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Carbohydrate Metabolism Study Guide
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how and where breakdown of simple sugars and fats generates
the NADH and FADH2 electron carriers
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The major pathway for metabolism of glucose
• Ancient and found in many organisms
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• Occurs in the cytoplasm of cells
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• Much more efficient under aerobic conditions: complete
oxidation of glucose under aerobic conditions yields 36-38
molecules of ATP
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− Rarely found in the ‘open’ form (so doesn’t react with blood
proteins to ‘glycate them’)
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− Could have been a fuel source for primitive biochemical
systems (which would have evolved pathways to utilise
glucose for energy production)
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• Acquisition: new synthesis (gluconeogenesis); diet (“carbs”)
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Glucose from dietary carbohydrates
• Dietary carbohydrate is complex; starch glycogen, di and
trisaccharides, not usually glucose
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• Monosaccharides are transported across the intestinal wall to
the bloodstream
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The energy yield under anaerobic conditions is -96kJmol^-1
(23kcalmol^-1)
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− 1a – cleavage of glucose into 3 carbon units
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• Glucose is taken into cells by specific transporter proteins
then enters glycolysis (or the “glycolytic pathway”)
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• Costs energy (1 x ATP)
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• Glc-6P cannot diffuse through the cell
membrane
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• Glc-6P is relatively unstable and easier
to break open
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Phosphoglucoisomerase
• Converts an aldose to a ketose
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• Drives isomerisation to form / stabilise
the open form of Fructose-6P (which
has a ketone group at C2)
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• This reaction is reversible (so, unlike
hexokinase, this isomerase can be used in gluconeogenesis)
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• Costs energy (1 x ATP)
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• This reaction is irreversible and
is the rate-limiting step in glycolysis
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• The aldolase reaction is reversible and indeed the enzyme is
named for the opposite reaction (i
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, production of F1, 6BP)
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But, at
equilibrium, 96% of
these two isomers are
in the form of DHAP
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• Triose phosphate isomerase (TPI) is incredibly catalytically
efficient; it converts every DHAP it meets to G3P
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• TPI keeps stage 2 supplied with G3P
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•

•

•
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•

The 1st reaction, catalysed by
glyceraldehdye 3-phosphate
dehydrogenase (GAPDH)
makes 1, 3 bis
phosphoglycerate (1, 3BPG)
which has lot of trapped
energy; phosphoglycerate
kinase harvests this energy
to generate ATP
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Since 2 G3P molecules enter stage 2 for every glucose
starting stage 1, the 2 ATPs per glucose generated have paid
the cost of stage 1
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The first two reactions in stage 2 used a theme of making a
compound that is slightly unstable, but has high potential energy, in
the first step and letting the second step collect that energy
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•

•

•

The last step created 3phosphoglycerate; 2-phosphoglycerate
would’ve been better
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Dehydration - removal of water - from
2-phosphoglycerate makes it possible to squeeze a little more
energy out of the pathway
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• Enolase dehydrates 2-phosphoglycerate
to yield phosphoenol pyruvate (PEP)
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• PEP is unstable
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• The final reaction is essentially irreversible
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Metabolic Fates of Pyruvate
Glycolysis yields two molecules of pyruvate and 2 of ATP per
glucose entering the system; but there is a deficiency of 2 x NAD+
per glucose
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• In micro-organisms, under anaerobic conditions, ethanol is
formed
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The fate of pyruvate during
anaerobic metabolism;
lactic acid – hurts but
generates the NAD+
necessary for glycolysis to
continue
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The Citric Acid Cycle
Also known as the “TriCarboxylic Acid (TCA)” cycle or “Krebs Cycle”
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• Generates >90% of energy used by human cells under
aerobic conditions
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• Provides precursors for synthesis of other macromolecules
(amino acids, nucleotides etc)
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• Is widespread, being found in many organisms and tissues
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• Uses oxidative decarboxylation to release CO2 and harvest
electrons
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• RE-oxidation (loss of electrons) of co-factors powers ATP
synthesis in oxidative phosphorylation (3 x ATP / NADH, 2 x
ATP / FADH2)
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− Harvesting energy
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• Currency conversion:
In the mitochondrial
electron transport
(respiratory) chain
each NADH leads to
production of 3 ATP; each FADH2 yields 2 ATP
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• The pyruvate
dehydrogenase
complex irreversibly
converts the endproduct of glycolysis pyruvate - to a twocarbon unit that can
enter the citric acid cycle associated with the co-factor
Coenzyme A (CoA)
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AcetylCoA can now enter the citric acid cycle and act as its
fuel
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Citrate synthase
• Performs an aldol condensation joining oxaloacetate (C4) and
acetyl-CoA (C2)
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• Citryl-CoA has a high energy, unstable thioester bond
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• Releases reduced CoA (HSCoA) to keep PDH supplied
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OAA must
be replenished
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But, just like 3-posphoglycerate in glycolysis, some
groups aren’t in the best place
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• Catalyses a two-step isomerisation
reaction
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• Cis aconitate is then re-hydrated to yield
isocitrate
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• All the functional groups are now in the
correct place for the subsequent enzymes to work optimally
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Phase 2: Collecting Energy
The citric acid cycle collects energy form electrons with high
transfer potential using oxidation-reduction reactions
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Isocitrate dehydrogenase
• Catalyses a two-step process
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• The unstable “oxalosuccinate”
degrades
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• This is a key regulatory step in the
TCA cycle
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It is inhibited by
NADH and by ATP and activated by
ADP
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α-ketoglutarate dehydrogenase
• Generates a high energy
electron carrier (NADH)
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• Produces a high energy product
(Succinyl-CoA)
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• The cycle is now ‘carbon neutral’
as the two C taken in as acetate
have been balanced by release
of two CO2 molecules
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And OAA must be regenerated
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The reaction sequence converts a methylene group (-CH2-) to a
carbonyl (C=O) via an oxidation, a hydration and a final oxidation;
this “theme” is also found in fat metabolism
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• Uses FAD as the hydrogen acceptor
(insufficient energy to use NAD+)
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• Is directly associated with components of
the electron transport chain (coenzyme
Q)
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Malate Dehydrogenase
• Oxidises malate to OAA
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• Reaction has a ΔGo’ = +29
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• Driven by use of reaction products
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Fumarase
• Hydrates fumarate to L-malate
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The regeneration of OAA allows the citric acid
cycle to commence again, and also links to
multiple pathways
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Regulation of the Citric Acid Cycle
Entry into, and metabolism within, the CA cycle is tightly controlled
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Pyruvate Dehydrogenase
• “Gatekeeper”
• Activated by ADP and pyruvate
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Isocitrate Dehydrogenase
• Activated by ADP
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α-ketoglutarate dehydrogenase
• Inhibited by ATP and NADH
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Citric Acid Cycle in Total
The net reaction of the Citric Acid Cycle is:

•
•
•

Two carbons enter as acetyl CoA and leave as CO2; two
waters are used
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Three reduced NADH and one FADH2 are generated for use in
oxidative phosphorylation
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The Cori Cycle: Re-utilisation of Lactate in Liver
•
•

The transport and interconversion of lactate and glucose is
known as the Cori Cycle
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The LDH reaction is reversible; lactate can be converted to
pyruvate and this happens in the liver
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Moreover, this pyruvate is a substrate for hepatic
gluconeogenesis and the glucose formed is released into the
blood for use by the brain or exercising muscle
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Irreversible (exergonic) steps in
glycolysis are bypassed, and specific
gluconeogenic enzymes catalyse
these reverse reactions
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Unique steps:
All three unique steps in gluconeogenesis by-pass irreversible steps
in glycolysis
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• Pyruvate carboxylase: converts
pyruvate to OAA; uses ATP
(irreversible); activated by CoA
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• This is costly
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By-passing phosphofructokinase
• Once formed, PEP is
converted to F1,6 BP by the
simple reverse reactions
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• Fructose 1,6 bisphosphate: removes the phosphate from the
C1 position (hence the ‘phosphatase name); large negative
∆G (therefore irreversible); inhibited by fructose 2,6
bisphosphate (which activates PFK); activated by citrate
(which inactivates PFK); is reciprocally regulated’ with PFK
(only one is ‘on’ at a time)
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• Must by-pass the initial step of glycolysis catalysed by
hexokinase
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Substrates for Gluconeogenesis
Any metabolite that can be converted to pyruvate or OAA can be a
precursor of G6P and hence glucose in gluconeogenic tissues
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• Converted to pyruvate by LDH
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Glycerol
• Generated from breakdown of triacylglycerols (lipids)
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Amino Acids
• Carbon skeletons are catabolised to pyruvate or TCA cycle
intermediates (e
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α-ketoglutarate)
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