Importance of Acetyl CoA

Introduction
• Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in protein,
carbohydrate and lipid metabolism.
• Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to
be oxidized for energy production.
• Structurally, Coenzyme A (CoASH or CoA) consists of a β-mercaptoethylamine group
 linked to the vitamin pantothenic acid (B5) through an amide linkage and 3'-
phosphorylated ADP.
• CoA is acetylated to acetyl-CoA by the breakdown
of carbohydrates through glycolysis and by the breakdown of fatty acids through β-
oxidation.
• Acetyl-CoA then enters the citric acid cycle, where
the acetyl group is oxidized to carbon dioxide and
water
• Konrad Bloch and Feodor Lynen were awarded the
1964 Nobel Prize in Physiology and Medicine for
their discoveries linking acetyl-CoA and fatty acid
metabolism. 
• Fritz Lipmann won the Nobel Prize in 1953 for his
discovery of the cofactor coenzyme A.
Synthesis of Acetyl CoA

1. Extramitochondrial
•At high glucose levels,
•glycolysis takes place rapidly, thus increasing the amount
of citrate produced from the tricarboxylic acid cycle.
•This citrate is then exported to other organelles outside the mitochondria to
be broken into acetyl-CoA and oxaloacetate by the enzyme ATP citrate
lyase (ACL).
•This principal reaction is coupled with the hydrolysis of ATP.
Synthesis of Acetyl CoA

•At low glucose levels:

• CoA is acetylated using acetate by acetyl-CoA synthetase (ACS), also coupled with 
ATP hydrolysis.
• Ethanol also serves as a carbon source for acetylation of CoA utilizing the enzyme 
alcohol dehydrogenase.
• Degradation of branched-chain ketogenic amino acids such as valine, leucine, and 
isoleucine occurs.
• These amino acids are converted to α-ketoacids by transamination and eventually to
isovaleryl-CoA through oxidative decarboxylation by an α-ketoacid dehydrogenase complex.
• Isovaleryl-CoA undergoes dehydrogenation, carboxylation and cleaved into acetyl-CoA and 
acetoacetate.
2. Intramitocondrial
• At high glucose levels
• acetyl-CoA is produced through glycolysis.
• Pyruvate undergoes oxidative decarboxylation in which it loses its carboxyl group (as 
carbon dioxide) to form acetyl-CoA.
• The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate
dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex.
• Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate
formate lyase disproportionate pyruvate into acetyl-CoA and formic acid.
 • At low glucose levels
• the production of acetyl-CoA is linked to β-oxidation of fatty acids. Fatty acids are first
converted to acyl-CoA.
• Acyl-CoA is then degraded in a four-step cycle of oxidation, hydration, oxidation and 
thiolysis catalyzed by four respective enzymes, namely acyl-CoA dehydrogenase, enoyl
-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and thiolase. The cycle produces a
new fatty acid chain with two fewer carbons and acetyl-CoA as a byproduct
Reactions involved in synthesis of Acetyl CoA

Pyruvate dehydrogenase complex reaction

Reactions involved
Acetyl CoA synthase
2. Acetate + ATP +CoASH Acetyl CoA +AMP + Pi

Citrate lyases

3. Citrate+ CoASH +ATP Acetyl CoA +oxaloacetate

+ADP + Pi
Beta oxidation of fatty acids
Functions in intermediatory metabolism
1. In Cellular Respiration
•Citric acid cycle:
• energy is released through the oxidation of acetyl-CoA derived from carbohydrates,
fats, and proteins into adenosine triphosphate (ATP) and carbon dioxide.
•Fatty acid metabolism
• Acetyl-CoA is produced by the breakdown of both carbohydrates (by glycolysis) and 
lipids (by β-oxidation). It then enters the citric acid cycle in the mitochondrion by
combining with oxaloacetate to form citrate.
• Two acetyl-CoA molecules condense to form acetoacetyl-CoA, which gives rise to the
formation of acetoacetate and β-hydroxybutyrate.
Functions in intermediatory metabolism
2. Fatty acid metabolism
• They are also known as ketone bodies are released by the liver into the blood. All cells
with mitochondria can take ketone bodies up from the blood and reconvert them into
acetyl-CoA, which can then be used as fuel in their citric acid cycles.
• Unlike free fatty acids, ketone bodies can cross the blood–brain barrier and are therefore
available as fuel for the cells of the central nervous system, acting as a substitute for
glucose, on which these cells normally survive.
• The occurrence of high levels of ketone bodies in the blood during starvation, a 
low-carbohydrate diet, prolonged heavy exercise, and uncontrolled 
type-1 diabetes mellitus is known as ketosis, and in its extreme form in out-of-control
type-1 diabetes mellitus, as ketoacidosis.
• On the other hand, when the insulin concentration in the blood is high, and that of 
glucagon is low (i.e. after meals), the acetyl-CoA produced by glycolysis condenses as
normal with oxaloacetate to form citrate in the mitochondrion.
• the citrate is removed from the mitochondrion into the cytoplasm then it is cleaved by 
ATP citrate lyase into acetyl-CoA and oxaloacetate.
• This cytosolic acetyl-CoA can then be used to synthesize fatty acids through
carboxylation by acetyl-CoA carboxylase into malonyl CoA, the first committed step in
the synthesis of fatty acids.
• This conversion occurs primarily in the liver, adipose tissue and lactating 
mammary glands.
4. Synthesis of cholesterol
• The cytosolic acetyl-CoA can also condense with acetoacetyl-CoA to form 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) which is used synthesis of cholesterol.
• Cholesterol can be used as is, as a structural component of cellular membranes, or it can
be used to synthesize steroid hormones, bile salts, and vitamin D.
5. Synthesis of Polyphenols
• Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to 
malonyl-CoA, a substrate required for synthesis of flavonoids and related polyketides.
6. Steroid synthesis:
• Acetyl-CoA participates in the mevalonate pathway by partaking in the synthesis of 
hydroxymethyl glutaryl-CoA.
7. Acetylcholine synthesis:
• Acetyl-CoA is also an important component in the biogenic synthesis of the 
neurotransmitter acetylcholine. 
• Choline, in combination with acetyl-CoA, is catalyzed by the enzyme 
choline acetyltransferase to produce acetylcholine and coenzyme A as a byproduct.
8. Others
• Acetyl-CoA is also the source of the acetyl group incorporated into aminoacids which
is used in posttranslational modification acetylation. This acetylation affects 
cell growth, mitosis, and apoptosis.
• Acetyl-CoA serves as an allosteric regulator of pyruvate dehydrogenase kinase (PDK).
It regulates through the ratio of acetyl-CoA versus CoA. Increased concentration of
acetyl-CoA activates PDK.
Reactions involved
Citrate synthase
5. Acetyl coA + oxaloacetate citrate + coenzyme A

Acetyl CoA Carboxylase

6. Acetyl CoA + CO2+ ATP Malonyl CoA + ADP +Pi

Acetyl CoA Thiolase

7. 2 acetyl CoA Acetoacetyl CoA + Coenzyme A

HMG CoA Synthase

8. Acetyl CoA + Acetoacetyl CoA HMG CoA + Coenzyme A

Choline acetyl transferase

9. Acetyl CoA + Choline Acetylcholine + Coenzyme A
 malate synthase
10. Acetyl CoA + glyoxalate malate + Coenzyme A
Importance of shikimic acid
 Introduction
• Commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a
cyclohexanecarboxylic acid.
• It is an important biochemical metabolite in plants and microorganisms.
• Its name comes from the Japanese flower shikimi the Japanese star anise, Illicium
anisatum), from which it was first isolated in 1885 by Johan Fredrik Eykman.
• The shikimate pathway is a seven step metabolic route used by bacteria, fungi, algae,
parasites, and plants for the biosynthesis of aromatic amino acids (phenylalanine,
tyrosine, and tryptophan).
• This pathway is not found in animals; therefore, phenylalanine and tryptophan represent
essential amino acids that must be obtained from the animal's diet. Animals can
synthesize tyrosine from phenylalanine.
Biosynthesis of shikmic acid
• Phosphoenolpyruvate and erythrose-4-phosphate condense to form 3-deoxy-D
-arabinoheptulosonate-7-phosphate (DAHP), in a reaction catalyzed by the enzyme 
DAHP synthase. DAHP is then transformed to 3-dehydroquinate (DHQ), in a reaction
catalyzed by DHQ synthase.

DAHP synthase DHQ synthase

Phosphoenolpyruvate

3-deoxy-D-
arabinoheptulosonate-7- 3-dehydroquinate (DHQ),
phosphate (DAHP),
erythrose-4-phosphate
In Next step, DHQ is dehydrated to 3-dehydroshikimic acid by the enzyme 
3-dehydroquinate dehydratase, which is reduced to shikimic acid by the enzyme 
shikimate dehydrogenase, which uses nicotinamide adenine dinucleotide phosphate (NADPH)
as a cofactor. shikimate
dehydrogenase
3-
dehydroquinate
dehydratase

3-dehydroquinate (DHQ), 3-dehydroshikimic acid

shikimic acid
Importance of Shikmic acid in Biosynthesis of the aromatic amino acids

In Next step, shikimic acid in the presence of shikimate kinase, shikimate to form 
shikimate 3-phosphate . After this Shikimate 3-phosphate is then coupled with phosphoenol
pyruvate to give 5-enolpyruvylshikimate-3-phosphate via the enzyme 
5-enolpyruvylshikimate-3-phosphate (EPSP) synthase.
shikimic acid

5-enolpyruvylshikimate-3-phosphate (EPSP)
shikimate kinase
synthase

Shikimate 3-phosphate 5-enolpyruvylshikimate-3-phosphate

• Then 5-enolpyruvylshikimate-3-phosphate is transformed into chorismate by a 
chorismate synthase.

Chorismate
synthase

5-enolpyruvylshikimate-3-phosphate chorismate
• Prephenic acid is then synthesized by a Claisen rearrangement of chorismate by 
chorismate mutase

chorismate mutase

chorismate Prephenic acid

• Prephenate is oxidatively decarboxylated with retention of the hydroxyl group to give p-
hydroxyphenylpyruvate, which is transaminated using glutamate as the nitrogen source to give tyrosine and 
α-ketoglutarate.
2. Role of Shikimic Acid Pathway:
• Starting Point in The Biosynthesis of Some Phenolics Phenyl alanine and tyrosine are
the precursors used in the biosynthesis of phenylpropanoids.
• The phenylpropanoids are then used to produce the flavonoids, coumarins, tannins and
lignin.
• Gallic acid biosynthesis Gallic acid is formed from 3-dehydroshikimate by the action
of the enzyme shikimate dehydrogenase to produce 3,5-didehydroshikimate. The latter
compound spontaneously rearranges to gallic acid.
• Other compounds •Shikimic acid is a precursor for: indole, indole derivatives and
aromatic amino acid tryptophan and tryptophan derivatives such as the psychedelic
compound dimethyltryptamine.
• many alkaloids and other aromatic metabolites.
3. In the pharmaceutical industry, shikimic acid from the Chinese star anise (Illicium
verum) is used as a base material for production of oseltamivir (Tamiflu).
• Uses: Shikimate can be used to synthesize (6S)-6-Fluoroshikimic acid, an antibiotic
which inhibits the aromatic biosynthetic pathway.
• Glyphosate, the active ingredient in the herbicide Roundup, kills plants by interfering
with the shikimate pathway in plants.