BIOSYNTHESIS OF COENZYME A
SUBMITTED TO
DR. KUSUM YADAV
SUBMITTED BY
ANAM NESAR
M.SC BIOTECHNOLOGY
4TH SEMSTER
INTRODUCTION
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme that plays a role in the
synthesis and oxidation of fatty acids, as well as the citric acid cycle's pyruvate
oxidation. Around 4% of biological enzymes use coenzyme A (or a thioester) as
a substrate, according to all genomes sequenced to far. In humans, cysteine,
pantothenate (vitamin B5), and adenosine triphosphate are required for CoA
production (ATP). Coenzyme A is a highly flexible molecule in its acetyl form,
providing metabolic activities in both anabolic and catabolic pathways. To
maintain and support the partition of pyruvate synthesis and breakdown, acetyl-
CoA is used in the post-translational and allosteric regulation of pyruvate
dehydrogenase and carboxylase.
Coenzyme A's structure is as follows: 3′-phosphoadenosine is the first
phosphoadenosine. 2: organophosphate anhydride, diphosphate pantoic acid is
number three. -alanine is the fourth amino acid. Cysteine is number five.
DISCOVERY OF COENZYME A
Fritz Lipmann was the first to identify coenzyme A in 1946, and he was also the
first to name it. Lipmann and other researchers from Harvard Medical School
and Massachusetts General Hospital worked together at the Lister Institute in
London in the early 1950s to determine its structure. Lipmann set out to explore
acetyl transfer in animals, and as a result of his research, he discovered a unique
component that was not present in enzyme extracts but was present in all of the
animals' organs. He was able to isolate and purify the factor from pig liver, and
determined that its action was linked to a choline acetylation coenzyme.
Pantothenic acid was discovered to be a key component of coenzyme A through
collaboration with Beverly Guirard, Nathan Kaplan, and others. The coenzyme
was given the name coenzyme A, which stands for "acetate activation." Fritz
Lipmann was awarded the Nobel Prize in Physiology or Medicine in 1953 for
"discovering coenzyme A and its relevance in intermediate metabolism."
BIOSYNTHESIS
Pantothenate (vitamin B5) is naturally generated from coenzyme A, which can
be found in foods such meat, vegetables, cereal grains, legumes, eggs, and milk.
Pantothenate is an important vitamin that serves a range of roles in humans and
other living beings. Pantothenate can be synthesised de novo in some plants and
microorganisms, including Escherichia coli, and is hence not regarded essential.
Pantothenate is made by these bacteria from the amino acid aspartate and a
metabolite produced during valine biosynthesis.
Coenzyme A is produced in all living organisms in a five-step process that
involves four molecules of ATP, pantothenate, and cysteine (see figure):
The enzyme pantothenate kinase phosphorylates pantothenate (vitamin B5) to
4′-phosphopantothenate. This is the final stage in the biosynthesis of CoA, and
it necessitates the use of ATP.
The enzyme phosphopantothenoylcysteine synthetase adds a cysteine to 4′-
phosphopantothenate to generate 4'-phospho-N-pantothenoylcysteine (PPC).
This phase is performed in conjunction with ATP hydrolysis.
phosphopantothenoylcysteine decarboxylase converts PPC to 4′-
phosphopantetheine.
The enzyme phosphopantetheine adenylyl transferase adenylates 4′-
phosphopantetheine to produce dephospho-CoA.
Finally, the enzyme dephosphocoenzyme A kinase phosphorylates dephospho-
CoA to coenzyme A. This final step necessitates the use of ATP.
Mammalian, other eukaryotic, and prokaryotic enzymes are represented by
abbreviations in parenthesis, accordingly. COASY, a bifunctional enzyme
found in mammals, catalyses steps 4 and 5. Product inhibition controls this
pathwa. Pantothenate Kinase, which typically binds ATP, is competitively
inhibited by CoA. Biosynthesis yields coenzyme A, three ADP, one
monophosphate, and one diphosphate. When intracellular coenzyme A levels
are low and the de novo pathway is blocked, other mechanisms for coenzyme A
synthesis can be used.
Coenzyme A must be obtained from an external source, such as food, in order
to create 4′-phosphopantetheine in these pathways. Coenzyme A is degraded by
ectonucleotide pyrophosphates (ENPP) to 4′-phosphopantetheine, a stable
compound in organisms. Acyl carrier proteins (ACP) are also employed to make
4′-phosphopantetheine (such as ACP synthase and ACP degradation). This route
provides for the replenishment of 4′-phosphopantetheine in the cell as well as
the conversion of 4′-phosphopantetheine to coenzyme A via the enzymes PPAT
and PPCK.
FUNCTION
Synthesis of fatty acids
Because coenzyme A is a thiol in chemical terminology, it can produce
thioesters when it reacts with carboxylic acids, acting as an acyl group carrier. It
helps move fatty acids from the cytoplasm to the mitochondria. Acyl-CoA
refers to a molecule of coenzyme A with an acyl group attached. It's commonly
referred to as 'CoASH' or 'HSCoA' when it's not connected to an acyl group.
This mechanism makes it easier for cells to produce fatty acids, which are
necessary for cell membrane formation.Coenzyme A is also the source of the
phosphopantetheine group, which is attached to proteins such acyl carrier
protein and formyltetrahydrofolate dehydrogenase as a prosthetic group.
Production of energy
Coenzyme A is one of five coenzymes that are required in the citric acid cycle's
reaction mechanism. The citric acid cycle's principal input is acetyl-coenzyme
A, which comes from glycolysis, amino acid metabolism, and fatty acid beta
oxidation. This is the body's main catabolic route, and it's responsible for
breaking down the cell's building blocks like carbohydrates, amino acids, and
lipids.
Regulation
Coenzyme A is employed in the cytosol to synthesise fatty acids when there is
an excess of glucose. The acetyl-CoA carboxylase enzyme, which catalyses the
committed step in fatty acid synthesis, is regulated to carry out this activity.
Epinephrine and glucagon reduce the action of acetyl-CoA carboxylase,
whereas insulin promotes it.
Coenzyme A is generated during cell deprivation and transfers fatty acids from
the cytosol to the mitochondria. Acetyl-CoA is produced here for oxidation and
energy generation. Coenzyme A acts as an allosteric regulator in the citric acid
cycle, stimulating the enzyme pyruvate dehydrogenase.
Protein CoAlation has been discovered to have a crucial role in the control of
the oxidative stress response, according to new research. Protein CoAlation
prevents the irreversible oxidation of the thiol group in cysteine on the surface
of cellular proteins, as well as directly modulating enzymatic activity in
response to oxidative or metabolic stress, in a manner similar to S-
glutathionylation in the cell.
