Transcript Glycolysis II

Glycolysis II
Substrates for Gluconeogenesis
• Lactate, pyruvate
• Carbon skeletons of amino
acids, except leucine and
lysine
• Citric acid cycle intermediates
• Anything that can be converted
to oxaloacetate
• Substrates that can’t
contribute:
– Acetyl CoA
– Fatty acids – since fatty
acid breakdown generates
acetyl CoA
Phase II of
glycolysis seen from
the bottom up in
gluconeogenesis
Notice that reversing
the second
substrate
phosphorylation
step requires the
equivalent of 2 ATP,
and reversing the
first one costs
another ATP. The
other reactions of
Phase II are
reversible.
Phase I seen from the
bottom up – in the
absence of coupling to
ATP, the reactions can be
spontaneous, but a
different enzyme has to
be involved.
No futile cycles
• Obviously, the bypass routes of
gluconeogenesis and the main route of
glycolysis could not be allowed to operate
at the same time, or futile cycles would
result. This is prevented by the fact that
most cells simply don’t express the
gluconeogenic enzymes. For the cell types
that do…
Located in ER
membrane
The Cori Cycle recycles muscle lactate back to glucose
Lactate from muscle
can also be
metabolized
oxidatively (but not
recycled to glucose)
by high-oxidative
tissues such as the
heart and brain
To do all of this, we need more than one form of
lactate dehydrogenase
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• Heart and brain need a
form that favors
conversion of lactate to
pyruvate
• Non-oxidative muscle
needs the opposite – a
form that can efficiently
convert pyruvate to
lactate
• Liver and kidney need an
intermediate form,
because they may play
the game both ways
How to do this?
• LDH gene was duplicated and the two sister
genes underwent separate evolution to become
H (heart) type and M (muscle) types
• LDH enzyme is a tetramer that can be made up
of some mixture of both H and M types.
Combinatorial math gives us 5 different combos:
M4H0, M3H1, M2H2, H3M1, H4M0 with a
corresponding range of kinetic properties.
The solution
• So, non-oxidative skeletal muscle
expresses only the M gene
• Heart and brain express only the H gene
• Kidney and liver (and other tissues)
express some mix of H and M genes
Other sources of Acetyl CoA
Beta oxidation of fatty acids
• Each FA molecule undergoes an initial
activation step to become a fatty acyl-CoA
– this is energized by hydrolysis of an ATP
to AMP
• After activation, a repeating cycle of 4
reactions splits off acetyl Co-A until the
end of the fatty acid is reached
The activation step
Fatty acids: β-oxidation
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Fatty acids in cytosol are bound to
CoA.
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Transport into mitochondria
1st oxidation at β C and transformation
of FAD to FADH2.
Hydration of double bond.
Oxidation and transformation of NAD+
to NADH + H+.
Acetyl CoA splits off and rest of chain
is bound to another CoA.
… until fatty acid is at its end.
Special cases are unsaturated fatty
acids and fatty acids with odd numbers
of C atoms.
Fatty acid oxidation takes also place in
peroxisomes, but no ATP generation.
Acetyl-CoA back to cytosol (synthesis)
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The beta oxidation spiral
Mitochondria do beta-oxidation
• Beta oxidation takes place inside
mitochondria – so without mitochondria a
tissue cannot metabolize fat for energy.
Ketone bodies and ketoacidosis
• High rates of fat oxidation tend to leave us with
an overload of acetylCoA, which the liver
converts to acetate, acetone, acetoacetate, and
beta-OH butyrate. These are the so-called
ketone bodies that appear in the blood, sweat
and breath of individuals that are starving, or
suffering from untreated diabetes mellitus. Some
of them are acids, so their appearance in the
blood causes ketoacidosis. Some of them are
smelly, so they can be detected by a practitioner
without the use of chemical analysis.
Odd vs even-numbered fatty acids
• Since fatty acids are taken apart (and also
assembled) in 2-C pieces, some cells find
it harder to deal with odd-numbered fatty
acids – they are unusual in mammals but
common in plants and marine organisms.
The tail-end of an odd-numbered fatty acid
turns out to be 3-C propionyl-CoA, which
is decarboxylated in a multistep process to
form pyruvate. So, we can eat oysters,
after all.
Amino acids: protein is broken down to amino acids
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Proteins are digested to amino acids that are delivered to the cells.
Amino acids: transamination and deamination
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Transamination: an amino acid transfers its amino group to an α-keto acid. The amino
acid becomes an α-keto acid and the α-keto acid becomes an amino acid:
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In this way amino groups are collected in a few types of amino acids (often
glutamate).
Oxidative deamination: an amino acid (often glutamate) is oxidized and deaminated
with liberation of ammonium:
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Amino acids: carbon skeletons enter catabolic
pathways
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The carbon skeletons of amino acids enter at different points into catabolic pathways.