Cellular Metabolism
I. Use of Glucose as an Energy Source - Catabolic Reactions
A. Glycolysis
B. Krebs Cycle or Citric Acid Cycle
C. Electron Transport System
D. Chemiosmotic Theory of Oxidative Phosphorylation
E. Energy Efficiency of the Complete Oxidation of Glucose
II. Use of Amino Acids and TrigIycerides as Energy Sources - Further Catabolic
Reactions
A. Amino Acids
B. Triglycerides
III. Interrelationship of the Metabolic.Pathways - Anabolic Reactions
IV. Nutrient Pools
A. Protein - the nutrient pool is amino acids
B. Carbohydrate and Triglycerides - the nutrient pool is glucose and triglyceride they are considered
together because carbohydrate and triglyceride are easily converted into each other.
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Cellular Metabolism
The sum of all chemical reactions of the body is called metabolism. Some metabolic reaction (catabolic
reactions) process complex molecules, such as glycogen, proteins and triglycerides (fats), for energy use by the
body, i.e., for the production of ATP and also to produce heat. The ATP then provides energy to drive
biochemical and physiological activities. Other metabolic reactions (anabolic reactions) use simple molecules
for synthesis of new complex molecules, for example amino acids for protein synthesis, glucose for complex
carbohydrate synthesis, triglycerides for complex lipid synthesis and nucleotide for nucleic acid synthesis.
However, these simple molecules have a great amount of energy stored in them and by catabolic reactions
release this energy.
I. Use of Glucose as an Energy Source - Catabolic Reactions
Glucose is the principle molecule used as an energy source in the formation of ATP. The chemical bonds
between C-C and C-H contain energy. This energy is not useable by the cells until the energy is placed into the
chemical bonds of ATP.
Glucose is broken down in a stepwise series of reactions, with a small release of energy at a time, so that most
of the energy can be trapped and put into the chemical bonds of ATP. Energy that is not trapped is lost as heat.
A specific enzyme catalyzes each reaction of the series. The reactions are linked together in a metabolic
pathway in which the product of one reaction serves as a substrate for the next reaction in the pathway.
A
Enzyme 1
B
Enzyme 2
C
Summary of Catabolic Metabolic Pathways:
Glycolysis breaks the 6C, glucose to 2 3C, pyruvic acid molecules with the release of energy to produce a small
amount of ATP. In the absence of O2 (anaerobic conditions) pyruvic acid goes to lactic acid. In the presence of
O2 (aerobic conditions) pyruvic acid is broken down to CO2 and H2O during the Krebs cycle and the electron
transport system. As the pyruvic acid is going through these pathways, considerable energy is released and
trapped in the chemical bonds of ATP.
A. Glycolysis
The enzymes for the glycolytic reactions are in the cytosol of the cell.
In the first half of glycolysis the 6C, glucose picks up 2 PO4 groups to form a 6C 1,6-fructose diphosphate.
This requires the use of two molecules of ATP. Thus the initial stages of glycolysis do not produce energy,
but use energy.
Then the 6C molecule is split to 2 3C molecules, 3-phosphoglyceraldehyde (3-PGAL). The remaining steps
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of glycolysis occur twice for every glucose molecule used.
Next, inorganic phosphate (PO4 or Pi) is added to each 3-PGAL. Then 2 electrons and 2 H+ are transferred
from the 3-PGAL to a coenzyme NAD+ (oxidized) forming NADH+H+ (reduced) and the 2 PO4 are
transferred to 2 ADP to form 2 ATP.
These steps beyond the 3-PGAL occur twice for each glucose used.
In summary in glycolysis one 6C glucose goes to 2 3C, pyruvic acid molecules. In glycolysis 2 ATPs are
used but generate 4 ATPs for a net gain of 2 ATPs and two molecules of reduced NADH. Remember that
the steps beyond 3-PGAL occur twice for each glucose molecule used.
Definition of oxidation-reduction reaction: The removal of electrons from a molecule is called oxidation; this
results in a decrease in the energy content of the molecule. The gain of electrons by a molecule is called
reduction; this results in an increase in the energy content of the molecule. Thus 3-PGAL is oxidized, NAD+ is
reduced.
In terms of energy consideration, the types of chemical bonds in the intermediate molecules to which the PO4
attaches make the phosphate bond a high-energy phosphate bond. A swiggle line indicates the high-energy bond
(~).
Y
O


X-O~P-O
O-
Y-can be C or O
O

C-O~P
X-can be C or P
The ~P can then be transferred to ADP to form ATP. Ultimately 2 3C, pyruvic acid molecules are formed.
Oxidized NAD+ in the cell is present in small amount. The oxidized NAD+ must be regenerated for glycolysis to
continue. To regenerate oxidized NAD+ reduced NADH must get rid of the hydrogen by transferring these
atoms to some acceptor molecule.
Under anaerobic conditions (no O2) pyruvic acid acts as the H acceptor and is converted to lactic acid, with
oxidized NAD+ regenerated to be used again. If glucose goes to 2 molecules of lactic acid this is an anaerobic
pathway, which requires no O2. However, the energy within the chemical bonds of lactic acid is not used. The
anaerobic catabolism of glucose to lactic acid by glycolysis yields a net of only 2 ATPs. Glycolysis cannot
produce enough ATP to support the biochemical and physiological activities of a cell. Glycolysis allows the
cells to produce some ATP under anaerobic conditions.
In yeast: (3C) Pyruvic acid + NADH2  (2C) Ethanol + (1C) Carbon dioxide + NAD+.
To produce sufficient ATP to support activities, aerobic (O2) metabolism is necessary. When O2 is available, it
accepts the H from reduced NADH. The aerobic pathway allows the pyruvic acid to enter biochemical
pathways to extract most of the energy from the chemical bonds of the pyruvic acid molecule. The pyruvic acid
enters the Krebs cycle where it is broken down into CO2 and H (H++e-). The H+ and the e- are passed to the
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electron transport system where energy of the electrons is released. Some of the energy is trapped in highenergy phosphate bonds of ATP by chemisomosis and some is released as heat.
B. Krebs Cycle or Citric Acid Cycle
Oxidative Decarboxylation
The enzymes of the Krebs cycle are within the mitochondrial matrix. For pyruvic acid to enter the
mitochondria it combines with Coenzyme A (Co A). During the reaction one of the 3 carbons of the pyruvic
acid is lost as CO2, H++ e- are passed onto oxidized NAD+. The combination of the 2C fragment and
Coenzyme A is called acetyl-CoA. The acetyl-CoA links glycolysis in the cytosol with the Krebs cycle in the
mitochondrial matrix.
The acetyl-CoA enters the Krebs cycle. The 2C-acetyl group combines with a 4C molecule to form 6C citric
acid. The Krebs cycle involves reactions in which the 6C, citric acid is reformed into the 4C molecule. Along
the way 2C of the acetyl group is lost as CO2. The H++e- are transferred to oxidized NAD+ to form reduced
NADH and to oxidized FAD to form reduced FADH2 with a molecule of ATP formed.
Since 2 pyruvic acids enter the Krebs cycle for every glucose molecule 6 CO2, 2 ATPs, 8 reduced NADH and
2 reduced FADH2 are formed.
To keep the Krebs cycle going the oxidized forms of NAD+ and FAD must be regenerated. The regeneration
is accomplished as the reduced molecules (NADH, FADH) transfer H+ and e-- to the electron transport
system. This system then passes the H+ and e- on to an O atom to form H2O.
C. Electron Transport System and D. Chemiosmotic Theory Oxidative Phosphorylation
1. Electron Transport System
The final step in aerobic generation of ATP is the transfer of H+ and e- from the reduced NADH and
FADH2 to an O atom to form H2O with the regeneration of oxidized NAD+ and FAD. The activities of the
electron transport system is located on the inner mitochondrial membrane (cristae). The electron transport
system consists of a series of electron carriers that accept and donate electrons. Some of the electron
carriers are coenzymes (NAD, Vit. B3, FAD, Vit.B2) that are B vitamins. Others are proteins called
cytochromes, which contain iron (Fe) atoms that act as the electron carrier. The carrier after accepting
electrons and being reduced passes the electrons onto the next carrier in the system and becomes
reoxidized again. Ultimately the electrons (e-) plus H+ are passed to the oxygen atom (O) to form H2O.
What is the purpose of passing e- down the electron transport system?
The reduced NAD produced during the Krebs cycle possess high amounts of energy, but not in biological
useable form, enter the electron transport system at the beginning of the system. As the electrons are
passed, the energy that they possess is released. At three places along the system, the released energy can
be trapped into ATP.
ADP + Pi  ATP
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Three ATPs are produced for each reduced NADH that enters the electron transport system.
Since the reduced FADH2 enters the system after the 1st ATP generation site and only 2 ATPs are produced
from each reduced FADH2.
The entire process of synthesizing ATP in the electron transport system is called oxidative phosphorylation.
The ATP is produced by chemiosmosis.
2. Chemiosmotic Theory of ATP Production – Chemi – chemical forces, Osmosis – pushing forces
The chemiosmotic theory of ATP production is based on the fact that ATP production in the mitochondria
involves chemical processes and active and passive transport processes across the semi-permeable inner
mitochondrial membrane. The chemical part involves release of the energy as the electrons pass along the
electron transport chain and the use of the released energy to build up an H+ ion concentration gradient.
The osmosis part involves pushing the H+ across the semi-permeable membrane by active transport using
the energy just released from the electrons and then transport of H+ by passive diffusion along an H+
concentration gradient at specific places on the inner mitochondrial membrane to make ATP.
The energy required to attach Pi to ADP is provided by a mechanism that establishes H+ concentration
gradient across the inner mitochondrial membrane. According to chemisomotic theory, the transfer of
electrons in the electron transport system in the inner mitochondrial membrane and release of the energy
is accompanied by active transport pumping of H+ from the inner matrix of a mitochondrion into the
space between the two mitochondrial membranes. This establishes an H+ concentration gradient
chemically and electrically between the outer compartment and the matrix or inner compartment. The H+
concentration gradient has potential energy.
The inner membrane is essentially impermeable to the H+ as the H+ are not lipid soluble, except at 3
places where there are H+ channels through which H+ can move by diffusion into the matrix. As the H+
pass through these channels their potential energy is released as kinetic energy. These channels contain the
enzyme, ATP synthase that uses the energy of the H+ diffusing back to form ATP.
ADP + Pi + E  ADP~P (ATP)
As a result, for each pair of electrons removed from NADH 3 ATPs are produced for every 6 H+ that
diffuse back into the matrix through the channels. For each pair of electrons removed from FADH 2 ATPs
are produced for every 4 H+ that diffuse back into the matrix through the channels. The production of ATP
in the mitochondria is called oxidative phosphorylation, as the reactions that take place within the inner
mitochondria membrane uses O2.
E. Energy Efficiency of Complete Oxidation of a Glucose Molecule
The complete oxidation of a glucose molecule to CO2 + H2O yields 686,000 calories/molecule of glucose.
The production of one ATP from ADP + Pi traps 7,300 calories of energy. The aerobic breakdown of a
single glucose molecule produces a net of 38 ATP. The total net energy trapped is 38 x 7,300 = 277,400
calories. About 40% of the energy is trapped in the ATP and about 60% appears as heat.
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Anaerobic (2)
2 ATP
–substrate-level phosphorylations – occur when ~PO4
group is transferred directly from the phosphorylated
– substrate to ADP to form ATP
glycolysis
Aerobic
(36) 2 ATP--- Krebs cycle
24 ATP--- from 8 reduced NADH produced
in the Krebs cycle
4 ATP--- from 2 reduced FADH produced
in the Krebs cycle
6 ATP---from 2 reduced NADH produced
in glycolysis
net of 38 ATP
Key molecules in aerobic cellular metabolism
oxidative phosphorylation,
ATP formed during
electron transport by the
chemiosmotic process
Glucose (initial)  glucose-6-P  fructose-1,6-P  3-PGAL  pyruvic acid  acetyl-CoA  Citric acid
cycle  NADH + H+ + FADH2  cytochromes  H+ + e- + O  H2O (final) + ATP + E (heat) + CO2
Overall aerobic metabolic chemical equation
C6H12O6 + 6O2 + 38 ADP + 38 Pi  6CO2 + 6H2O + 38 ATP + E (heat)
II. Use of Amino Acids and Triglycerides as Energy Sources - Further Catabolic Reactions
Amino acids and triglycerides can undergo conversions to intermediates and enter the glycolytic or Krebs cycle
pathways to provide energy.
A. Amino Acids – Protein Catabolism
Amino acids lose the amino group and are converted to -ketoacids, which by the way of pyruvic acid,
acetyl-CoA or intermediates of the Krebs cycle enter the Krebs cycle and can be used as energy
sources. As a result of the amino group (NH2) being removed (deamination), ammonia is formed which
is converted to urea by the liver. The kidneys excrete the urea.
NH2 O
|
||
R—CC—OH
|
H
Amino acid
-NH2

O
||
R—C—COH + NH2
||
O
-ketoacid
B. Triglycerides (Fats) – Lipid Catabolism (Lipolysis)
Triglycerides can be broken into glycerol and fatty acids. The glycerol can be converted to 3-PGAL and
enters the glycolytic path. The fatty acids undergo a stepwise breakdown into the 2C molecules,
acetyl-CoA. The acetyl-CoA then enters the Krebs cycle (Beta-Oxidation).
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III. Interrelationships of the Metabolic Pathways - Anabolic Reactions
In addition to being broken down and used as energy sources, the glucose, amino acids and triglycerides can be
used to build larger molecules. For example, amino acids are assembled into protein; glucose linked together to
form glycogen, the storage form of carbohydrate. The metabolic pathways followed by carbohydrate, protein
and triglycerides are interrelated.
Pathways exist by which amino acids or glucose is converted to fat or amino acids to glucose. Gluconeogenesis
is the formation of glucose from non-carbohydrate sources, such as proteins and fats. This occurs in the liver
and adipose tissue.
The ability to perform inter-conversions enables the body to make many substances it needs. Some are essential
substances the body cannot make. These must be obtained in the diet, such as essential amino acids, fatty acids
and vitamins.
IV. Nutrient Pools
The process of metabolism involves anabolism occurring simultaneously with catabolism. In view of the
constant changing (turnover) of the atoms and molecules of the body, it is useful to consider the existence of
nutrient pools in the body that can be drawn upon to meet its needs.
A. Protein
In terms of protein, the nutrient pool is the amino acids. Ingested amino acids or the body’s own protein can
be broken down into amino acids and contribute to the amino acid pool. The amino acids from the pool then
can be used to synthesize proteins and other N-containing molecules. Or if NH2 group is removed the
remainder of the molecule can be used as an energy source or converted to carbohydrate or triglyceride.
B. Carbohydrates and Triglycerides
In terms of carbohydrates and triglyceride, the nutrient pool is glucose and triglycerides. These are
considered together because carbohydrates and triglycerides are easily converted into each other. The body's
major energy reserve is triglyceride and a smaller amount as glycogen. Carbohydrates and Triglycerides are
used in catabolism for energy production or converted to amino acids or used for building specialized
molecules or structural molecules.
There are two major differences between the carbohydrate-triglycreide (fat) pool and the amino acid pool.
1. Carbohydrate-fat molecules are oxidized directly to produce ATP, while amino acid molecules supply
energy only after being converted to a carbohydrate intermediate molecule.
2. Excess carbohydrate-fat molecules can be stored as glycogen or triglyceride. Excess amino acids are not
stored as protein. The amino acids are oxidized for energy or converted to glycogen or triglyceride for
storage. The two macromolecules which are not stored are proteins and nucleic acids.
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