Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme
, notable for its role in the synthesis
of fatty acid
s, and the oxidation of pyruvate
in the citric acid cycle
. All genome
s sequenced to date encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it (or a thioester
) as a substrate. In humans, CoA biosynthesis requires cysteine
), and adenosine triphosphate
In its acetyl form
, coenzyme A is a highly versatile molecule, serving metabolic functions in both the anabolic
pathways. Acetyl-CoA is utilised in the post-translational regulation
and allosteric regulation
of pyruvate dehydrogenase
to maintain and support the partition of pyruvate
synthesis and degradation.
Discovery of structure
Coenzyme A was identified by Fritz Lipmann
in 1946, who also later gave it its name. Its structure was determined during the early 1950s at the Lister Institute
, London, together by Lipmann and other workers at Harvard Medical School
and Massachusetts General Hospital
Lipmann initially intended to study acetyl transfer in animals, and from these experiments he noticed a unique factor that was not present in enzyme extracts but was evident in all organs of the animals. He was able to isolate and purify the factor from pig liver and discovered that its function was related to a coenzyme that was active in choline acetylation.
The coenzyme was named coenzyme A to stand for "activation of acetate". In 1953, Fritz Lipmann
won the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism".
Coenzyme A is naturally synthesized from pantothenate
), which is found in food such as meat, vegetables, cereal grains, legumes, eggs, and milk. In humans and most living organisms, pantothenate is an essential vitamin that has a variety of functions. In some plants and bacteria, including ''Escherichia coli
'', pantothenate can be synthesised ''de novo'' and is therefore not considered essential. These bacteria synthesize pantothenate from the amino acid aspartate and a metabolite in valine biosynthesis.
In all living organisms, coenzyme A is synthesized in a five-step process that requires four molecules of ATP, pantothenate and cysteine
) is phosphorylated to 4′-phosphopantothenate by the enzyme pantothenate kinase
(PanK; CoaA; CoaX). This is the committed step in CoA biosynthesis and requires ATP.
# A cysteine
is added to 4′-phosphopantothenate by the enzyme phosphopantothenoylcysteine synthetase
(PPCS; CoaB) to form 4'-phospho-N-pantothenoylcysteine (PPC). This step is coupled with ATP hydrolysis.
# PPC is decarboxylated to 4′-phosphopantetheine
by phosphopantothenoylcysteine decarboxylase
# 4′-Phosphopantetheine is adenylated (or more properly, AMPylated
) to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase
# Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase
(DPCK; CoaE). This final step requires ATP.
Enzyme nomenclature abbreviations in parentheses represent eukaryotic and prokaryotic enzymes respectively. This pathway is regulated by product inhibition. CoA is a competitive inhibitor for Pantothenate Kinase, which normally binds ATP.
Coenzyme A, three ADP, one monophosphate, and one diphosphate are harvested from biosynthesis.
New research shows that coenzyme A can be synthesized through alternate routes when intracellular coenzyme A level are reduced and the ''de novo'' pathway is impaired. In these pathways, coenzyme A needs to be provided from an external source, such as food, in order to produce 4′-phosphopantetheine
. Ectonucleotide pyrophosphates (ENPP) degrade coenzyme A to 4′-phosphopantetheine, a stable molecule in organisms. Acyl carrier proteins (ACP)
(such as ACP synthase and ACP degradation) are also used to produce 4′-phosphopantetheine. This pathways allows for 4′-phosphopantetheine to be replenished in the cell and allows for the conversion to coenzyme A through enzymes, PPAT and PPCK.
Coenzyme A is produced commercially via extraction from yeast, however this is an inefficient process (yields approximately 25 mg/kg) resulting in an expensive product. Various ways of producing CoA synthetically, or semi-synthetically have been investigated although none are currently operating at an industrial scale.
Fatty acid synthesis
Since coenzyme A is, in chemical terms, a thiol
, it can react with carboxylic acid
s to form thioester
s, thus functioning as an acyl
group carrier. It assists in transferring fatty acid
s from the cytoplasm
. A molecule of coenzyme A carrying an acyl group
is also referred to as ''acyl-CoA
''. When it is not attached to an acyl group, it is usually referred to as 'CoASH' or 'HSCoA'. This process facilitates the production of fatty acids in cells, which are essential in cell membrane structure.
Coenzyme A is also the source of the phosphopantetheine
group that is added as a prosthetic group
to proteins such as acyl carrier protein
and formyltetrahydrofolate dehydrogenase
Coenzyme A is one of five crucial coenzymes that are necessary in the reaction mechanism of the citric acid cycle
. Its acetyl-coenzyme A form is the primary input in the citric acid cycle and is obtained from glycolysis
, amino acid metabolism, and fatty acid beta oxidation. This process is the body's primary catabolic pathway
and is essential in breaking down the building blocks of the cell such as carbohydrate
s, amino acid
s, and lipid
When there is excess glucose, coenzyme A is used in the cytosol for synthesis of fatty acids.
This process is implemented by regulation of acetyl-CoA carboxylase
, which catalyzes the committed step in fatty acid synthesis. Insulin
stimulates acetyl-CoA carboxylase, while epinephrine
inhibit its activity.
During cell starvation, coenzyme A is synthesized and transports fatty acids in the cytosol to the mitochondria. Here, acetyl-CoA is generated for oxidation and energy production.
In the citric acid cycle, coenzyme A works as an allosteric regulator in the stimulation of the enzyme pyruvate dehydrogenase
New research has found that protein CoAlation plays an important role in regulation of the oxidative stress response. Protein CoAlation plays a similar role to ''S''-glutathionylation
in the cell, and prevents the irreversible oxidation of the thiol group
in cysteine on the surface of cellular proteins, while also directly regulating enzymatic activity in response to oxidative or metabolic stress.
Use in biological research
Coenzyme A is available from various chemical suppliers as the free acid and lithium
salts. The free acid of coenzyme A is detectably unstable, with around 5% degradation observed after 6 months when stored at −20 °C,
and near complete degradation after 1 month at 37 °C. The lithium and sodium salts of CoA are more stable, with negligible degradation noted over several months at various temperatures.
Aqueous solutions of coenzyme A are unstable above pH 8, with 31% of activity lost after 24 hours at 25 °C and pH 8. CoA stock solutions are relatively stable when frozen at pH 2–6. The major route of CoA activity loss is likely the air oxidation of CoA to CoA disulfides. CoA mixed disulfides, such as CoA-''S''–''S''-glutathione, are commonly noted contaminants in commercial preparations of CoA.
Free CoA can be regenerated from CoA disulfide and mixed CoA disulfides with reducing agents such as dithiothreitol
Non-exhaustive list of coenzyme A-activated acyl groups
(activated form of all fatty acids; only the CoA esters are substrates for important reactions such as mono-, di-, and triacylglycerol synthesis, carnitine palmitoyl transferase
, and cholesterol esterification
(used in flavonoid
* Acyl derived from dicarboxylic acid
(important in chain elongation in fatty acid biosynthesis
(used in heme
(used in isoprenoid
(used in biotin