A complete Kreb's cycle with structures...

1. KREB’S CYCLEKREB’S CYCLE

2.  Kreb’s cycle orKreb’s cycle or
 Citric Acid Cycle orCitric Acid Cycle or
 Tricarboxylic Acid CycleTricarboxylic Acid Cycle
(TCA cycle)(TCA cycle)

3. The Aerobic Breakdown of CarbohydratesThe Aerobic Breakdown of Carbohydrates
 Glycolysis isGlycolysis is inhibitedinhibited by aerobic conditions i.e.by aerobic conditions i.e.
thethe presence of oxygenpresence of oxygen, mainly due to 2 reasons:, mainly due to 2 reasons:
 (1)-(1)- The presence of oxygenThe presence of oxygen inhibitsinhibits thethe
dehydrogenationdehydrogenation of pyruvic acid to lactic acid.of pyruvic acid to lactic acid.
 (2)-(2)- The pyruvic acid produced in glycolysis isThe pyruvic acid produced in glycolysis is
rapidly oxidizedrapidly oxidized as it is produced.as it is produced.
 The aerobic breakdown involves theThe aerobic breakdown involves the samesame
sequencesequence of reactions as inof reactions as in glycolysisglycolysis upto theupto the
formation offormation of pyruvic acidpyruvic acid..

4. Entry of pyruvic acid into the TCAEntry of pyruvic acid into the TCA
cyclecycle
 TheThe pyruvic acidpyruvic acid is thenis then oxidizedoxidized to COto CO22 &&
HH22O in theO in the presence of oxygenpresence of oxygen throughthrough Kreb’sKreb’s
cyclecycle..
 For entry into the TCA cycle, it has to convertFor entry into the TCA cycle, it has to convert
toto Acetyl CoAAcetyl CoA..
 Oxidation of pyruvate to Acetyl CoA isOxidation of pyruvate to Acetyl CoA is
catalyzed by thecatalyzed by the Pyruvate dehydrogenasePyruvate dehydrogenase in thein the
mitochondria.mitochondria.

5. NADNAD NADHNADH22
 Pyruvic acidPyruvic acid acetyl – SCo – Aacetyl – SCo – A
SHCoA COSHCoA CO22
CH3-CO-COOH + CoASH + NAD
CH3-CO-SCoA + CO2 + NADH
*

6. Oxaloacetate
Acetyl CoA
Citric acid Cis-aconitic acid
Isocitric acidOxalosuccinateα-Ketoglutarate
Succinyl-CoA Succinate Fumarate
MalateOxaloacetate
Citrate synthase Aconitase , Fe
Aconitase
Fe
Dehydrogenase
α-ketoglutarte dehydrogenase
Succinate thiokinase
Succinate
dehydrogenase
Fumarase
Malate dehydrogenase
H2O CoA-SH
H2O
++
++
+H2O
NADH+H NAD
Isocitrate dehydrogenase
CO2
NAD
NADH+H
CoA-SH
CO2
ADP+Pi ATP
CoA-SH FAD FADH2
H2O
NADH2 NAD
(1) (2)
(3)
(4)(5)
(6)
(7) (8)
(9)
(10)
*

7. Step-wise reactions of the TCA cycle
 1)- Aldol condensation of oxaloacetate with
acetyl CoA followed by hydrolysis of
CoASH to give citrate. Enzyme: citrate
synthase.
 2,3)- Dehydration followed by hydration
leads to interchange of -H and –OH &
isomerization of citrate to isocitrate.
 Enzyme aconitase

8.  4,5)Oxidative decarboxylation of isocitrate is
catalyzed by isocitrate dehydrogenase to form
α-keto-glutarate - NAD is reduced to NADH
& one C is removed as CO2.
 6) This is the second oxidative decarboxylaion
catalyzed by αα-ketoglutarate dehydrogenase.
CO2 is removed, NADH is formed from NAD
& a thioester bond is formed with CoASH to
form succinyl CoA.
 7) Conversion of thioester of Succinyl CoA to

9.  8) Succinate is oxidized to fumarate by
succinate dehydrogenase. A double bond is
introduced between the 2 central carbons &
FAD is reduced to FADH2.
 9) Fumarate is hydrated to malate by the
enzyme fumarase.
 10) In the final step, malate is oxidized to
oxaloacetate with the coupled reduction of
NAD to NADH by the enzyme malate
dehydrogenase.

10. ENERGATICS OF TCA cycle.ENERGATICS OF TCA cycle.
 As a result of oxidation by dehydrogenases – 4
molecules of NADH & 1 of FADH2 are
produced for each molecule of acetyl-CoA.
 Reoxidation of each NADH results in
formation of 3 ATP, FADH2 - 2 ATP.
 In addition, 1 ATP is formed by substrate-
level phosphorylation by succinate thiokinase.

11.  ATP gained = 15 for one molecule of pyruvic
acid (one cycle).
 Total ATPs for two molecule of pyruvic acid =
15 * 2 = 30
According to old concept
 ATP from glycolysis = 8
 ATP from Kreb’s cycles = 30
 Total --------- 38

12. According to New concept
 ATP from glycolysis = 6
 ATP from Kreb’s cycle = 30
 Total --------------- = 36

13. Significance of TCA cycleSignificance of TCA cycle
 Several intermediates of this cycle take part
in the formation of substances of great
physiological importance.
 1) – Citrate is provided to the lens of the eye,
bone & seminal fluid. Citrate stimulate fatty
acid synthesis by activating acetyl-CoA
carboxylase.
 2) – Succinyl-CoA is utilized in the synthesis
of porphyrins needed for Hb formation.

14.  3) – Acetyl-CoA is used in the synthesis of
cholesterol, fatty acids, acetylcholine etc.
 4) – αα-Ketoglutarate & Oxaloacetate can
undergo transamination forming glutamic acid
& aspartic acid (amino acids).

15.  Mitochondria = consist of inner & outer membrane & matrix, PDH complexMitochondria = consist of inner & outer membrane & matrix, PDH complex
& TCA cycle in matrix (except succinate dehydrogenase).& TCA cycle in matrix (except succinate dehydrogenase).
 FAD = Flavin Adenine Dinucleotide – oxidized form.FAD = Flavin Adenine Dinucleotide – oxidized form.
 FADH2 = Flavin Adenine Dinucleotide – reduced form.FADH2 = Flavin Adenine Dinucleotide – reduced form.
 NAD = Nicotinamide Adenine Dinucleotide – oxidized form.NAD = Nicotinamide Adenine Dinucleotide – oxidized form.
 NADH + H = Nicotinamid Adenine Dinucleotide – reduced form.NADH + H = Nicotinamid Adenine Dinucleotide – reduced form.
 NADP = Nicotinamide Adenine Dinucleotide Phosphate – oxidized form.NADP = Nicotinamide Adenine Dinucleotide Phosphate – oxidized form.
 NADPH = Nicotinamide Adenine Dinucleotide Phosphate – reduced form.NADPH = Nicotinamide Adenine Dinucleotide Phosphate – reduced form.
 Harper’s , Mushtaq Ahmed volume I, and Hashmi’s .Harper’s , Mushtaq Ahmed volume I, and Hashmi’s .