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Citric Acid Cycle

The citric acid cycle is a series of chemical reactions in the mitochondria that break down acetate derived from carbohydrates, fats, and proteins into carbon dioxide. It produces reduced electron carriers and GTP/ATP to conserve energy. The cycle has 8 steps where substrates are oxidized and carbon dioxide is released. It generates 12 ATP per acetyl-CoA molecule. The cycle is regulated by substrate availability and inhibition of key enzymes by accumulating products and allosteric regulators.

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92 views21 pages

Citric Acid Cycle

The citric acid cycle is a series of chemical reactions in the mitochondria that break down acetate derived from carbohydrates, fats, and proteins into carbon dioxide. It produces reduced electron carriers and GTP/ATP to conserve energy. The cycle has 8 steps where substrates are oxidized and carbon dioxide is released. It generates 12 ATP per acetyl-CoA molecule. The cycle is regulated by substrate availability and inhibition of key enzymes by accumulating products and allosteric regulators.

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Kunda Joseph
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CITRIC ACID CYCLE

LIKANDO CHABABA
likandochababa@yahoo.com
Biomedical Importance
• The citric acid cycle (Krebs cycle, tricarboxylic acid cycle) is a series of
reactions in mitochondria that oxidize acetyl residues (as acetyl-CoA).

• The acetyl groups are fed into the citric acid cycle, which enzymatically
oxidizes them to CO2. The energy released by oxidation is conserved in
the reduced electron carriers NADH and FADH2.

• It is the final common pathway for the aerobic oxidation of carbohydrate,


lipid, and protein because glucose, fatty acids, and most amino acids are
metabolized to acetyl-CoA or intermediates of the cycle.

• It also has a central role in gluconeogenesis, lipogenesis, and


interconversion of amino acids.
Catabolism of proteins, fats, and carbohydrates in the
three stages of cellular respiration.
Transport and Production of Acetyl-CoA

• Pyruvate generated in the cytoplasm by glycolysis must be transported


across the inner mitochondrial membrane via a pyruvate/H+ symport.

• This transport uses some of the energy stored in the mitochondrial inner
membrane electrical potential gradient.

• Pyruvate derived from glucose and other sugars by glycolysis, is oxidized to


acetyl-CoA and CO2 by the pyruvate dehydrogenase (PDH) complex,
located in the mitochondria of eukaryotic cells and in the cytosol of
prokaryotes.
• The overall reaction catalyzed by the pyruvate dehydrogenase complex is
an oxidative decarboxylation, an irreversible oxidation process in which
the carboxyl group is removed from pyruvate as a molecule of CO2 and the
two remaining carbons become the acetyl group of acetyl-CoA.
The Pyruvate Dehydrogenase Complex Consists of Three
Distinct Enzymes

• The PDH complex contains three enzymes—pyruvate dehydrogenase (E1),


dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase
(E3)—each present in multiple copies.

The Pyruvate Dehydrogenase Complex Requires Five


Coenzymes

• They are thiamine pyrophosphate (TPP), flavin adenine dinucleotide


(FAD), coenzyme A, nicotinamide adenine dinucleotide (NAD), and
lipoate.

• The active site of E1 has bound TPP, E2 is the point of connection for the
prosthetic group lipoate, and that of E3 has bound FAD.
Reactions of the Citric Acid Cycle
The Citric Acid Cycle Has Eight Steps

1. Formation of Citrate: The first reaction of the cycle is the condensation


of acetyl-CoA with oxaloacetate to form citrate, catalyzed by citrate
synthase:
2. Formation of Isocitrate via cis-Aconitate: The enzyme aconitase
(aconitate hydratase) catalyzes the reversible transformation of citrate to
isocitrate, through the intermediary formation of the tricarboxylic acid
cis-aconitate, which normally does not dissociate from the active site.
3. Oxidation of Isocitrate to α-Ketoglutarate and CO2: In the next step,
isocitrate dehydrogenase catalyzes oxidative decarboxylation of
isocitrate to form α-ketoglutarate.
4. Oxidation of α-Ketoglutarate to Succinyl-CoA and CO2: The next step is
another oxidative decarboxylation, in which α-ketoglutarate is converted
to succinyl-CoA and CO2 by α-ketoglutarate dehydrogenase complex.
5. Conversion of Succinyl-CoA to Succinate: Succinyl-CoA has a thioester
bond; the energy released in the breakage of this bond is used to
synthesize GTP or ATP.

• Succinate is formed in the process:

• The enzyme that catalyzes this reversible reaction is called succinyl-CoA


synthetase or succinic thiokinase.
6. Oxidation of Succinate to Fumarate: The succinate formed from succinyl-
CoA is oxidized to fumarate by succinate dehydrogenase:

• Malonate, an analog of succinate, is a strong competitive inhibitor of


succinate dehydrogenase and therefore blocks the citric acid cycle.
7. Hydration of Fumarate to Malate: The reversible hydration of fumarate
to L-malate is catalyzed by fumarase.
8. Oxidation of Malate to Oxaloacetate: In the last reaction of the citric
acid cycle, NAD+-linked L-malate dehydrogenase catalyzes the oxidation
of L-malate to oxaloacetate:

• Products of one turn of the citric acid cycle: 3 NADH, 1 FADH2, 1 GTP (or
ATP), and 2 CO2.

• The cycle generates the equivalent of 12 ATPs from one acetyl-CoA (3


NADH = 9 ATPs, 1 FADH2 = 2 ATPs, 1 ATP (GTP) directly).
Citric Acid Cycle Components Are Important Biosynthetic Intermediates

• α-Ketoglutarate and oxaloacetate serve as precursors of the amino acids


aspartate and glutamate by simple transamination.

• Through aspartate and glutamate, the carbons of oxaloacetate and α-


ketoglutarate are then used to build other amino acids, as well as purine
and pyrimidine nucleotides.

• Oxaloacetate is converted to glucose in gluconeogenesis.

• Succinyl-CoA is a central intermediate in the synthesis of the porphyrin


ring of heme groups, which serve as oxygen carriers (in hemoglobin and
myoglobin) and electron carriers (in cytochromes).

• And the citrate produced in some organisms is used commercially for a


variety of purposes.
Biosynthetic precursors produced by Citric Acid Cycle
Regulation of the Citric Acid Cycle
Regulation of acetyl-CoA production by the PDH complex

• The pyruvate dehydrogenase complex of vertebrates is strongly inhibited


by ATP, acetyl-CoA, and NADH, the products of the reaction catalyzed by
the complex.

• When long chain fatty acids are available, and can provide acetyl-CoA via
β-oxidation, pyruvate oxidation is inhibited.

• When acetate flow through the cycle decreases, AMP, CoA, and NAD+ all
accumulate and allosterically activate the pyruvate dehydrogenase
complex.
The Citric Acid Cycle Is Regulated at Its Three Exergonic Steps

• Three factors govern the rate of flux through the cycle:


- substrate availability,
- inhibition by accumulating products, and
- allosteric feedback inhibition of the enzymes that catalyze early steps in the cycle.

• The availability of the substrates for citrate synthase (acetyl-CoA and


oxaloacetate) varies with the metabolic state of the cell and sometimes
limits the rate of citrate formation.

• NADH, a product of isocitrate and α-ketoglutarate oxidation, accumulates


under some conditions, and at high [NADH] both isocitrate and α-
ketoglutarate dehydrogenase reactions are severely inhibited by mass
action.
• Product accumulation inhibits all three limiting steps catalyzed by citrate
synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase:
- Succinyl-CoA inhibits α-ketoglutarate dehydrogenase (and also citrate synthase);
- Citrate blocks citrate synthase; and
- The end product, ATP, inhibits both citrate synthase and isocitrate dehydrogenase.

• ADP is an allosteric activator of citrate synthase enzyme.

• Ca2+ activates both isocitrate dehydrogenase and α–ketoglutarate


dehydrogenase, as well as the PDH complex.

• Citrate, the product of the first step of the citric acid cycle, is an important
allosteric inhibitor of phosphofructokinase-1 in the glycolytic pathway.

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