MBM 110: MEDICAL

BIOCHEMISTRY
Lecture 1;
-High energy intermediates and ETC

Lecturer: Dr. Biwott Felix K.

Contacts: Email; fekiott@gmail.com
Mobile No: 0697-529-032

KIUT
1st Semester, 2023/2024
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 High-energy compounds
• Also called energy-rich compounds.
• Compounds present in the biological system that
when hydrolysed, produce free energy that is greater
or equal to that of ATP (△G is -7.3 kcal/mol).
• Low-energy compounds have an energy yield of less
than -7.3 kcal/mol.
• High-energy bonds are found in the majority of high-
energy compounds that produce energy upon
hydrolysis.
• Most of the high energy compounds contain
phosphate groups and thus they are also termed high-
energy phosphates.
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 Classification of high-energy compounds

• They are mainly classified into five groups:

1.Pyrophosphates
2.Acyl phosphate
3.Enol phosphate
4.Thiol phosphate
5.Phosphagens or guanido phosphates

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 Pyrophosphates

• Pyrophosphate energy bonds are nothing but acid

anhydride bonds.
• Condensation of acid groups (primarily phosphoric
acid) or their derivatives results in the formation of
these bonds.
• ATP (△G = -7.3 kcal/mol) is an example of a
pyrophosphate. It has two phosphoanhydride
diphosphate bonds.

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 Acyl phosphates

• The reaction between the carboxylic acid group

and the phosphate group forms a high energy bond
in this compound.
• 1,3-bisphosphoglycerate (△G = -11.8 kcal/mol) is
an example of acyl phosphate.

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 Enol phosphates

• The enol phosphate bond is present here.

• It is formed when a phosphate group binds to a
hydroxyl group that is bound to a double-bonded
carbon atom.
• As an example,
consider phosphoenolpyruvate (△G = -14.8
kcal/mol).

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 Thiol phosphates
• There is no high energy phosphate bond here.
• Instead, a high energy thioester bond is found
here.
• Thioester bonds are formed by the reaction of
thiol and carboxylic acid groups.
• Acetyl CoA (△G = -7.7 kcal/mol) is an example.

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 Phosphagens

• Guanidine phosphate bonds are present in

phosphagens or guanido phosphates.
• The phosphate group is attached to the guanidine
group to form it.
• Phosphocreatine (△G = -10.3 kcal/mol) is the
most important compound with this type of bond.

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 ATP – Cell’s Energy Currency

• The majority of ATP is produced in the mitochondrial

matrix during cellular respiration.
• Thus mitochondria are termed the powerhouse of the cell.
• ATP is a nucleotide made up of the molecule adenosine
and three phosphate groups.
• It is water soluble and contains a lot of high energy due to
the presence of 2 phosphoanhydride bonds connecting the
3 phosphate groups.

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 Cont…

• As a significant amount of energy is released when they

are broken, and they are referred to as high energy bonds.
• The available energy is stored in the phosphate bonds and
is released when they are split into molecules. This is
accomplished by the addition of a water molecule
(hydrolysis).
• When the outer phosphate group of ATP is removed to
yield energy, ATP is converted into ADP, which is the form
of the nucleotide with only two phosphates.

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 Cont…

Hydrolysis of ATP (exergonic)

ATP + H2O → ADP + Pi
Dehydration of ADP (endergonic)
ADP + Pi → ATP + H2O
• Hydrolysis of ATP is associated with the release of large
amounts of energy (7.3 kcal/mol) which is used for various
processes like active transport, muscle contraction, etc.

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 Synthesis of ATP

• ATP can be synthesized in two ways

1. Oxidative phosphorylation : This is the major source of
ATP in aerobic organisms. It is linked with the
mitochondrial electron transport chain.
2. Substrate level phosphorylation : ATP may be directly
synthesized during substrate oxidation in the
metabolism. The high-energy compounds such as
phosphoenolpyruvate and 1,3-bisphosphoglycerate
(intermediates of glycolysis) and succinyl CoA (of citric
acid cycle) can transfer high-energy phosphate to
ultimately produce ATP.

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 BIOLOGICAL OXIDATION

• Oxidation is the loss of electrons and reduction is the gain

of electrons.
• The electron lost in the oxidation is accepted by an
acceptor which is said to be reduced. Thus the oxidation-
reduction is a tightly coupled process.

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 ELECTRON TRANSPORT CHAIN

• The energy-rich carbohydrates, fatty acids and amino acids

undergo a series of metabolic reactions and, finally, get
oxidized to CO2 and H2O.
• The reducing equivalents from various metabolic
intermediates are transferred to coenzymes NAD + and FAD
to produce, respectively, NADH and FADH2.
• The NADH and FADH2 pass through the electron transport
chain (ETC) or respiratory chain and, finally, reduce
oxygen to water.
• The passage of electrons through the ETC is associated
with the loss of free energy. A part of this free energy is
utilized to generate ATP from ADP and Pi.
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 Functions of the Electron Transport Chain
• It serves two important purposes:
1. Regeneration of Electron Carriers: NADH and
FADH2 transfer electrons to the electron transport
chain, reverting to NAD+ and FAD. This is significant
because the oxidised forms of these electron carriers
are required for glycolysis and the citric acid cycle to
function properly.
2. Generates a Proton Gradient: The transport chain
creates a proton gradient across the inner
mitochondrial membrane, with more H+ in the
intermembrane space and less in the matrix. This
gradient represents a form of stored energy and is
used to make ATP.
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 Location of Electron Transport Chain

• As the citric acid cycle occurs in the

mitochondria, high-energy electrons are also
present within the mitochondria. As a result, in
eukaryotes, the electron transport chain also
occurs in the mitochondria.
• Mitochondria are organelles inside eukaryotic
cells that produce adenosine triphosphate (ATP),
the fundamental energy atom utilised by the cell.

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Components of the Electron Transport Chain

• The electron transport chain consists of four multisubunit

protein complexes located in the inner mitochondrial
membrane.
• The proteins in each complex oxidize NADH and/or
FADH2 and carry the electrons to the next acceptors.
• As the name implies, the electrons travel through a
sequence of proteins in the electron transport chain until
they are donated to oxygen, reducing it to water.
• The protein complexes that make up the electron transport
chain are:

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1. Complex I: NADH-Coenzyme Q Oxidoreductase
• NADH from earlier cellular respiration stages donates two
electrons to FMN. Each electron donated to FMN is
transferred to the Fe-S, which is transferred to CoQ.
• The fully oxidized form of CoQ is also known
as ubiquinone (UQ). UQ can be reduced to ubisemiquinone
(UQH) when receiving one electron and
to ubiquinol (UQH2) when receiving a second electron.
• Subsequently, reduced UQ, UQH, or UQH2 transfer
electrons to Complex III of the electron transport chain.
• Four (4) protons are simultaneously transported from the
mitochondrial matrix to the intermembrane space, setting
the electrochemical gradients that drive ATP synthesis in
oxidative phosphorylation.
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2. Complex II: Succinate-Coenzyme Q Oxidoreductase

• Most enzymes in Complex II of the electron transport

chain are similar to the ones found in Complex I.
• However, unlike Complex I, electron transport in Complex
II is not coupled with the transport of protons from the
inner mitochondrial membrane to the intermembrane
space.
• Another major difference is Complex II’s direct connection
to the Krebs cycle and, in certain cells, β-oxidation, a
pathway that breaks down fatty acids into acetyl CoA.
• In Complex II, the enzyme succinate dehydrogenase in the
inner mitochondrial membrane reduce FADH2 to FAD+.

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Cont…

• Simultaneously, succinate, an intermediate in the Krebs

cycle, is oxidized to fumarate.
• Fumarate returns to the mitochondrial matrix, where it re-
enters the Krebs cycle and undergoes a series of enzymatic
reactions.
• Similar to the electron flow in Complex I, the electrons
from the oxidation of FADH2 are passed to Fe-S and
subsequently to CoQ, reducing it to UQH and UQH2,
respectively.
• Eventually, electrons carried by UQH2 are sent to Complex
III.

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Cont…

• Unlike Complex I, the protons in Complex II are not

transported to the intermembrane space during electron
transport.
• Thus, Complex II’s contribution to ATP synthesized from
oxidative phosphorylation is considerably less than other
complexes.

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3. Complex III: Cytochrome bc1 Oxidoreductase
• Complex III of the electron transport chain consists of
cytochrome b and cytochrome c1 complexes, which contain
a two-iron two-sulfur cluster (2Fe-2S) called the Rieske
center and a heme prosthetic group.
• Electrons that enter Complex III are carried by UQH2 from
Complex I or II to Complex III. Since UQH2 carries two
electrons, while the heme prosthetic group in either
cytochrome can accommodate only one electron at a time,
the transfer of electrons in Complex III occurs in a series
of redox reactions called the Q cycle.
• The Q cycle starts when the first UQH2 enters Complex III
and binds to the Rieske center. There, UQH2 is oxidized
into UQH, donating one electron to cytochrome c1.
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Cont…
• The reduced cytochrome c1 carries the accepted electron
to cytochrome c, which brings the electron to Complex IV,
the last complex of the electron transport chain.
• In cases of reduced cytochrome b, the electron is
transferred from cytochrome b to CoQ on the other side of
the complex, replenishing UQH in the process.
• Finally, UQH is further reduced to UQH2 when it accepts
another electron from the next cytochrome b that is
reduced by the second UQH2 that enters Complex III.
• As a result, when two UQH2 enter Complex III, four
electrons move through the Q cycle in Complex III, and
one UQH2 is regenerated. Two electrons are carried to
Complex IV by cytochrome c, and two electrons are used
to regenerate UQH2. FKBIWOTT/BIO121/2023-2024
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4. Complex IV: Cytochrome c Oxidase

• The last complex in the electron transport chain receives

electrons from Complex III and transfers them to oxygen,
the final electron acceptor in cellular respiration.
• Complex IV consists of cytochrome a, cytochrome a3, a
copper atom CuB, and a copper atom pair
CuA center, which can accommodate four electrons, acting
as a redox center.
• One oxygen molecule can accept four electrons. For this
reason, four cytochrome c, each carrying one electron from
Complex III, are required to reduce one oxygen molecule
into two water molecules.

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Cont…

• The last complex in the electron transport chain receives

electrons from Complex III and transfers them to oxygen,
the final electron acceptor in cellular respiration.
• Complex IV consists of cytochrome a, cytochrome a3, a
copper atom CuB, and a copper atom pair
CuA center, which can accommodate four electrons, acting
as a redox center.
• One oxygen molecule can accept four electrons. For this
reason, four cytochrome c, each carrying one electron from
Complex III, are required to reduce one oxygen molecule
into two water molecules.

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Importance of the Electron Transport Chain

• The electron transport chain (ETC) is critical to cellular

respiration. It culminates in: The generation of the
majority of ATP molecules, which are synthesized during
oxidative phosphorylation. The synthesized ATP molecules
are subsequently used in other energy-consuming activities
such as the biosynthesis of complex macromolecules.
• The complete oxidation of NADH and FADH2, which
resupplies the cellular metabolic pool with NAD+ and
FAD+. Both serve as cofactors and substrates in various
catabolic and anabolic pathways that contribute to cellular
energy metabolism.

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Cont…

• ETC uses FADH2, NADH, and H+ to yield either 30 or 32

ATP depending on the complexes involved (I, III and IV or
II, III, and IV process).

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