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3.the Citric Acid Cycle

The citric acid cycle is the final common pathway that oxidizes carbohydrates, lipids, and amino acids in mitochondria. It generates energy in the form of ATP and reduces NAD+ and FAD to drive the electron transport chain. Key reactions include the condensation of acetyl-CoA and oxaloacetate to form citrate, and oxidative decarboxylations that produce NADH, FADH2, and GTP or ATP. The cycle is regulated by energy status and calcium levels to meet cellular energy demands.

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70 views7 pages

3.the Citric Acid Cycle

The citric acid cycle is the final common pathway that oxidizes carbohydrates, lipids, and amino acids in mitochondria. It generates energy in the form of ATP and reduces NAD+ and FAD to drive the electron transport chain. Key reactions include the condensation of acetyl-CoA and oxaloacetate to form citrate, and oxidative decarboxylations that produce NADH, FADH2, and GTP or ATP. The cycle is regulated by energy status and calcium levels to meet cellular energy demands.

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قتيبه خالد دحام خلف
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THE CITRIC ACID CYCLE

The Central Pathway of Carbohydrate, Lipid & Amino Acid Metabolism


The citric acid cycle (the Krebs or tricarboxylic acid cycle) is a sequence of
reactions in mitochondria. It is the final common pathway for the oxidation of
carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids
are metabolized to acetyl-CoA or intermediates of the cycle. The citric acid cycle
also has a central role in gluconeogenesis, lipogenesis, and interconversion of
amino acids.
Reactions of The Citric Acid Cycle
1. Acetyl-CoA and oxaloacetate are condensed to form citrate, catalyzed by
citrate synthase.

First, a carbon-carbon bond is formed between the methyl carbon of acetyl-CoA


and the carbonyl carbon of oxaloacetate. Then, the thioester bond of the resultant
citryl-CoA is hydrolyzed, releasing citrate and CoASH. This reaction is
irreversible.
2. Citrate is isomerized to isocitrate by the enzyme aconitase (citrate
isomerase).

The reaction occurs in two steps: dehydration to cis-aconitate and rehydration to


isocitrate. Although citrate is a symmetric molecule, aconitase reacts with citrate
asymmetrically (atoms originated from acetyl-CoA is not used). This asymmetric
behavior is the result of channeling or the transfer of the product of citrate synthase
Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad
directly onto the active site of aconitase, without entering free solution. This
channeling provides integration of citric acid cycle activity and providing citrate in
the cytosol as a source of acetyl-CoA for fatty acid synthesis. Citrate is only
available in free solution to be transported from the mitochondria to the cytosol for
fatty acid synthesis when aconitase is inhibited by accumulation of its product,
isocitrate.
The poison fluoracetate is found in some of plants, and their consumption can be
fatal to animals. Some fluorinated compounds used as anticancer agents and
industrial chemicals (including pesticides) are metabolized to fluoroacetate. It is
toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate,
which inhibits aconitase, causing citrate to accumulate.
3. Isocitrate undergoes dehydrogenation (forming oxalosuccinate) then
decarboxylation to form α –ketoglutarate; the reaction is catalyzed by
isocitrate dehydrogenase.

There are three isoenzymes of isocitrate dehydrogenase. One, which uses NAD+, is
found only in mitochondria. The other two use NADP+ and are found in
mitochondria and the cytosol.
4. α -Ketoglutarate undergoes oxidative decarboxylation reaction catalyzed by
α -ketoglutarate dehydrogenase complex forming succinyl-CoA.

α -ketoglutarate dehydrogenase complex is a multienzyme complex similar to that


involved in the oxidative decarboxylation of pyruvate. It requires the same
Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad
cofactors as the pyruvate dehydrogenase complex (thiamin diphosphate, lipoate,
NAD+, FAD, and CoA). As in the case of pyruvate dehydrogenase, arsenite
inhibits the enzyme, causing the substrate, α -ketoglutarate, to accumulate. High
concentrations of ammonia inhibit α -ketoglutarate dehydrogenase.
5. Succinyl-CoA is converted to succinate by the enzyme succinate thiokinase
(succinyl-CoA synthetase).

This is the only example of substrate level phosphorylation in the citric acid cycle.
Tissues in which gluconeogenesis occurs (the liver and kidney) contain two
isoenzymes of succinate thiokinase, one specific for GDP and the other for ADP.
The GTP formed is used for the decarboxylation of oxaloacetate to
phosphoenolpyruvate in gluconeogenesis. Nongluconeogenic tissues have only the
isoenzyme that phosphorylates ADP.
6. Dehydrogenation of succinate forming fumarate, catalyzed by succinate
dehydrogenase. Malonate competitively inhibits succinate dehydrogenase.

7. Fumarate is hydrated to L-malate by fumarase.

8. Malate is dehydrogenated by malate dehydrogenase to yield oxaloacetate.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad


There is no direct participation of oxygen in the citric acid cycle. However, the
cycle operates only under aerobic conditions. This is due to the fact that NAD+
and FAD (from NADH and FADH2, respectively) required for the operation of the
cycle can be regenerated in the electron transport chain only in the presence of O2.
Therefore, citric acid cycle is strictly aerobic in contrast to glycolysis which
operates in both aerobic and anaerobic conditions.

Energetics of the Citric Acid Cycle


As a result of oxidations catalyzed by the
dehydrogenases of the citric acid cycle, three
molecules of NADH and one of FADH2 are
produced for each molecule of acetyl-CoA
catabolized in one turn of the cycle. These
reducing equivalents are transferred to the
respiratory chain, where reoxidation of each
NADH results in formation of ~2.5 ATP, and
of FADH2 ~1.5 ATP. In addition, 1 ATP (or
GTP) is formed by substrate-level
phosphorylation catalyzed by succinate
thiokinase.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad


The overall reactions of the citric acid cycle, showing sites of action of inhibitors

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad


Roles of the B vitamins in the Citric Acid Cycle
Four of the B vitamins are essential in the citric acid cycle. The name, form and the
reaction in which they participate are shown in the following table.
Vitamin Form Reaction catalyzed by:
Thiamin (B1) Thiamin diphosphate α -ketoglutarate dehydrogenase (4)
FAD (flavin adenine
Riboflavin (B2) Succinate dehydrogenase (6)
dinucleotide)
Isocitrate dehydrogenase (3)
NAD+ (nicotinamide
Niacin (B3) α -ketoglutarate dehydrogenase (4)
adenine dinucleotide)
Malate dehydrogenase (8)
Pantothenic
Coenzyme A α -ketoglutarate dehydrogenase (4)
acid (B5)

Anaplerotic reactions
The citric acid cycle is an amphibolic pathway, and is not only a pathway for
oxidation of the two carbon units of acetyl-CoA; but, it is also a major pathway for
interconversion of metabolites arising from amino acids (by tansamination and
deamination), and providing the substrates for amino acid synthesis, as well as for
gluconeogenesis, and fatty acid synthesis. Thus, the citric acid cycle intermediate
may be used in the synthesis of many biological molecules; and in order to
maintain efficient metabolic pathway these intermediate need to be replenished.
Different anaplerotic reactions do so. Anaplerosis is the act of replenishing the
citric acid cycle intermediates that have been extracted for biosynthesis.
Regulation of the Citric Acid Cycle
Regulation occurs through regulation of acetyl-CoA formation by pyruvate
dehydrogenase, or regulation of the reactions of the cycle itself. The main sites for
regulation of the cycles’ reaction are the nonequilibrium reactions catalyzed by
citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. The
energy status as shown by the [ATP]/[ADP] and [NADH]/[NAD+] ratios regulate
the activity of these enzymes. Allosteric inhibition of isocitrate dehydrogenase by
ATP results in isocitrate accumulation and thus citrate accumulation, which
transport to the cytoplasm where it inhibits phosphofructokinase, an important
regulatory enzyme of glycolysis.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad


The dehydrogenases are activated by Ca2+, which increases in concentration during
contraction of muscle and during secretion by other tissues, when there is increased
energy demand. The concentration of oxaloacetate, limits the rate of the citrate
synthase reaction.

Dr. Ali A. Kasim/ College of Pharmacy/ University of Baghdad

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