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Learning Objective: Energy Metabolism
3. Describe the pathways involved in energy metabolism: glycolysis, gluconeogenesis,
beta-oxidation, amino acid breakdown, TCA cycle and electron transport chain. For each,
include the cellular location, the major organs in which each pathway is active and the
effect of starvation or flux of substrates through the pathway.
4. Outline how chemical energy released from the oxidation of food molecules is used to
drive ATP synthesis and describe the role of the electron transport chain as an
intermediate in this process.
a) Glycolysis – the oxidation of glucose
Glycolysis converts one molecule of glucose into 2 molecules of pyruvate (along with
‘reducing’ equivalents and ATP). In aerobic conditions, the pyruvate will go on to be further
metabolised in the TCA cycle, whilst in anaerobic conditions, the pyruvate will be converted
into lactate to later take part in gluconeogenesis.
Glycolysis itself is anaerobic.
Depending on which book you look at, Glycolysis consists of 2 or 3 phases. The first phase is
the ‘chemical priming’ phase which requires energy in the form of ATP. The second phase
yields ATP in 2 of its steps.
Regulation of Glycolysis;
In general, the points of regulation are at IRREVERSIBLE STEPS.
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The three regulatory enzymes in the process are Hexokinase, Phosphofructokinase
and pyruvate kinase. This is because their reactions are accompanied by a free
energy decrease and therefore the reverse reaction is not spontaneous.
When blood sugar levels fall (i.e. in starvation), glycolysis is halted in order for
gluconeogenesis to take place.
Further regulation;
1. Hormonally mediated
o Insulin and glucagon regulate enzymes of irreversible steps
o Fed state = Glucose = Insulin = Glycolysis
2. Circulating glucose
3. ATP demand
o PFK is inhibited by ATP and activated by ADP/AMP
 PFK also regulates by citrate (Signals CAC has sufficient substrate)
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1,3-bisphosphoglycerate and phosphoenolpyruvate are high energy
intermediateries, which also yield ATP.
Hexokinase is the least important here as G6P can be derived from the breakdown
of glycogen and therefore this step can be by-passed in glycolysis.
Glycolysis takes place in the cytosol of the cell
GULATION OF GLYCOLYSIS
b) Gluconeogenesis
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Gluconeogenesis is almost the opposite of Glycolysis in its function in the body. The
ultimate outcome is to increase blood sugar levels.
It is the biosynthesis of new glucose (i.e. not from glycogen) from carbon substrates
such as lactate, glycerol and amino acids.
This process takes place in the liver and to a much smaller extent, in the kidneys
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Lactate is taken back to the liver where it is converted back into pyruvate in the cori
cycle so that it can enter into gluconeogenesis
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All 20 of the amino acids, excepting leucine and lysine, can be degraded to TCA cycle
intermediates. This allows the carbon skeletons of the amino acids to be converted
to those in oxaloacetate and subsequently into pyruvate, thereby, then being able to
participate in gluconeogenesis (see amino acid breakdown)
The glycerol backbone of lipids can be used for gluconeogenesis. This requires
phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to
dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate
dehydrogenase (G3PDH).
Regulation of gluconeogenesis is in direct contract to glycolysis
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Regulation of the activity of PFK-1 and F1,6BPase is the most significant site
for controlling the flux toward glucose oxidation or glucose synthesis
c) Beta-oxidation
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Beta-oxidation is the initial phase of fatty acid oxidation
This occurs in the mitochondria
There are quite a few reactions, but the result is that the fatty acid chains are broken
into two-carbon acetic acid fragments, and coenzymes are reduced. Acetic acid
molecules then fuse with coenzyme A, making acetyl CoA (which can then of course
go into the TCA cycle to make energy)
Entry of Acetyl CoA into the TCA cycle is limited and therefore, some of the acetyl
CoA is directed into Ketogenesis
Remember – fatty acids yield a huge amount of energy, therefore the oxidation of
fatty acids often produces an over supply of acetyl CoA
(The term “beta oxidation” reflects the fact that the carbon in the beta (third) position is
oxidized during the process and cleavage of the fatty acid in each case occurs between the
alpha and beta carbons)
Reactions
1) Acyl-CoA dehydrogenase
2) Enoyl-CoA hydratase
3) 3-hydroxyacyl-CoA dehydrogenase
4) Thiolase
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b-oxidation continues to cleave 2C units from acetyl group until final turn of the
cycle produces 2 Acetyl CoAs
Fate of Acetyl CoA:
d) amino-acid breakdown
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Amino acids are degraded to acetyl-CoA, either
directly or via pyruvate
 Glucogenic amino acids (an amino acid that can
be turned to glucose through gluconeogenesis)
feed into the TCA cycle or glycolysis.
 Ketogenic amino acids (an AA that can be
converted to ketones via ketogenesis) are
degraded to acetyl-CoA.
 Obviously, this process is important for
gluconeogenesis, which would be utilized in times
of starvation.
(Only leucine and lysine are purely ketogenic,
whereas some of the larger amino acids, including
isoleucine and the three aromatic amino acids
phenylalanine, tyrosine, and tryptophan, are both.)
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The Amino Group of the Amino Acids is released
as Ammonia.
During amino acid catabolism, the nitrogen of the
amino acids produces urea. Initially, however, it is
released as ammonia. The most important ammoniaforming reaction, catalysed by glutamate
dehydrogenase in liver and other tissues. This
oxidative deamination/ reductive amination is freely
reversible and can function both in the synthesis and degradation of glutamate. Either
nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide
phosphate (NADP) can serve as a co-substrate, but NAD+ is mainly used as for glutamate
degradation and NADPH is used for its synthesis. The glutamate dehydrogenase reaction
implies that glutamate is both nonessential and glucogenic.
Most other amino acids do not form ammonia directly. They transfer their a-amino
group to a-ketoglutarate to form glutamate. The enzymes that catalyse these reversible
amino group transfers are called transaminases or aminotransferases. The a-amino
group is turned into ammonia by successive transamination and oxidative deamination.
Ammonia is detoxified into Urea, which is synthesized in the Urea Cycle
Ammonia is a hazardous waste, which is neurotoxic in low concentrations. Urea is the
quickest, most non-toxic way of disposing of this ammonia.
Most amino acid catabolism takes place in the liver, and the liver is also the only
important site for ammonia detoxification in the urea cycle.
e) TCA cycle
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Occurs in the mitochondrion
Final common pathway for oxidation of fuel molecules (Fatty acids, glucose, amino
acids)
May also provide intermediates for synthesis of larger biological molecules
Defects involving enzymes of cycle are rare
Essential to sustain life
Strips e- from fuels via oxidation, thereby producing majority of reduced coenzymes
used for generation of ATP in ETC
2 major functions
o Energy production
o Biosynthesis
Pneumonic to remember
all the intermediaries;
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Money Officer
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f) electron transport chain
KEY ANABOLIC PATHWAYS
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Each step involves REDOX reaction where e- leave components with more –ve
reduction potentials
Each subsequent carrier has more +ve reduction potential or a greater tendency to
accept electrons
Free energy change drives transport of protons from matrix into intermembrane
space
Notes:
Key Anabolic Pathways;
Pathway
Gluconeogenesis
Glycogen Synthesis
Protein Synthesis
Lipogenesis
Main Substrate(s)
Lactate, alanine, glycerol
G-1-P
Amino Acids
Acetyl CoA
End Products
Glucose
Glycogen
Protein
Fatty Acids, triglycerides
Main Substrate(s)
Glucose
Acetyl CoA
Glycogen
Triglycerides  Fatty acids
Proteins
End Products
Pyruvate
ATP, CO2, H2O
G-1-P, Glucose
Glycerol, Acetyl CoA
Amino Acids  Glucose
Amino Acids  Ketones
Key catabolic Pathways;
Pathway
Glycolysis
TCA Cycle
Glycogenesis
Lipolysis (Beta-oxidation)
Proteolysis