Table of Contents:
Bio-thermodynamics
Adenosine Triphosphate
Mitochondria
Aerobic Cellular Respiration
ATP Yield of Aerobic Cellular Respiration
Anaerobic Cellular Respiration and Fermentation
Alternative Sources of Energy Generation
Preview
The food we eat gives our cells energy to carry out various functions, such as
growth and division. How do cells convert food into a form of energy that they
can understand and use? The answer is metabolism, which is the whole web of
metabolic pathways that occur in a cell at any given time. Metabolic pathways
string together individual chemical reactions, where the product of an earlier
reaction serves as the reactant for the next.
Some metabolic pathways are catabolic. Catabolic processes break down large
macromolecules into smaller pieces (think catabolism ~ cannibalism), and usually
release energy in the form of adenosine triphosphate ATP . On the other hand,
anabolic processes extract energy from ATP and use it to build larger, more
complex macromolecules, where the energy is stored.

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 Carbohydrates (like glucose) are our cell's preferred fuel source. There are two
central pathways our cells use to catabolize carbohydrates. The first is called
aerobic cellular respiration, which occurs in the presence of oxygen to produce
an abundance of ATP. The other type is called anaerobic cellular respiration,
which creates a smaller amount of ATP when oxygen is not readily accessible.
In addition to learning the details of each pathway, we will also learn about a few
funky methods our cells use to produce energy from different fuels, like fats and
proteins. First, let’s learn more about bio-thermodynamics.
Bio-thermodynamics
Energy is the ability to do work - i.e., to create some change in a biological
system, such as ourselves. Chemical energy is a unique type of potential energy,
where the chemical bonds serve as a store of energy, and has the potential to be
used to do work. .
Catabolic reactions release free energy, so they are an example of exergonic
reactions (energy release). They are spontaneous reactions (negative Gibbs free
energy,  ΔG because they do not require energy input to proceed.
Mnemonic: EXergonic reactions mean that free energy is EXiting the system.
Anabolic reactions absorb free energy, so they are an example of endergonic
reactions (requires energy). These are non-spontaneous processes because they
require energy input to proceed to the final state.
Adenosine Triphosphate
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 https://www.youtube.com/embed/ 6VyMFQ7rRo?rel=0&showinfo=0

Adenosine triphosphate ATP is an RNA nucleoside triphosphate, meaning it

has three phosphates covalently linked to a ribose sugar. The ribose also
connects to an adenine nitrogenous base. As a whole, ATP molecules are
unstable because the three phosphate groups are all negatively charged and
repel each other.

https://commons.wikimedia.org/wiki/File:Nucleoside_nucleotide_general_format.png

There are high energy bonds between phosphate groups. These release
significant free energy whenever they are broken by a hydrolysis reaction.
ATP hydrolysis reactions release free energy, making them spontaneous ( ΔG
and exergonic. The free energy can then power endergonic processes to keep
cells out of chemical equilibrium.
Reaction coupling is the process of powering an energy-requiring reaction with
an energy-releasing one. It allows an unfavorable reaction to be powered by a

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 favorable reaction, making the net ΔG negative (exergonic = releases energy +
spontaneous).
For example, use the power of ATP hydrolysis (energy releasing) to move ions
against their concentration gradient (energy requiring).
Critical Review of ATP
ATP is an unstable RNA nucleoside triphosphate.
ATP hydrolysis reactions are exergonic and spontaneous.
Reaction coupling links unfavorable reactions with favorable ones.
Mitochondria
Mitochondria are the powerhouses of the cell! They make many ATP molecules
through cellular respiration, which is a catabolic process described in detail in
coming sections.
Mitochondria are oval shaped organelles found in eukaryotic cells. They float
around in the cell’s cytosol, and because they are organelles, they are membrane-
bound - with two membranes!
The outer membrane surrounds the entire surface area of the mitochondrion,
while the inner membrane has many indentations called cristae that increase the
surface area.
The acidic region between the outer and inner membranes is the intermembrane
space, while the area deep to the inner membrane is the mitochondrial matrix.
The multi-compartment organization of a mitochondrion is useful for aerobic
cellular respiration.

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 Mitochondria are found in most eukaryotic cell types. However, their abundance
varies depending on the cell’s particular energy needs. For example, human
muscle cells (myocytes) have a high energy requirement, so there are many
mitochondria in them. Conversely, red blood cells (erythrocytes) function to
carry as much oxygen as possible, so they lack most organelles (including
mitochondria).
As an aside, the matrix contains its own circular DNA and ribosomes. The same
is true of chloroplasts Chapter 4 . Why might mitochondria and chloroplasts
contain DNA and ribosomes that are separate from the nucleus DNA and
cytosol (ribosomes)?

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 It’s because at one point they likely were free lively aerobic cells, that eventually
were absorbed by other cells to form eukaryotes (explained by the
endosymbiotic theory).
The endosymbiotic theory states that aerobic bacteria were internalized as
mitochondria while the photosynthetic bacteria became chloroplasts. Some
evidence for this includes size similarities and the fact that mitochondria and
chloroplasts contain their own circular DNA and ribosomes.
Critical Review of Mitochondria:
Mitochondria are double membrane organelles that are powerhouses of the
cell
The inner membrane of a mitochondrion has cristae
The intermembrane space lies between the outer and inner membrane
The intermembrane space has a low pH (shown later)
The space inside the inner membrane is called the mitochondrial matrix.
Mitochondria contain separate DNA and ribosomes
The endosymbiotic theory says that mitochondria were aerobic, free-living
bacteria.
Aerobic Cellular Respiration
Aerobic cellular respiration is a sizable catabolic pathway that requires oxygen.
It strings together a series of four smaller catabolic pathways to create ATP.

https://www.youtube.com/embed/7J4LXs-oDCU?rel=0&showinfo=0

1. Glycolysis:
Glycolysis converts a six-carbon glucose molecule into two three-carbon
compounds called pyruvate. Glycolysis is the only pathway in aerobic glycolysis
that does not require oxygen, it an anaerobic process..

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 Glycolysis occurs within the cytosol of the cell.
Glycolysis also extracts high-energy electrons as the glucose is broken down,
using them to reduce NAD⁺ (a coenzyme) into NADH, which may travel to the
electron transport chain for further ATP creation. Overall, glycolysis has ten
steps; however, the details of each of these steps are beyond the scope of the
DAT. This section will outline the key steps you should focus on for the DAT.
Glycolysis has two main phases, an energy investment phase, and an energy
payoff phase.
The energy investment phase begins as glucose enters the cytosol of the cell.
Here, it gets phosphorylated via the hydrolysis of one ATP into ADP + Pᵢ.
This phosphorylation is carried out by hexokinase, and it is a non-reversible
process.
Now, the glucose is called glucose-6-phosphate (because a phosphate was
added to carbon six), which is a molecule that cannot exit the cell.
An isomerase enzyme modifies glucose-6-phosphate into fructose-6
phosphate (remember, glucose and fructose are isomers of each other).
More energy investment occurs with the hydrolysis of a second ATP molecule.
In this way, fructose-6-phosphate gets phosphorylated to become fructose-1,6
bisphosphate. This step is carried out by an enzyme called phosphofructokinase
PFK , and it is another irreversible reaction.
DAT Pro-Tip: phosphofructokinase PFK is an essential regulatory enzyme.
Levels of various molecules influence the speed with which
phosphofructokinase functions, leading to regulation of the rate of glycolysis
as a whole.
One of the three-carbon sugars is called dihydroxyacetone phosphate DHAP ,
and the other is called glyceraldehyde-3-phosphate G3P . These sugars exist
in equilibrium, using an isomerase enzyme to convert back and forth between the
two forms.
The G3P molecules then undergo a series of redox reactions to produce four ATP
through substrate-level-phosphorylation, 2 pyruvate and 2 NADH. Keep in mind

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 we required an energy investment of two ATP. So the net products of glycolysis
are:
Two ATP
Two Pyruvate
Two NADH

Adapted from: https://commons.wikimedia.org/w/index.php?curid=53712885

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 Critical Review of Glycolysis:
Glycolysis does not need oxygen, and it takes place in the cytosol.
Steps one through five are the energy investment phase.
Steps six through ten are the energy payoff phase.
Step one uses hexokinase to irreversibly trap glucose in the cytosol as
glucose-6-phosphate via the hydrolysis of one ATP.
Step three uses phosphofructokinase (the most significant regulatory
enzyme in glycolysis) to irreversibly create a six-carbon fructose-1,6
bisphosphate molecule from the hydrolysis of another ATP.
Fructose-1,6-bisphosphate is unstable, so it breaks down into two three-
carbon sugars at the end of the energy investment phase.
The energy payoff phase produces two ATP through substrate-level
phosphorylation, one NADH electron carrier, and one pyruvate for each G3P
that enters.
Because two G3P molecules result from the oxidation of one glucose
molecule during the energy investment phase, the energy payoff phase
occurs twice to produce four ATP, two NADH, and two pyruvates.
Four ATP produced - two ATP invested = two net ATP from glycolysis.
2. Pyruvate manipulations:
Pyruvate molecules must first pass from the cytosol, and into the mitochondrial
matrix.
Here, the pyruvate molecules 3 carbons) will be decarboxylated to release a
carbon atom as carbon dioxide. Pyruvate manipulations occur in the cytosol for
prokaryotes, because they do not have membrane-bound organelles.
After pyruvate loses a carbon dioxide, it is now a two-carbon molecule.
Then, it will undergo oxidation to become a two-carbon acetyl group. As this
occurs, there is a reduction of NAD⁺ to NADH.
After the decarboxylation and oxidation steps, the remaining acetyl group will
bind to a particular coenzyme, known as Coenzyme A CoA .
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 DAT Pro-Tip: the three manipulations described above are carried out by
pyruvate dehydrogenase, which is a complex of three interconnected
enzymes.
The pyruvate manipulations produce:
Two carbon dioxides
Two NADH
Two acetyl-CoA
... for each glucose that enters cellular respiration.

https://commons.wikimedia.org/w/index.php?curid=49924804

Critical Review of Pyruvate Manipulations:

Pyruvate manipulations occur in the mitochondrial matrix.
The pyruvate decarboxylation step removes carbon dioxide from pyruvate.
The pyruvate oxidation step indirectly depends on oxygen, and it reduces
NAD⁺ to NADH.

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 Coenzyme A CoA is added to the two-carbon acetyl group to make acetyl-
CoA, which can enter the Krebs cycle.
The pyruvate manipulations are carried out via pyruvate dehydrogenase.
For one glucose, two pyruvate manipulations will occur, releasing two carbon
dioxides, reducing two NAD⁺ into two NADH, and forming two acetyl-CoA.
3. The Krebs cycle also goes by some other names.
AKA the citric acid cycle because citrate the first molecule produced.
AKA the tricarboxylic acid TCA cycle because each of the first two
intermediates contains three (tri-) carboxylate functional groups.
The Krebs cycle occurs in the mitochondrial matrix in eukaryotes. It takes place
in the cytosol for prokaryotes (they do not contain membrane-bound organelles).
In the first step of the Krebs cycle, a two-carbon acetyl-CoA joins four-carbon
oxaloacetate to form six-carbon citrate. Each citrate will then go through several
rearrangements. During these rearrangements, the six carbon molecule will lose
two of its carbon atoms as two carbon dioxide molecules. NAD⁺ undergoes
reduction to NADH each time a carbon dioxide leaves.
The four-carbon molecule (left over from the rearrangements that released
carbon dioxide and produced NADH then progresses through the remainder of
the Krebs cycle.
As this occurs a GTP is produced via substrate-level phosphorylation.
DAT Pro-Tip: GTP is guanosine triphosphate. It is an RNA nucleoside
triphosphate, just like ATP.
The four-carbon compound will then be manipulated again, passing electrons to
flavin adenine dinucleotide FAD , which is another electron carrying coenzyme
similar to NAD⁺. The FAD undergoes a reduction to FADH₂.
Finally, the four-carbon molecule transforms back into four-carbon oxaloacetate.
Here, another NAD undergoes a reduction to NADH.
Realize that the Krebs cycle is just that - a cycle. The pathway's final reaction
reforms the starting compounds so the cycle can continue (four carbon
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 oxaloacetate).
The Krebs cycle produces:
Two carbon dioxides
Three NADH,
One FADH₂,
One GTP
Because two acetyl-CoA molecules are produced in the pyruvate manipulation
reactions, the Krebs cycle will occur two times for each glucose that enters
cellular respiration.
Therefore, for each glucose molecule that makes two acetyl-CoA molecules the
Krebs cycle makes four carbon dioxides, six NADH, two FADH₂, and two GTP.

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 Critical Review of the Krebs TCA Cycle:
Krebs cycles indirectly depend on oxygen.
The Krebs cycle occurs in the mitochondrial matrix.
Two carbons (added into the cycle by each acetyl-CoA leave as two
separate carbon dioxide molecules.
For every one acetyl-CoA entering Krebs: 2 CO₂, 3 NADH, 1 FADH₂, and 1
GTP ATP .
Two acetyl-CoA molecules are oxidized by the Krebs cycle for every one
glucose.

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 So, for every two acetyl-CoA molecules: 4 CO₂, 6 NADH, 2 FADH₂, and 2 GTP
ATP .
4. Oxidative phosphorylation is last in cellular respiration. This stage
encompasses two linked components - the electron transport chain and
chemiosmosis. These components work together to synthesize ATP and produce
water.
The electron transport chain ETC has proteins and other organic molecules,
which pass high-energy electrons from one component to the next.
With each transfer, the electrons release a little free energy that the ETC uses to
form an electrochemical gradient. Chemiosmosis uses the energy stored in that
gradient to synthesize ATP.
As electrons reach the end of the ETC, they are passed on to an oxygen molecule
to form water; therefore, oxygen serves as the final electron acceptor for
aerobic ETCs. This step is the reason why aerobic oxidative phosphorylation
directly depends on oxygen.
The mitochondrial inner membrane contains the ETC for eukaryotes. Conversely,
in prokaryotes the ETC occurs along the cellular membrane.
The ETC proteins are four large clusters, named protein complexes I IV.
High-energy electrons travel through the ETC because each ETC protein is more
“electron hungry” than the last. For example, electrons travel from complex-I to
complex-II because complex-II is more “electron hungry” than complex-I.
With each transfer of electrons, the electron source (i.e., the thing that was
carrying the electrons) becomes oxidized, while the electron target (i.e., the thing
that accepts the electrons from the electron source) becomes reduced. In this
way, the ETC operates through a series of oxidation-reduction (redox)
reactions.
As the redox reactions occur, the protein complexes pump protons from the
mitochondrial matrix into the intermembrane space, forming an electrochemical
gradient. This chemiosmotic gradient will be used to create ATP.

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 How do electrons get to the ETC in the first place? Recall the electron carriers
generated through the cellular respiration of one glucose molecule so far.
Glycolysis made two NADH, the oxidation of two pyruvates made two NADH.
Two Krebs cycles produced six NADH and two FADH₂.
These reduced coenzymes travel to different complexes in the ETC.
NADH is more effective than FADH₂. It travels directly to complex-I and donates
its electrons to it.
In the process, NADH goes from being reduced to oxidized, and becomes NAD⁺
that can be used for future reactions as a substrate in the earlier stages of
oxidative phosphorylation. As NAD⁺ is regenerated, complex-I undergoes a
reduction.
FADH₂ carries electrons that are lower in energy than the electrons found in
NADH. As FADH₂ reduces a complex, it leads to the regeneration of FAD (the
oxidized form). The FAD will be used in the Krebs cycles as a future substrate.
DAT Pro-Tip: oxidative phosphorylation directly depends on oxygen as the
final electron acceptor of aerobic ETCs. Without oxygen, oxidative
phosphorylation would stop, which means the regeneration of the coenzymes
needed for pyruvate oxidation NAD⁺) and the Krebs cycle NAD⁺ and FAD
would also stop.
Hence, aerobic pyruvate oxidations and Krebs cycles indirectly depend on
oxygen.
Note that glycolysis has its own way of regenerating NAD⁺ without the ETC,
and it does not rely on oxygen (anaerobic). This will be discussed coming up.
The electrons are passed along the electron transport chain until they reach the
final electron acceptor, to form water! Here, oxygen molecules combine with
protons to form water. Remember that the final electron acceptor of ETC is
oxygen, and it produces water.
Because FADH₂ passes its electrons to a complex later in the ETC, it will
contribute to less proton pumping. The electrons FADH₂ release will only be used
for pumping protons at complex-III and IV.

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 ATP Creation:
Chemiosmosis harnesses energy stored within the proton gradient to synthesize
ATP as protons diffuse across the inner membrane, from an area of high
concentration (the intermembrane space) to an area of low concentration (the
mitochondrial matrix).
A special enzyme called ATP synthase is responsible for synthesizing ATP. It
accomplishes this because it is like a big fan that spins as protons travel through
it, the proton-motive force. As it spins, ATP synthase catalyzes the condensation
of ADP + Pᵢ into ATP in the mitochondrial matrix.
The ETC and chemiosmosis generate ATP through oxidative phosphorylation. It
is oxidative because NADH and FADH₂ electron carriers are oxidized to release
the high-energy electrons they carry.

Adapted from: https://commons.wikimedia.org/w/index.php?curid=49924811

Critical Review of Oxidative Phosphorylation:

The ETC is in the mitochondrial inner membrane of eukaryotes

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 The ETC is in the cell membrane of prokaryotes
NADH becomes oxidized as it reduces complex-I
FADH₂ becomes oxidized as it reduces complex-II
Electrons release energy through the ETC, which goes toward proton
pumping.
Electrons travel from complex-IV to oxygen, producing water in the matrix.
Aerobic ETCs directly depend on oxygen as the final electron acceptor.
Proton pumping forms an electrochemical gradient across the inner
membrane.
The intermembrane space of the mitochondrion is acidic due to the gradient.
Protons spontaneously seek to increase the entropy of the matrix.
Protons cannot diffuse directly across membranes because membranes are
hydrophobic.
Protons travel “down” their electrochemical gradient through ATP synthase.
ATP synthase is in the inner membrane; cell membrane for prokaryotes.
ATP synthase relies upon the proton motive force of chemiosmosis.
ATP synthase spins to phosphorylate ADP to produce ATP in the
mitochondrial matrix of eukaryotes.
Critical Review of Aerobic Cellular Respiration:

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 ATP Yield of Aerobic Cellular Respiration
Aerobic respiration is hugely exergonic, with a ΔG of - 686 kcal/glucose (this
number does show up on DATs).
Still, how much ATP does aerobic respiration make per glucose? Recall that a net
amount of 2 ATP result from substrate-level phosphorylation in glycolysis.
Similarly, 2 GTP (energetically equivalent to ATP result from substrate level
phosphorylation in the Krebs cycle.
The other 32 34 ATP come from oxidative phosphorylation. Therefore, cells that
are entirely efficient in generating energy can produce a total of 36 38 ATP per
glucose molecule. Scientists seem to think that 4 protons must travel through
ATP synthase for 1 ATP molecule to be synthesized.
A single NADH coenzyme will produce about 3 ATP NADH from glycolysis
produces less).
Because FADH₂ reduces a later complex, a single FADH₂ will produce about 2
ATP.

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 Notice that the 2 NADH generated via glycolysis are capable of producing 4 6
ATP. Recall that glycolytic NADH coenzymes lie in the cytosol of the cell. NADH
cannot pass through the inner membrane of the mitochondrion to reduce
complex-I. NADH must use shuttles to get in the matrix, and the type of shuttle
affects the amount of ATP produced. So the NADH from glycolysis produces less
ATP than the NADH generated elsewhere.
Prokaryotes, like bacteria, carry out the entirety of cellular respiration in their
cytosol, and their ETC is in their cell membrane. Thus, they do not need to use
any shuttle systems for glycolytic NADH to reduce complex-I. Therefore, they will
produce 6 ATP from the 2 NADH made in glycolysis.
Critical Review of Aerobic Respiration ATP Yield:
The full aerobic respiration is exergonic with ΔG = - 686 kcal/glucose
Eukaryotic cells will generate 36 38 ATP/glucose if they are entirely efficient
A single NADH can contribute to the synthesis of 3 ATP
A single FADH2 can contribute to the synthesis of 2 ATP
Prokaryotes do not use shuttle systems
Prokaryotes make 38 ATP if they are entirely efficient
Fermentation
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 https://www.youtube.com/embed/YbdkbCU20_M?rel=0&showinfo=0&
amp;start=39&end=500

Recall that glycolysis needs NAD⁺ to accept high energy electrons at step six of
the energy payoff phase. The NADH this reaction produces delivers its electrons
to the ETC to regenerate NAD⁺ so glycolysis can continue. However if oxygen is
not available as the final electron acceptor, the processes that follow glycolysis
cannot occur, and NAD⁺ cannot be regenerated.
Glycolysis makes two ATP via substrate level phosphorylation. While this is a
small amount in comparison to the full capabilities of cellular respiration, it still
helps the cell during times of electron acceptor scarcity.
Fermentation is a unique anaerobic pathway. Its primary purpose is to oxidize
NADH back to NAD⁺ so that glycolysis can continue to make ATP.
Lactic acid fermentation regenerates NAD⁺ as NADH by reducing pyruvate into
lactic acid.
NADH transfers its electrons to pyruvate, regenerating NAD⁺. As this occurs,
lactate/lactic acid is formed.
If you work out your muscles hard, you might feel muscle soreness because our
muscle cells (myocytes) undergo lactic acid fermentation due to the available
oxygen being consumed quickly, and the cells still wanting to produce ATP..
Human red blood cells (erythrocytes) do not have mitochondria and thus cannot
perform aerobic cellular respiration, so they always ferment.

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 https://commons.wikimedia.org/w/index.php?curid=17293840

Once oxygen has become available again, humans can use a process called the
Cori cycle to convert lactate back into glucose. The Cori cycle ensures that we
get the most energy possible out of each glucose molecule, irrespective of the
conditions we find ourselves.

https://www.youtube.com/embed/g6XUYLa5eZE?rel=0&showinfo=0&a
mp;start=101

The Cori cycle transports lactate from the myocyte, through the bloodstream,
and to liver cells (hepatocytes). Once at a hepatocyte, the lactate can oxidize
back into pyruvate. Pyruvate can form glucose through gluconeogenesis.
Gluconeogenesis creates new glucose from different types of fuel sources. In
the case of gluconeogenesis from pyruvate in the Cori cycle, we need an energy
investment of six ATP. While this may appear like a lot of ATP, it pays off in the
end because it means the glucose can be broken down via aerobic respiration
once oxygen has become available again.

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 DAT Pro-Tip: hepatocytes contain an enzyme that “undoes” the hexokinase
reaction of glycolysis. For this reason, the liver is the only organ that can
release glucose into the bloodstream, allowing other cells to use the glucose
as a fuel source.

https://commons.wikimedia.org/w/index.php?curid=6624860

Alcohol fermentation is another type of fermentation. Yeast use alcohol

fermentation, which is similar to lactic acid fermentation in that it regenerates
NAD⁺ for glycolysis to continue making two ATPs. However, the electrons from
NADH will not reduce the pyruvate produced.
Instead, the pyruvate will be decarboxylated to lose carbon as carbon dioxide.
The leftover molecule is acetaldehyde. NADH will reduce acetaldehyde into
ethanol, in the process, oxidizing back into NAD⁺ for more rounds of
fermentative glycolysis. Alcohol fermentation produces the ethanol found in
alcoholic beverages.

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 Adapted from: https://commons.wikimedia.org/w/index.php?curid=17301493

Various types of organisms are identifiable based on their ability to grow in the
presence of oxygen.
1. Obligate aerobes are organisms that can only metabolize their fuel sources
via aerobic respiration. They can not undergo fermentation.
2. Obligate anaerobes will only metabolize their fuel sources via anaerobic
respiration or fermentation. Oxygen is toxic to them.
3. Facultative anaerobes can utilize aerobic respiration, anaerobic respiration,
or fermentation. However, because aerobic respiration generates the most
ATP, they will be undergo aerobic respiration if they are able to (if oxygen is
present).
4. Microaerophiles are similar to obligate aerobes in the sense that they cannot
live without oxygen. Therefore they cannot undergo anaerobic respiration or
fermentation. However, high concentrations of oxygen are harmful to them.
5. Aerotolerant organisms are similar to obligate anaerobes in the sense that
they cannot use oxygen; therefore, they only utilize anaerobic respiration or
fermentation. However, the presence of oxygen does not poison them.
Critical Review of Anaerobic Respiration and Fermentation:

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 The Cori cycle can convert lactate into glucose at the liver
Obligate aerobes need oxygen and only respire aerobically
Obligate anaerobes only use anaerobic respiration because oxygen is
poisonous
Facultative anaerobes can respire aerobically, anaerobically, or ferment
Microaerophiles are similar to obligate aerobes, but too much oxygen will kill
them
Aerotolerant organisms are similar to obligate anaerobes but can live with
oxygen
Alternative Sources of Energy Generation
So far, we have discussed how glucose molecules are broken down via cellular
respiration (aerobic or anaerobic) and fermentation. How do other types of
carbohydrates, fats, and proteins get broken down?
As it turns out, the cellular respiration of glucose is a central hub for the
catabolism of other carbohydrates, fats, and proteins. The components that make
up these different fuel sources can enter cellular respiration at various stages.

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 1. Carbohydrates
Other carbohydrates can enter cellular respiration, and for the most part, they
enter during glycolysis. Let’s begin by examining how glycogen, our storage form
of glucose, enters glycolysis.
Glycogenolysis releases glucose-6-phosphate from glycogen, allowing it to enter
glycolysis. Because glycogen can enter glycolysis as glucose-6-phosphate, it
does not require the hexokinase reaction that results in the investment of an ATP.

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 Glycogen is a highly branched polysaccharide, meaning it is a polymer of many
monomeric carbohydrates.

Carbohydrates are the preferred energy source because they are rapidly and
efficiently catabolized to provide 4 kcal/gram. However, it is hard to store much
glucose as glycogen at one time, because glycogen is a hydrophilic polymer that
attracts water and takes up a lot of cell volume.
For this reason, a few primary locations store glycogen, such that glucose can be
made accessible to metabolically active cell types. The liver stores about two-
thirds of the body’s glycogen, and it is the only organ that can make glucose
available to other tissues. Muscles contain the other one-third of glycogen.
When energy and fuel sources are abundant, other carbohydrates can go toward
making new glucose to be stored as glycogen; this is called gluconeogenesis,
and it occurs in the liver. Recall gluconeogenesis from our discussion of the Cori
cycle.
2. Fats
Now let’s examine the breakdown of fats.
Most fats exist as triglycerides, which contain three (tri-) fatty acid tails attached
to a single, three-carbon glycerol backbone. The attachments exist as ester
bonds, and dehydration reactions make them. Below is a triglyceride molecule.
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 https://commons.wikimedia.org/w/index.php?curid=30131156

Humans need to digest fats before absorbing them. Lipases convert triglycerides
into free fatty acids and alcohols. The alcohols can be free glycerol molecules, as
well as other types like monoglycerides. Digesting a triglyceride with a lipase is
called lipolysis.
Humans absorb digested fats at enterocytes of the small intestine. Here, free
fatty acids and monoglycerides enter the cell. Once contained within the
enterocyte, the free fatty acids and monoglycerides will reform into triglycerides.
Once the triglycerides have reformed, they will pair up with proteins,
phospholipids, and cholesterol in the enterocyte.
Chylomicrons are lipoprotein transport structures formed by the fusing of
triglycerides with proteins, phospholipids, and cholesterol. They leave
enterocytes and enter lacteals, small lymphatic vessels that take fats to the rest
of the body.

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 Adapted from: https://www.flickr.com/photos/ajc1/5891020466

Cells called adipocytes store triglycerides. Adipocytes come together to form

adipose tissue. For a triglyceride to enter an adipocyte from a chylomicron, it
must again be acted upon by a lipase enzyme, causing it to break down into free
fatty acids and monoglycerides. Once inside the adipocyte, the triglyceride will
reform.
When it finally comes time to break down our stored triglycerides for energy, we
need to remove the triglycerides from the adipose tissue. Again, we need a lipase
to do this.
The hormone sensitive lipase enzymes create free fatty acids and glycerol
molecules via lipolysis. The free fatty acids and glycerols can then travel through
the blood via a multitude of ways.
They can reform into triglycerides along with proteins, phospholipids, and
cholesterol to make different types of lipoproteins. Alternatively, the fatty acids

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 can travel in their free state (not esterified to glycerol) by binding to a particular
protein called albumin.
Low-density lipoproteins LDLs) have a low density of proteins. They are
generally considered to be unhealthy because they deliver cholesterol to
peripheral tissues via the bloodstream. As this occurs, they can end up clogging
blood vessels that supply the muscle tissue of the heart - which can lead to a
heart attack!
High-density lipoproteins HDLs) have a high density of proteins. They are
generally considered to be healthy because they take cholesterol away from
peripheral tissues and deliver it to the liver. Once at the liver, the cholesterol can
be used to make bile, which ultimately gets expelled from the body via a
mechanism we will discuss in chapter 10.

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 When a glycerol molecule travels to the liver, it can undergo a conversion to enter
glycolysis or make new glucose via gluconeogenesis at the liver.
Free fatty acids enter cellular respiration as acetyl-CoA molecules, which is
made possible via a process called beta-oxidation. Beta-oxidation occurs in the
mitochondrial matrix of a eukaryotic cell’s mitochondria. Beta-oxidation is an
important process that explains why fats yield 9 kcal/gram.
Before a fatty acid chain enters beta-oxidation, we need to activate the entire
chain via the investment of ATP. This is an investment of ATP consumption to
produce more ATP down the road.
Now, it can go through a series of cleavages into two-carbon acetyl-CoA
molecules. Each of the acetyl-CoA molecules will then travel to the Krebs cycle.
As it is chopped up, it also produces NADH and FADH₂, which can be used to
make ATP.
We can see how one triglyceride has the potential of making way more ATP than
one glucose molecule. A triglyceride glycerol molecule can contribute to
glycolysis. Additionally, its fatty acid chains contain many highly reduced
carbons, which can contribute to the production of “bonus” electron carriers and
acetyl-CoA through beta-oxidation.

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 4. Proteins
When it comes to cellular respiration, proteins are the least desirable fuel source.
They are only catabolized when cells are starving due to unavailability of
carbohydrates and fats. When we consume proteins, we break them down into
amino acids. Proteins provide 4 kcal/gram (lower energy yield) and we are
breaking down the proteins that are body needs for essential bodily functions!
Before amino acids undergo cellular respiration, they must undergo oxidative
deamination in the liver. Here, ammonia NH₃) molecules are removed from the
amino acid to create a slightly different molecule that is easier to shuttle into
cellular respiration.
The ammonia that gets cleaved off is toxic to vertebrates. Insects, reptiles, and
birds convert the ammonia to uric acid before excreting it. Sharks, most
amphibians, and mammals (like humans) convert the ammonia to urea before

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 they excrete it as urine. Many aquatic species and invertebrates excrete
ammonia directly. They do not need to convert it to a safer compound.
The amino acid byproducts created via oxidative deamination can enter cellular
respiration at various points, depending on the starting amino acid. They can
enter by converting to pyruvate, acetyl-CoA, and several of the Krebs cycle
intermediates.
However, the processes used to get amino acid byproducts into cellular
respiration require energy, which makes proteins an inefficient fuel source. The
biggest downside for proteins comes from the fact that cells need a pool of
amino acids for making the various proteins they use to carry out their functions.
Therefore proteins are a last resort in cellular respiration.
Critical Review of the Alternative Sources of Energy Generation:
The preference of fuel sources is: carbohydrates > fats > proteins
The storage form of glucose is glycogen, which is broken down by
glycogenolysis
Other carbohydrates can contribute to glycogen via gluconeogenesis
Carbohydrates have 4 kcal/gram
Fats undergo digestion (using lipase enzymes) before absorption at the
enterocyte
Fats travel from enterocytes to adipocytes via chylomicrons and lacteals
Glycerol enters glycolysis or gluconeogenesis at the liver
Free fatty acids undergo beta-oxidation in the mitochondrial matrix
Beta oxidation makes many reduced coenzymes and acetyl-CoA → tons of
ATP
Acetyl-CoA from free fatty acids cannot contribute to gluconeogenesis
Fats have 9 kcal/gram and are long-term energy stores
Proteins give 4 kcal/gram and can contribute to gluconeogenesis at the liver
Amino acids need to undergo oxidative deamination before cellular
respiration
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 Oxidative deamination creates toxic ammonia
Congrats! Chapter 3 is in the books! 💪

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