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Citric Acid Cycle
R.C. Gupta
Professor and Head
Dept. of Biochemistry
National Institute of Medical Sciences
Jaipur, India
Citric acid cycle (CAC) is a metabolic
pathway in which acetyl CoA is oxidized
Acetyl CoA is obtained from diverse
sources...
Several scientists contributed
to the discovery of citric acid
cycle
The complete cycle was
described by Hans Adolf
Krebs
...
• Krebs cycle
• Tricarboxylic acid cycle
• Central oxidative pathway
Citric
acid
cycle is
also
known
as:
EMB-RCG
Location
The pathway is present in all the
cells having mitochondria
Enzymes of this pathway are
located in the mitochondr...
Acetyl CoA, a two-carbon compound
With the condensation of:
The cycle begins ...
Citrate, a six-carbon compound
to form:
O...
By a series of reactions …
Citrate is re-converted into oxaloacetate
These are oxidized to water in the
respiratory chain
...
Oxaloacetate
(4-carbon)
CoA
Citrate
(6-carbon)
CO2
Acetyl CoA
(2-carbon)
CO2
CAC begins with the entry of acetyl group
Sources of oxaloacetate
Hence, there is no net utilization of
oxaloacetate in CA...
But to increase the overall rate of
CAC reactions, the concentration of
intermediates has to be raised
Reactions which lea...
An important anaplerotic reaction is
synthesis of oxaloacetate from pyruvate
ATP provides energy for the formation
of cova...
Pyruvate carboxylase is an allosteric
enzyme; it is activated by acetyl CoA
CH — C3 — COOH + CO2 + ATP
Pyruvate
carboxylas...
Oxaloacetate is also formed by a trans-
amination reaction between aspartate
and a-ketoglutarate
H2N—CH—COOH
|
CH2—COOH
As...
However, the transamination reaction
is not anaplerotic
One intermediate of citric acid cycle,
oxaloacetate, is formed at ...
Sources of acetyl CoA
Acetyl CoA occupies a unique place in
metabolism
It can be formed from:
Glucose Fatty acids Amino ac...
Pyruvate is an important source of
acetyl CoA
Pyruvate is formed from glucose, lactate
and some amino acids
Amino acids fo...
Fatty acid are converted into acetyl CoA
by b-oxidation
Ketone bodies are also converted into
acetyl CoA
Some amino acids ...
Oxidative decarboxylation of pyruvate
Pyruvate formed from various compounds
can be converted into acetyl CoA
Conversion o...
Oxidative decarboxylation occurs by a
series of reactions in mitochondria
These reactions are catalysed by
pyruvate dehydr...
The enzymes are:
Pyruvate
dehydro-
genase
Dihydrolipoyl
acetyl-
transferase
Dihydrolipoyl
dehydro-
genase
The coenzymes ar...
CH3— C— COOH
O
|| 
T ‒ H
CH3— C— COOH
OH
|
|
T CO2
CH3— C— H
OH
|
|
TPyruvate
Thiamin pyro-
phosphate
CoA – SH
Coenzyme A...
Reactions 1 and 2 are catalysed by
pyruvate dehydrogenase
Reactions 3 and 4 are catalysed by
dihydrolipoyl acetyl transfer...
CH3—C— COOH + CoA ‒ SH + NAD+ →
O
||
CH3—C ~ S ‒ CoA + NADH + H+ + CO2
O
||
The net reaction catalysed by
pyruvate dehydro...
A major fate of acetyl CoA is its
oxidation in the citric acid cycle
This produces a large amount of
energy in the form of...
When energy is not required, acetyl CoA is
used to synthesize fatty acids
Small amounts are used for various
acetylation r...
Reactions of citric acid cycle
In the first reaction of the cycle, acetyl CoA
reacts with oxaloacetate
The acetyl group is...
The high-energy thio-ester bond of
acetyl CoA is broken in this reaction
This releases free energy which ensures
that the ...
O = C — COOH
|
CH2 — COOH
Citrate
synthetase
O
||
CH3 — C ~ S — CoA + H2O
CoA — SH
|
HO — C — COOH
|
Citrate
Acetyl CoA
Ox...
In the second reaction, aconitase removes
a molecule of water from citrate
Citrate is converted into cis-aconitate
This re...
Aconitase
H2O
CH2— COOH
|
C — COOH
||
CH — COOH
cis-Aconitate
CH2— COOH
|
HO — C — COOH
|
CH2— COOH
Citrate
EMB-RCG
In the third reaction, a water molecule is
added back to cis-aconitate by aconitase
The net result of this and the precedi...
EMB-RCG
Aconitase
H2O
CH2— COOH
|
CH — COOH
|
HO—CH — COOH
cis-Aconitate
CH2— COOH
|
C — COOH
||
CH — COOH
Isocitrate
In the fourth reaction, isocitrate is
dehydrogenated to oxalosuccinate
The reaction is catalysed by isocitrate
dehydrogena...
Mitochondrial isocitrate dehydrogenase uses
NAD as an acceptor of reducing equivalents
Cytosolic isocitrate dehydrogenase ...
HO — CH — COOH
Isocitrate
dehydrogenase
CH2— COOH
|
CH — COOH
|
O = C — COOH
CH2— COOH
|
CH — COOH
|
Isocitrate
NAD
+
NADH...
In the fifth reaction, oxalosuccinate is
decarboxylated to a-ketoglutarate
The reaction is catalysed by isocitrate
dehydro...
CH — COOH2
|
CH2
|
O = C — COOH
CH — COOH2
|
CH — COOH
|
O = C — COOH
Oxalosuccinate
CO2
a-Ketoglutarate
Isocitrate
dehydr...
In the sixth reaction, a-ketoglutarate
undergoes oxidative decarboxylation to
succinyl CoA
This reaction is analogous to o...
a-Ketoglutarate dehydrogenase complex
is made up of:
a-Ketoglutarate dehydrogenase
Dihydrolipoyl acetyltransferase
Dihydro...
a-Ketoglutarate
dehyrogenase
complex
CH2— COOH
|
CH2
|
O = C ~ S — CoA
CH2— COOH
|
CH
|
O = C — COOH
a-Ketoglutarate
CO2 +...
This is the second reaction in which a
carbon atom is removed
This is also an example of substrate-linked
oxidative phosph...
The seventh reaction is splitting of succinyl
CoA into succinate and CoA
It is catalysed by succinate thiokinase
(succinyl...
GDP + Pi
Succinate
thiokinase
CH2 — COOH
|
CH2 —COOH
CH2 — COOH
|
CH2
|
O = C ~ S — CoA
Succinyl CoA
Succinate
GTP + CoA–SH
Succinate is a four-carbon dicarboxylic
acid
It is converted into oxaloacetate, another
four-carbon dicarboxylic acid
The ...
In the eighth reaction, two hydrogen atoms
are transferred from succinate to FAD
The reaction is catalysed by succinate
de...
Succinate
dehydrogenase
H— C — COOH
||
HOOC — C — H
CH2— COOH
|
CH2— COOH
FADH2
Succinate
FAD
Fumarate
Fumarase
HO — CH — COOH
|
CH2 — COOH
H — C — COOH
||
HOOC — C — H
Fumarate
H2O
L-Malate
In the ninth reaction, fumarate is...
In the tenth reaction, L-malate is dehydro-
genated to oxaloacetate by malate
dehydrogenase
NAD accepts the reducing equiv...
Malate
dehydrogenase
O —— C — COOH
|
CH2 — COOH
HO — CH — COOH
|
CH2 — COOH
L-Malate
NAD+
NADH + H+
Oxaloacetate
Citric acid cycle
Oxaloacetate Acetyl CoA
CoA
Citrate
cis-Aconitate
Isocitrate
Oxalosuccinate
CO2
a-Ketoglutarate
CoA
Succ...
During complete oxidation of one molecule of
acetyl Co A in citric acid cycle:
These are oxidised in the respiratory chain...
Oxidation of three molecules of NADH will
phosphorylate nine molecules of ADP to ATP
Oxidation of one molecule of FADH2 wi...
One GTP is formed when succinyl CoA is
converted into succinate
This, in turn, can convert one ADP into one
ATP
Thus, 12 A...
Succinyl CoA
to succinate
Isocitrate to
oxaloacetate NAD+ NADH 3 ATP equivalents
Reaction Change in
coenzyme
Energy
captu...
Eight ATP equivalents are formed when one
molecule of glucose is oxidised to two
molecules of pyruvate
One molecule of NAD...
Conversion of two pyruvate molecules into
acetyl CoA will form 6 ATP equivalents
Oxidation of two acetyl CoA molecules in ...
Energy of hydrolysis of the terminal phosphate
bond of ATP is 7.3 kcal/mol
38 ATP equivalents represent a capture of
38x7....
Potential energy present in glucose is 686
kcal per mol
Hence, efficiency of oxidation of glucose is
277.4  686  100% or...
Importance of citric acid cycle
• Final catabolic pathway for
carbohydrates, lipids and proteins
• Glucose, fatty acids an...
All the carbohydrates can be converted
into glucose
Glucose is converted into pyruvate in the
glycolytic pathway
Pyruvate ...
Oxidation of fatty acids produces acetyl
CoA which is oxidised in the CAC
Propionyl CoA is formed from fatty acids
having ...
Glycerol
Glycerol-3-phosphate
Dihydroxyacetone phosphate
Pyruvate
Glycerol is also released from lipids
This can be conver...
Several amino acids are converted into
pyruvate
These are glycine, alanine, serine,
threonine, cysteine, tryptophan and
hy...
Glutamine, arginine, histidine and proline
can be converted into glutamate
Glutamate can be converted into a-keto-
glutara...
Valine, isoleucine and methionine can enter
CAC as succinyl CoA
Phenylalanine and tyrosine are partially
converted into fu...
Anabolic function
Glucose, fatty acids and many amino
acids can be synthesized from inter-
mediates of citric acid cycle
T...
All the intermediates of CAC can be
converted into oxaloacetate
Oxaloacetate is a substrates for gluco-
neogenesis
Therefo...
Some intermediates can be trans-
aminated to amino acids
a-Ketoglutarate can be transaminated to
glutamate and oxaloacetat...
Fatty acids are synthesized from acetyl
CoA
Major source of acetyl CoA is pyruvate
Acetyl CoA is formed in mitochondria bu...
Acetyl CoA is converted into citrate in
the mitochondria
Citrate goes to cytosol, and is cleaved
into acetyl CoA and oxalo...
Citrate + CoA
ATP-Citrate
lyase
ATP
ADP + Pi
Acetyl CoA + Oxaloacetate
Citric acid cycle performs catabolic as
well as anabolic functions
Therefore, it is said to be an
amphibolic pathway
Oxaloacetate
Citrate
cis-Aconitate
Isocitrate
Oxalosuccinate
a-Ketoglutarate
Succinyl CoA
Succinate
Phe, Tyr Fumarate
Mala...
Capture of energy
Much of the energy is captured as ATP
when these fuels are oxidized in the
citric acid cycle
An importan...
Regulation
The major function of citric acid cycle is
to capture energy
Availability of energy in the cell is the
major re...
The allosteric enzymes are:
Ca++ is the allosteric activator of all the
three
a-Ketoglutarate dehydrogenase
Isocitrate deh...
The allosteric inhibitors are:
Enzyme Inhibitor
Citrate synthetase ATP and acyl CoA
Isocitrate
dehydrogenase
ATP and NADH
...
Citrate
synthetase
ATP, acyl CoACa++
+ -
Isocitrate
dehydrogenase
ATP, NADHCa++
+
+
-
a-Ketoglutarate
dehydrogenase
NADH, ...
Glucose is major source of energy for brain
Pyruvate formed by glycolysis is converted
into acetyl CoA
Glucose is oxidized...
Rate of citric acid cycle reactions in brain
depends upon the availability of acetyl CoA
PDH complex is regulated by allos...
The components of PDH complex are:
Pyruvate dehydrogenase
Dihydrolipoyl dehydrogenase
Dihydrolipoyl acetyltransferase
Dihydrolipoyl acetyltransferase and dihydro-
lipoyl dehydrogenase are allosteric enzymes
Dihydrolipoyl dehydrogenase is
al...
PDH can exist in two forms: PDH-a and
PDH-b
PDH-b is the phosphorylated form
PDH-a is the dephosphorylated form
Pyruvate d...
PDH-a is the active form; PDH-b is
the inactive form
PDH-b is dephosphorylated to PDH-a
by PDH phosphatase
PDH-a is phosph...
PDH–a
(active)
PDH–b
(inactive)
ATP ADP
PDH kinase
PDH phosphatase
Pi H2O
‒℗
EMB-RCG
PDH kinase and PDH phosphatase are
allosteric enzymes
PDH phosphatase is activated by Ca++ and
Mg++
PDH kinase is activate...
High concentrations of acetyl CoA, NADH and
ATP convert active PDH into inactive PDH
A high concentration of pyruvate has ...
ATP
PDH PDH‒
NADHAcetyl CoA
  
  -
ATP ADP
PDH kinase
Pyruvate
PDH phosphatase
Pi H2O
Mg
++
Ca
++
Insulin
(in adipos...
In adipose tissue, insulin activates PDH
phosphatase
This increases the oxidative
decarboxylation of pyruvate into acetyl ...
Citric acid cycle
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Citric acid cycle Slide 1 Citric acid cycle Slide 2 Citric acid cycle Slide 3 Citric acid cycle Slide 4 Citric acid cycle Slide 5 Citric acid cycle Slide 6 Citric acid cycle Slide 7 Citric acid cycle Slide 8 Citric acid cycle Slide 9 Citric acid cycle Slide 10 Citric acid cycle Slide 11 Citric acid cycle Slide 12 Citric acid cycle Slide 13 Citric acid cycle Slide 14 Citric acid cycle Slide 15 Citric acid cycle Slide 16 Citric acid cycle Slide 17 Citric acid cycle Slide 18 Citric acid cycle Slide 19 Citric acid cycle Slide 20 Citric acid cycle Slide 21 Citric acid cycle Slide 22 Citric acid cycle Slide 23 Citric acid cycle Slide 24 Citric acid cycle Slide 25 Citric acid cycle Slide 26 Citric acid cycle Slide 27 Citric acid cycle Slide 28 Citric acid cycle Slide 29 Citric acid cycle Slide 30 Citric acid cycle Slide 31 Citric acid cycle Slide 32 Citric acid cycle Slide 33 Citric acid cycle Slide 34 Citric acid cycle Slide 35 Citric acid cycle Slide 36 Citric acid cycle Slide 37 Citric acid cycle Slide 38 Citric acid cycle Slide 39 Citric acid cycle Slide 40 Citric acid cycle Slide 41 Citric acid cycle Slide 42 Citric acid cycle Slide 43 Citric acid cycle Slide 44 Citric acid cycle Slide 45 Citric acid cycle Slide 46 Citric acid cycle Slide 47 Citric acid cycle Slide 48 Citric acid cycle Slide 49 Citric acid cycle Slide 50 Citric acid cycle Slide 51 Citric acid cycle Slide 52 Citric acid cycle Slide 53 Citric acid cycle Slide 54 Citric acid cycle Slide 55 Citric acid cycle Slide 56 Citric acid cycle Slide 57 Citric acid cycle Slide 58 Citric acid cycle Slide 59 Citric acid cycle Slide 60 Citric acid cycle Slide 61 Citric acid cycle Slide 62 Citric acid cycle Slide 63 Citric acid cycle Slide 64 Citric acid cycle Slide 65 Citric acid cycle Slide 66 Citric acid cycle Slide 67 Citric acid cycle Slide 68 Citric acid cycle Slide 69 Citric acid cycle Slide 70 Citric acid cycle Slide 71 Citric acid cycle Slide 72 Citric acid cycle Slide 73 Citric acid cycle Slide 74 Citric acid cycle Slide 75 Citric acid cycle Slide 76 Citric acid cycle Slide 77 Citric acid cycle Slide 78 Citric acid cycle Slide 79 Citric acid cycle Slide 80 Citric acid cycle Slide 81 Citric acid cycle Slide 82 Citric acid cycle Slide 83 Citric acid cycle Slide 84 Citric acid cycle Slide 85 Citric acid cycle Slide 86 Citric acid cycle Slide 87 Citric acid cycle Slide 88 Citric acid cycle Slide 89 Citric acid cycle Slide 90
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Citric acid cycle

  1. 1. Citric Acid Cycle R.C. Gupta Professor and Head Dept. of Biochemistry National Institute of Medical Sciences Jaipur, India
  2. 2. Citric acid cycle (CAC) is a metabolic pathway in which acetyl CoA is oxidized Acetyl CoA is obtained from diverse sources Intermediates of this pathway can be used to synthesize a variety of compounds CAC is a cyclic pathway
  3. 3. Several scientists contributed to the discovery of citric acid cycle The complete cycle was described by Hans Adolf Krebs Hans A. Krebs
  4. 4. • Krebs cycle • Tricarboxylic acid cycle • Central oxidative pathway Citric acid cycle is also known as: EMB-RCG
  5. 5. Location The pathway is present in all the cells having mitochondria Enzymes of this pathway are located in the mitochondria EMB-RCG
  6. 6. Acetyl CoA, a two-carbon compound With the condensation of: The cycle begins ... Citrate, a six-carbon compound to form: Oxaloacetate, a four-carbon compound with
  7. 7. By a series of reactions … Citrate is re-converted into oxaloacetate These are oxidized to water in the respiratory chain A number of reducing equivalents are also removed Two carbon atoms are removed as carbon dioxide in these reactions
  8. 8. Oxaloacetate (4-carbon) CoA Citrate (6-carbon) CO2 Acetyl CoA (2-carbon) CO2
  9. 9. CAC begins with the entry of acetyl group Sources of oxaloacetate Hence, there is no net utilization of oxaloacetate in CAC But oxaloacetate is regenerated at the end Oxaloacetate is the acceptor of acetyl group
  10. 10. But to increase the overall rate of CAC reactions, the concentration of intermediates has to be raised Reactions which lead to net entry of intermediates into the cycle are known as anaplerotic reactions
  11. 11. An important anaplerotic reaction is synthesis of oxaloacetate from pyruvate ATP provides energy for the formation of covalent bond Biotin is required as a coenzyme This reaction is catalysed by pyruvate carboxylase
  12. 12. Pyruvate carboxylase is an allosteric enzyme; it is activated by acetyl CoA CH — C3 — COOH + CO2 + ATP Pyruvate carboxylase Biotin O = C — COOH | CH — COOH + ADP + Pi2 Oxaloacetate O || Pyruvate
  13. 13. Oxaloacetate is also formed by a trans- amination reaction between aspartate and a-ketoglutarate H2N—CH—COOH | CH2—COOH Aspartate GOT, PLP O=C—COOH | CH2—COOH Oxaloacetate O || HOOC—CH2—CH2—C—COOH a-Ketoglutarate NH2 | HOOC—CH2—CH2—CH—COOH Glutamate
  14. 14. However, the transamination reaction is not anaplerotic One intermediate of citric acid cycle, oxaloacetate, is formed at the expense of another, a-ketoglutarate
  15. 15. Sources of acetyl CoA Acetyl CoA occupies a unique place in metabolism It can be formed from: Glucose Fatty acids Amino acids EMB-RCG
  16. 16. Pyruvate is an important source of acetyl CoA Pyruvate is formed from glucose, lactate and some amino acids Amino acids forming pyruvate are glycine, alanine, serine, threonine, cysteine, tryptophan and hydroxyproline
  17. 17. Fatty acid are converted into acetyl CoA by b-oxidation Ketone bodies are also converted into acetyl CoA Some amino acids are directly converted into acetyl CoA Such amino acids are phenylalanine, tyrosine, tryptophan, lysine and leucine
  18. 18. Oxidative decarboxylation of pyruvate Pyruvate formed from various compounds can be converted into acetyl CoA Conversion of pyruvate into acetyl CoA occurs by oxidative decarboxylation
  19. 19. Oxidative decarboxylation occurs by a series of reactions in mitochondria These reactions are catalysed by pyruvate dehydrogenase complex The complex consists of three enzymes and requires five coenzymes
  20. 20. The enzymes are: Pyruvate dehydro- genase Dihydrolipoyl acetyl- transferase Dihydrolipoyl dehydro- genase The coenzymes are: TPP Lipoic acid Co A FAD NAD EMB-RCG
  21. 21. CH3— C— COOH O ||  T ‒ H CH3— C— COOH OH | | T CO2 CH3— C— H OH | | TPyruvate Thiamin pyro- phosphate CoA – SH Coenzyme A O L || CH3 — C ~ S SH S-Acetyl lipoic acid L S — S Oxidised lipoic acid O || CH3— C ~ S— CoA Acetyl CoA L SH SH Reduced lipoic acid FAD FADH2 NADH+ + H NAD +      EMB-RCG
  22. 22. Reactions 1 and 2 are catalysed by pyruvate dehydrogenase Reactions 3 and 4 are catalysed by dihydrolipoyl acetyl transferase Reactions 5 and 6 are catalysed by dihydrolipoyl dehydrogenase EMB-RCG Note: Lipoic acid is bonded to a lysine residue of dihydrolipoyl acetyl transferase
  23. 23. CH3—C— COOH + CoA ‒ SH + NAD+ → O || CH3—C ~ S ‒ CoA + NADH + H+ + CO2 O || The net reaction catalysed by pyruvate dehydrogenase complex
  24. 24. A major fate of acetyl CoA is its oxidation in the citric acid cycle This produces a large amount of energy in the form of ATP Fate of acetyl CoA EMB-RCG
  25. 25. When energy is not required, acetyl CoA is used to synthesize fatty acids Small amounts are used for various acetylation reactions and for synthesis of: Cholesterol Steroid hormones Vitamin D Ketone bodies EMB-RCG
  26. 26. Reactions of citric acid cycle In the first reaction of the cycle, acetyl CoA reacts with oxaloacetate The acetyl group is transferred from acetyl CoA to oxaloacetate forming citrate CoA is released The reaction is catalysed by citrate synthetase
  27. 27. The high-energy thio-ester bond of acetyl CoA is broken in this reaction This releases free energy which ensures that the reaction proceeds in the forward direction only EMB-RCG
  28. 28. O = C — COOH | CH2 — COOH Citrate synthetase O || CH3 — C ~ S — CoA + H2O CoA — SH | HO — C — COOH | Citrate Acetyl CoA Oxaloacetate CH2 — COOH CH2 — COOH EMB-RCG
  29. 29. In the second reaction, aconitase removes a molecule of water from citrate Citrate is converted into cis-aconitate This reaction is inhibited by fluoro-acetate EMB-RCG
  30. 30. Aconitase H2O CH2— COOH | C — COOH || CH — COOH cis-Aconitate CH2— COOH | HO — C — COOH | CH2— COOH Citrate EMB-RCG
  31. 31. In the third reaction, a water molecule is added back to cis-aconitate by aconitase The net result of this and the preceding reaction is that the position of the –OH group is shifted Citrate is converted into isocitrate EMB-RCG
  32. 32. EMB-RCG Aconitase H2O CH2— COOH | CH — COOH | HO—CH — COOH cis-Aconitate CH2— COOH | C — COOH || CH — COOH Isocitrate
  33. 33. In the fourth reaction, isocitrate is dehydrogenated to oxalosuccinate The reaction is catalysed by isocitrate dehydrogenase Isocitrate dehydrogenase is present in mitochondria as well as cytosol EMB-RCG
  34. 34. Mitochondrial isocitrate dehydrogenase uses NAD as an acceptor of reducing equivalents Cytosolic isocitrate dehydrogenase uses NADP as an acceptor of reducing equivalents EMB-RCG
  35. 35. HO — CH — COOH Isocitrate dehydrogenase CH2— COOH | CH — COOH | O = C — COOH CH2— COOH | CH — COOH | Isocitrate NAD + NADH + H + Oxalosuccinate
  36. 36. In the fifth reaction, oxalosuccinate is decarboxylated to a-ketoglutarate The reaction is catalysed by isocitrate dehydrogenase in the presence of Mn++ This is the first reaction of the cycle in which a carbon atom is removed as carbon dioxide EMB-RCG
  37. 37. CH — COOH2 | CH2 | O = C — COOH CH — COOH2 | CH — COOH | O = C — COOH Oxalosuccinate CO2 a-Ketoglutarate Isocitrate dehydrogenase, Mn++
  38. 38. In the sixth reaction, a-ketoglutarate undergoes oxidative decarboxylation to succinyl CoA This reaction is analogous to oxidative decarboxylation of pyruvate to acetyl CoA It is catalysed by a-ketoglutarate dehydrogenase complex EMB-RCG
  39. 39. a-Ketoglutarate dehydrogenase complex is made up of: a-Ketoglutarate dehydrogenase Dihydrolipoyl acetyltransferase Dihydrolipoyl dehydrogenase
  40. 40. a-Ketoglutarate dehyrogenase complex CH2— COOH | CH2 | O = C ~ S — CoA CH2— COOH | CH | O = C — COOH a-Ketoglutarate CO2 + NADH + H+ Succinyl CoA CoA ‒ SH + NAD+
  41. 41. This is the second reaction in which a carbon atom is removed This is also an example of substrate-linked oxidative phosphorylation Energy released during oxidation of a-keto- glutarate is used to form a high-energy thio- ester bond
  42. 42. The seventh reaction is splitting of succinyl CoA into succinate and CoA It is catalysed by succinate thiokinase (succinyl CoA synthetase) The energy released in the reaction is used to phosphorylate GDP to GTP GTP can transfer a high-energy phosphate to ADP forming ATP
  43. 43. GDP + Pi Succinate thiokinase CH2 — COOH | CH2 —COOH CH2 — COOH | CH2 | O = C ~ S — CoA Succinyl CoA Succinate GTP + CoA–SH
  44. 44. Succinate is a four-carbon dicarboxylic acid It is converted into oxaloacetate, another four-carbon dicarboxylic acid The conversion occurs by a series of reactions
  45. 45. In the eighth reaction, two hydrogen atoms are transferred from succinate to FAD The reaction is catalysed by succinate dehydrogenase Succinate dehydrogenase is a flavo- protein having FAD as a prosthetic group
  46. 46. Succinate dehydrogenase H— C — COOH || HOOC — C — H CH2— COOH | CH2— COOH FADH2 Succinate FAD Fumarate
  47. 47. Fumarase HO — CH — COOH | CH2 — COOH H — C — COOH || HOOC — C — H Fumarate H2O L-Malate In the ninth reaction, fumarate is hydrated to L-malate by fumarase
  48. 48. In the tenth reaction, L-malate is dehydro- genated to oxaloacetate by malate dehydrogenase NAD accepts the reducing equivalents Thus, oxaloacetate is regenerated and acetyl CoA is oxidised
  49. 49. Malate dehydrogenase O —— C — COOH | CH2 — COOH HO — CH — COOH | CH2 — COOH L-Malate NAD+ NADH + H+ Oxaloacetate
  50. 50. Citric acid cycle Oxaloacetate Acetyl CoA CoA Citrate cis-Aconitate Isocitrate Oxalosuccinate CO2 a-Ketoglutarate CoA Succinyl CoA GDP+Pi CoA+GTP Succinate FAD FADH2 Fumarate H2O L-Malate NAD+ NADH + H+ NAD+ NAD+ NADH+H+ NADH + H+ H2O H2O H2O CO2
  51. 51. During complete oxidation of one molecule of acetyl Co A in citric acid cycle: These are oxidised in the respiratory chain Energetics Three molecules of NAD are reduced One molecule of FAD is reduced
  52. 52. Oxidation of three molecules of NADH will phosphorylate nine molecules of ADP to ATP Oxidation of one molecule of FADH2 will phosphorylate two molecules of ADP to ATP Thus, 11 ATP equivalents are formed by oxidative phosphorylation in the respiratory chain per molecule of acetyl Co A oxidised
  53. 53. One GTP is formed when succinyl CoA is converted into succinate This, in turn, can convert one ADP into one ATP Thus, 12 ATP equivalents are formed on complete oxidation of one molecule of acetyl CoA in citric acid cycle and respiratory chain
  54. 54. Succinyl CoA to succinate Isocitrate to oxaloacetate NAD+ NADH 3 ATP equivalents Reaction Change in coenzyme Energy captured a-Ketoglutarate to succinyl CoA NAD+ NADH 3 ATP equivalents Malate to oxaloacetate 3 ATP equivalentsNAD+ NADH 2 ATP equivalentsFAD  FADH2 Succinate to fumarate 1 ATP equivalentGDP GTP 12 ATP equivalentsNet gain
  55. 55. Eight ATP equivalents are formed when one molecule of glucose is oxidised to two molecules of pyruvate One molecule of NAD is reduced when pyruvate is converted into acetyl CoA This will form three ATP equivalents when it is oxidised in the respiratory chain Energetics of oxidation of glucose
  56. 56. Conversion of two pyruvate molecules into acetyl CoA will form 6 ATP equivalents Oxidation of two acetyl CoA molecules in CAC will form 24 ATP equivalents Thus, total ATP equivalents formed from complete oxidation of glucose are 8+6+24=38
  57. 57. Energy of hydrolysis of the terminal phosphate bond of ATP is 7.3 kcal/mol 38 ATP equivalents represent a capture of 38x7.3 = 277.4 kcal energy per mol of glucose Efficiency of oxidation
  58. 58. Potential energy present in glucose is 686 kcal per mol Hence, efficiency of oxidation of glucose is 277.4  686  100% or nearly 40%
  59. 59. Importance of citric acid cycle • Final catabolic pathway for carbohydrates, lipids and proteins • Glucose, fatty acids and many amino acids can be synthesized from intermediates of the cycle • Capture of energy as ATP
  60. 60. All the carbohydrates can be converted into glucose Glucose is converted into pyruvate in the glycolytic pathway Pyruvate can enter citric acid cycle after its conversion into acetyl CoA Catabolic function
  61. 61. Oxidation of fatty acids produces acetyl CoA which is oxidised in the CAC Propionyl CoA is formed from fatty acids having an odd number of carbon atoms Propionyl CoA is converted into succinyl CoA which is an intermediate of CAC
  62. 62. Glycerol Glycerol-3-phosphate Dihydroxyacetone phosphate Pyruvate Glycerol is also released from lipids This can be converted into pyruvate in the glycolytic pathway
  63. 63. Several amino acids are converted into pyruvate These are glycine, alanine, serine, threonine, cysteine, tryptophan and hydroxyproline Pyruvate is converted into acetyl CoA which enters the citric acid cycle
  64. 64. Glutamine, arginine, histidine and proline can be converted into glutamate Glutamate can be converted into a-keto- glutarate, an intermediate of CAC Thus, these five amino acids can enter the cycle as a-ketoglutarate
  65. 65. Valine, isoleucine and methionine can enter CAC as succinyl CoA Phenylalanine and tyrosine are partially converted into fumarate, an intermediate Asparagine and aspartate can enter the cycle as oxaloacetate Leucine and lysine enter as acetyl CoA
  66. 66. Anabolic function Glucose, fatty acids and many amino acids can be synthesized from inter- mediates of citric acid cycle Therefore, this cycle plays an important role in interconversion of nutrients
  67. 67. All the intermediates of CAC can be converted into oxaloacetate Oxaloacetate is a substrates for gluco- neogenesis Therefore, glucose can be synthesized from intermediates of citric acid cycle
  68. 68. Some intermediates can be trans- aminated to amino acids a-Ketoglutarate can be transaminated to glutamate and oxaloacetate to aspartate Some other amino acids can be formed from these two
  69. 69. Fatty acids are synthesized from acetyl CoA Major source of acetyl CoA is pyruvate Acetyl CoA is formed in mitochondria but fatty acids are synthesised in cytosol Acetyl CoA cannot traverse mitochondrial membrane but citrate can
  70. 70. Acetyl CoA is converted into citrate in the mitochondria Citrate goes to cytosol, and is cleaved into acetyl CoA and oxaloacetate Acetyl CoA is used for fatty acid synthesis
  71. 71. Citrate + CoA ATP-Citrate lyase ATP ADP + Pi Acetyl CoA + Oxaloacetate
  72. 72. Citric acid cycle performs catabolic as well as anabolic functions Therefore, it is said to be an amphibolic pathway
  73. 73. Oxaloacetate Citrate cis-Aconitate Isocitrate Oxalosuccinate a-Ketoglutarate Succinyl CoA Succinate Phe, Tyr Fumarate Malate Val Propionyl CoA Fatty acids (C)2n+1 Ile Met Glutamate Gln Pro Arg His Gly, Ala, Ser, Thr, Cys, Trp, Hyp PyruvateGlucose Glycerol Acetyl CoA Fatty acids (C)2n Asn Asp Acetyl CoA Amphibolic role of CAC
  74. 74. Capture of energy Much of the energy is captured as ATP when these fuels are oxidized in the citric acid cycle An important functions of citric acid cycle is to capture the energy present in carbohydrates, lipids and proteins
  75. 75. Regulation The major function of citric acid cycle is to capture energy Availability of energy in the cell is the major regulator of the pathway In addition, some enzymes are allosteric enzymes
  76. 76. The allosteric enzymes are: Ca++ is the allosteric activator of all the three a-Ketoglutarate dehydrogenase Isocitrate dehydrogenase Citrate synthetase
  77. 77. The allosteric inhibitors are: Enzyme Inhibitor Citrate synthetase ATP and acyl CoA Isocitrate dehydrogenase ATP and NADH a-Ketoglutarate dehydrogenase NADH and succinyl CoA
  78. 78. Citrate synthetase ATP, acyl CoACa++ + - Isocitrate dehydrogenase ATP, NADHCa++ + + - a-Ketoglutarate dehydrogenase NADH, Succinyl CoA - Ca++
  79. 79. Glucose is major source of energy for brain Pyruvate formed by glycolysis is converted into acetyl CoA Glucose is oxidized by glycolysis in brain Regulation in brain The fate of acetyl CoA is its oxidation in the citric acid cycle
  80. 80. Rate of citric acid cycle reactions in brain depends upon the availability of acetyl CoA PDH complex is regulated by allosteric mechanism as well as covalent modification Availability of acetyl CoA depends upon pyruvate dehydrogenase (PDH) complex
  81. 81. The components of PDH complex are: Pyruvate dehydrogenase Dihydrolipoyl dehydrogenase Dihydrolipoyl acetyltransferase
  82. 82. Dihydrolipoyl acetyltransferase and dihydro- lipoyl dehydrogenase are allosteric enzymes Dihydrolipoyl dehydrogenase is allosterically inhibited by NADH Dihydrolipoyl acetyltransferase is allosterically inhibited by acetyl CoA
  83. 83. PDH can exist in two forms: PDH-a and PDH-b PDH-b is the phosphorylated form PDH-a is the dephosphorylated form Pyruvate dehydrogenase (PDH) is regulated by covalent modification
  84. 84. PDH-a is the active form; PDH-b is the inactive form PDH-b is dephosphorylated to PDH-a by PDH phosphatase PDH-a is phosphorylated to PDH-b by PDH kinase
  85. 85. PDH–a (active) PDH–b (inactive) ATP ADP PDH kinase PDH phosphatase Pi H2O ‒℗ EMB-RCG
  86. 86. PDH kinase and PDH phosphatase are allosteric enzymes PDH phosphatase is activated by Ca++ and Mg++ PDH kinase is activated by acetyl CoA, NADH & ATP, and is inhibited by pyruvate
  87. 87. High concentrations of acetyl CoA, NADH and ATP convert active PDH into inactive PDH A high concentration of pyruvate has the opposite effect This, in turn, decreases the rate of citric acid cycle reactions Conversion of pyruvate into acetyl CoA is decreased
  88. 88. ATP PDH PDH‒ NADHAcetyl CoA      - ATP ADP PDH kinase Pyruvate PDH phosphatase Pi H2O Mg ++ Ca ++ Insulin (in adipose tissue) EMB-RCG ℗
  89. 89. In adipose tissue, insulin activates PDH phosphatase This increases the oxidative decarboxylation of pyruvate into acetyl CoA PDH phosphatase converts inactive PDH into active PDH
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Basics of Citric acid cycle for biology, biochemistry and medical undergraduates

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