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The TCA Cycle
A common metabolic pathway
for glucose, aa and fatty acid
• Citric Acid Cycle, Krebs Cycle
• Pyruvate (actually acetate) from glycolysis
is degraded to CO2
• Some ATP is produced
• More NADH is made
• NADH goes on to make more ATP in
electron transport and oxidative
phosphorylation
Entry into the TCA Cycle
• Pyruvate Dehydrogenase Complex
•
☻Pyruvate is oxidatively decarboxylated to form acetylCoA
☻Pyruvate dehydrogenase uses TPP, CoASH, lipoic
acid, FAD and NAD+
☻Pyruvate dehydrogenase (E1) (丙酮酸脱氢酶)
☻Dihydrolipoyl transacetylase (E2) (二氢硫辛酰转乙酰基酶)
☻Dihydrolipoyl dehydrogenase (E3) (二氢硫辛酰脱氢酶)
Pyruvate Dehydrogenase
Pyruvate
Acetyl-CoA
Complex
Pyruvate dehydrogenase complex consists of three enzymes
Arsenic Compounds Are Poisonous in
part because They Sequester Lipoamide
① Condensation
Citrate Synthase
• Formation of citrate
☻Another example for the induced fit model
☻OAA, the first substrate to bind to the enzyme,
induce a large conformational change, creating a
binding site for the second substrate, acetyl-CoA.
When citroyl-CoA forms on the enzyme surface,
another conformational change brings the side of a
crucial Asp residue into position to cleavage the
thioester.
☻This mechanism decreases the likelihood of
premature and unproductive cleavage of the thioester
bond of acetyl-CoA
Aconitase
• Isomerization of Citrate to Isocitrate
☻Citrate is a poor substrate for oxidation
☻So aconitase isomerizes citrate to yield isocitrate which
has a secondary -OH, which can be oxidized
☻Note the stereochemistry of the Rxn: aconitase
removes the pro-R H of the pro-R arm of citrate!
☻Aconitase uses an iron-sulfur cluster
② Dehydration and hygration
Isocitrate Dehydrogenase
• Oxidative decarboxylation of isocitrate to
yield  -ketoglutarate
☻Classic NAD+ chemistry (hydride removal)
followed by a decarboxylation
☻Isocitrate dehydrogenase is a link to the
electron transport pathway because it makes
NADH
☻Know the mechanism!
③ Oxidative decarboxylation
③ Oxidative decarboxylation
 -Ketoglutarate Dehydrogenase
Complex
• A second oxidative decarboxylation
☻This enzyme is nearly identical to pyruvate
dehydrogenase - structurally and
mechanistically
☻Five coenzymes used - TPP, CoASH,
Lipoic acid, NAD+, FAD
☻You know the mechanism if you remember
pyruvate dehydrogenase
☻Another target for arsenic compounds
④ Oxidative decarboxylation
Succinyl-CoA Synthetase
• A substrate-level phosphorylation
☻A nucleoside triphosphate is made
☻Its synthesis is driven by hydrolysis of a
CoA ester
☻The mechanism involves a
phosphohistidine
Succinate Dehydrogenase
• An oxidation involving FAD
☻This enzyme is actually part of the
electron transport pathway in the inner
mitochondrial membrane
☻The electrons transferred from succinate
to FAD (to form FADH2) are passed
directly to ubiquinone (UQ) in the
electron transport pathway
Fumarase
• Hydration across the double bond
☻trans-addition of the elements of water
across the double bond
☻The actual mechanism is not known for
certain
Malate Dehydrogenase
• An NAD+-dependent oxidation
☻The carbon that gets oxidized is the one that
received the -OH in the previous reaction
☻This reaction is energetically expensive
 Go' = +30 kJ/mol
☻This and the previous two reactions form a
reaction triad that we will see over and
over!
The Fate of Carbon in TCA
☻Carboxyl C of acetate turns to CO2 only in
the second turn of the cycle (following entry
of acetate)
☻Methyl C of acetate survives two cycles
completely, but half of what's left exits the
cycle on each turn after that.
TCA Cycle Summary
• Total rxn:
• Acetyl-CoA+3NAD＋
+FAD+GDP+Pi+2H2O→2CO2+3NADH+FADH2+G
TP+2H＋+CoA
• One Acetyl-CoA through the cycle produces two CO2,
one ATP, four reduced coenzymes
• Two H2Os are used as substrates
• Absolutely depends on O2
Function of the TCA Cycle
Produces More ATPs
As a source of biosynthetic precursors
A common final metabolic pathway for
glucose, aas and fatty acids
Some Immediates act as effectors to
regulate other metabolic pathways
Produces CO2
The Glyoxylate Cycle
• A variant of TCA for plants and bacteria
Acetate-based growth - net synthesis of
carbohydrates and other intermediates from
acetate - is not possible with TCA
Glyoxylate cycle offers a solution for plants and
some bacteria and algae
The CO2-evolving steps are bypassed and an
extra acetate is utilized
Isocitrate lyase and malate synthase are the
short-circuiting enzymes
Glyoxylate Cycle II
Isocitrate lyase produces glyoxylate and
succinate
Malate synthase does a Claisen condensation
of acetyl-CoA and the aldehyde group of
glyoxylate - classic CoA chemistry!
The glyoxylate cycle helps plants grow in the
dark!
Glyoxysomes borrow three reactions from
mitochondria: succinate to oxaloacetate