Camp 1

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The Central Role of the Citric Acid Cycle

• 3 processes play central roles in ________
  metabolism
• The citric acid cycle (TCA cycle)
• Electron transport (Chapter 20)
• Oxidative phosphorylation (Chapter 20)
• Metabolism consists of
• Catabolism the oxidative breakdown of nutrients
• Anabolism the reductive synthesis of
  biomolecules
• The citric acid cycle is ______________________
  that is, it plays a role in both catabolism and
  anabolism. It is the central metabolic pathway

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Relationship of TCA Cycle to Catabolism
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Where does the Citric Acid Cycle Take Place?

• In eukaryotes, cycle takes place in the
  mitochondrial matrix

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Features of TCA Cycle
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Pyruvate is Converted to Acetyl-CoA

• Pyruvate dehydrogenase complex is responsible for
  the conversion of pyruvate to CO2 and the acetyl
  portion of acetyl-CoA
• Five enzymes in complex pyruvate dehydrogenase,
  dihydrolipoyl transacetylase, dihydrolipoyl
  dehydrogenase, pyruvate dehydrogenase kinase,
  pyruvate dehydrogenase phosphatase

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Pyruvate is Converted to Acetyl-CoA

• First, pyruvate loses CO2 and hydroxyethylTPP
  (HETPP) is formed
• In the second step, the active form of
  ____________ acid is bound to the enzyme,
  dihydrolipoyl transacetylase, by an amide bond to
  the ?-amino group of a lysine
• The hydroxyethyl group (HE) is oxidized and
  transferred to a sulfur atom of the reduced form
  of lipoamide
• Lipoamide is reduced to dihydrolipoamide
• In step 3, the acetyl group is transferred to the
  ___________ group of coenzyme A
• Next, dihydrolipoamide is oxidized to lipoamide

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Mechanism of the Pyruvate Dehydrogenase Complex
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Summary

• The two-carbon unit needed at the start of the
  citric acid cycle is obtained by converting
  pyruvate to acetyl-CoA
• This conversion requires the three primary
  enzymes of the pyruvate dehydogenase complex, as
  well as, the cofactors TPP, FAD, NAD, and lipoic
  acid
• The overall reaction of the pyruvate dehydogenase
  complex is the conversion of pyruvate, NAD, and
  CoA-SH to acetyl-CoA, NADH H, and CO2

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Individual Reactions of the Citric Acid Cycle

• In step 1, there is a condensation of acetyl-CoA
  with oxaloacetate to form _______________
• ?G -32.8 kJmol-1, therefore, the reaction is
  ___________
• Reaction is catalyzed by citrate
  _____________, an allosteric enzyme that is
  inhibited by NADH, ATP, and succinyl-CoA

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Individual Reactions of the Citric Acid Cycle

• In step 2, citrate is isomerized to isocitrate.
  The reaction is catalyzed by _____________
• Citrate is achiral it has no stereocenter
• Isocitrate is chiral it has 2 stereocenters, so
  4 possible stereoisomers
• _____________ of the 4 stereoisomers of
  isocitrate is formed in the cycle

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Individual Reactions of the Citric Acid Cycle
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Individual Reactions of the Citric Acid Cycle

• In step 3, there is an oxidation of isocitrate
  followed by decarboxylation to form
  ________________ and CO2
• The reaction is catalyzed by isocitrate
  ______________, an allosteric enzyme, which is
  inhibited by ATP and NADH, and activated by ADP
  and NAD

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Individual Reactions of the Citric Acid Cycle

• In step 4, there is an oxidative decarboxylation
  of ?-ketoglutarate to _____________________
• This reaction is catalyzed by the
  ?-ketoglutarate dehydrogenase complex, which is,
  like pyruvate dehydrogenase, a multienzyme
  complex and requires _____________________________
  ____________________

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Individual Reactions of the Citric Acid Cycle

• Next, the thioester bond of succinyl-CoA if
  hydrolyzed in the formation of succinate
• The two CH2-COO- groups of succinate are
  equivalent
• This is the first __________________________ step
  of the cycle
• The overall reaction is slightly exergonic

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Individual Reactions of the Citric Acid Cycle

• Next, there is an oxidation of succinate to
  _____________
• Then, the hydration of fumarate to
  _____________________

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Individual Reactions of the Citric Acid Cycle

• Then, malate is oxidized to ______________________
  ____

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Oxidation of Pyruvate Forms CO2 and ATP
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Summary

• In the citric acid cycle and the pyruvate
  dehydrogenase reaction, one molecule of pyruvate
  is oxidized to three molecules of CO2 as a result
  of oxidative decarboxylation
• The oxidations are accompanied by reductions
  involving NAD to NADH FAD to FADH2
• GDP is phosphorylated to GTP

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Control of the Citric Acid Cycle

• There are 3 points of control within the cycle
• Citrate synthase inhibited by ATP, NADH, and
  succinyl CoA also product inhibition by citrate
• Isocitrate dehydrogenase activated by ADP and
  NAD, inhibited by ATP and NADH
• ?-ketoglutarate dehydrogenase complex inhibited
  by ATP, NADH, and succinyl CoA activated by ADP
  and NAD
• There is one control point outside the cycle
• Pyruvate dehydrogenase inhibited by ATP and
  NADH also product inhibition by acetyl-CoA

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Control of the Citric Acid Cycle
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Energetics of the Citric Acid Cycle
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Control of the Citric Acid Cycle (Contd)
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The Glyoxylate Cycle

• In plants and some bacteria, there may be a
  modification of the citric acid cycle to produce
  4-carbon dicarboxylic acids eventually glucose
• The glyoxylate cycle bypasses the two oxidative
  decarboxylations of the citric acid cycle
• Instead, it routes isocitrate via glyoxylate to
  malate
• Key enzymes in this cycle are _______ _________
  and _______________ _______________

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The Glyoxylate Cycle
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The Glyoxylate Cycle
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The Glyoxylate Cycle
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The Glyoxylate Cycle

• The glyoxylate cycle takes place
• In _______ in glyoxysomes, specialized
  organelles devoted to this cycle
• In _______and _______ in the cytoplasm
• Helps plants grow in the dark
• Seeds are rich in lipids, which contain fatty
  acids
• During germination, plants use the acetyl-CoA
  produced in fatty acid oxidation to produce
  oxaloacetate and other intermediates for
  carbohydrate synthesis
• Once plants begin photosynthesis and can fix CO2,
  glyoxysomes disappear

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The Citric Acid Cycle in Catabolism

• The catabolism of _______, _______, and _______
  _______ all feed into the citric acid cycle at
  one or more points

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Summary

• All metabolic pathways are related, and all of
  them operate simultaneously
• In catabolic pathways, nutrients, many of which
  are macromolecules, are broken down to smaller
  molecules, such as sugars, fatty acids, and amino
  acids
• Small molecules are processed further, and the
  end products of catabolism frequently enter the
  citric acid cycle, which plays a key role in
  metabolism

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The Citric Acid Cycle in Anabolism

• The citric acid cycle is the source of starting
  materials for the biosynthesis of other compounds
• If a component of the citric acid cycle is taken
  out for biosynthesis, it must be replaced
• Oxaloacetate, for example, is replaced by the
  ______________ ____________ _____________
• A reaction that replenishes a citric acid cycle
  intermediate is called an _________________
  reaction

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The Citric Acid Cycle in Anabolism
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The Citric Acid Cycle in Anabolism
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Lipid Anabolism

• Lipid anabolism begins with acetyl-CoA and takes
  place in the ______________
• acetyl-CoA is produced mainly in mitochondria
  from catabolism of fatty acids and carbohydrates
• an indirect transfer mechanism exists involving
  citrate
• Citrate CoA-SH ATP ? Acetyl-CoA
  Oxaloacetate ADP Pi
• the oxaloacetate thus formed provides a means
  for the production of the NADPH needed for
  biosynthesis

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Lipid Anabolism

• Oxaloacetate NADH H ? Malate NAD
• Malate NADP ? Pyruvate CO2 NADPH H
• The net effect of these two reactions is
  replacement of NADH by NADPH
• While there is some NADPH produced by this
  means, its principal source is the pentose
  phosphate pathway
• The anabolic reactions that produce amino acids
  and many other biomolecules begin with TCA cycle
  molecules that are transported into the cytosol

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Summary of Anabolism in the Citric Acid Cycle
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Summary

• The citric acid cycle plays a central role in
  anabolic pathways as well as in catabolism
• Pathways that give rise to sugars, fatty acids,
  and amino acids all originate with components of
  the citric acid cycle

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The Link To Oxygen

• The citric acid cycle is considered part of the
  aerobic metabolic process because of its link to
  the _______________ and _______________
• NADH and FADH2, two important cofactors generated
  by the citric acid cycle, ultimately pass their
  electrons to _____________