Coenzyme A (CoA, SHCoA, CoASH) is a
coenzyme
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
, notable for its role in the
synthesis and
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s, and the oxidation of
pyruvate in the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
. All
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
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,
pantothenate
Pantothenic acid, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, ...
(vitamin B
5), and
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...
(ATP).
In
its acetyl form, coenzyme A is a highly versatile molecule, serving metabolic functions in both the
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking ...
and
catabolic pathways. Acetyl-CoA is utilised in the
post-translational regulation
Post-translational regulation refers to the control of the levels of active protein.
There are several forms.
It is performed either by means of reversible events (posttranslational modifications, such as phosphorylation or sequestration) or b ...
and
allosteric regulation of
pyruvate dehydrogenase
Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.
Pyruvate dehydrogenase is u ...
and
carboxylase to maintain and support the partition of
pyruvate synthesis and degradation.
Discovery of structure
Coenzyme A was identified by
Fritz Lipmann
Fritz Albert Lipmann (; June 12, 1899 – July 24, 1986) was a German-American biochemist and a co-discoverer in 1945 of coenzyme A. For this, together with other research on coenzyme A, he was awarded the Nobel Prize in Physiology or Medicine in ...
in 1946, who also later gave it its name. Its structure was determined during the early 1950s at the
Lister Institute
The Lister Institute of Preventive Medicine, informally known as the Lister Institute, was established as a research institute (the British Institute of Preventive Medicine) in 1891, with bacteriologist Marc Armand Ruffer as its first director, u ...
, London, together by Lipmann and other workers at
Harvard Medical School
Harvard Medical School (HMS) is the graduate medical school of Harvard University and is located in the Longwood Medical Area of Boston, Massachusetts. Founded in 1782, HMS is one of the oldest medical schools in the United States and is consi ...
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.
Work with
Beverly Guirard
Beverly Marie Guirard was a microbiologist who worked on the biochemistry of microbial growth, especially with respect to vitamin B6. She is also known for her work defining the components of coenzyme A which was a part of the research that led to ...
,
Nathan Kaplan, and others determined that pantothenic acid was a central component of coenzyme A. The coenzyme was named coenzyme A to stand for "activation of acetate". In 1953,
Fritz Lipmann
Fritz Albert Lipmann (; June 12, 1899 – July 24, 1986) was a German-American biochemist and a co-discoverer in 1945 of coenzyme A. For this, together with other research on coenzyme A, he was awarded the Nobel Prize in Physiology or Medicine in ...
won the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism".
Biosynthesis
Coenzyme A is naturally synthesized from
pantothenate
Pantothenic acid, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, ...
(vitamin B
5), 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
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
'', 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
(see figure):
#
Pantothenate
Pantothenic acid, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, ...
(vitamin B
5) 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
The enzyme phosphopantothenoylcysteine decarboxylase () catalyzes the chemical reaction
:N- R)-4'-phosphopantothenoylL-cysteine \rightleftharpoons pantotheine 4'-phosphate + CO2
This enzyme belongs to the family of lyases, to be specific the car ...
(PPC-DC; CoaC)
# 4′-phosphopantetheine is adenylated (or more properly,
AMPylated) to form dephospho-CoA by the enzyme
phosphopantetheine adenylyl transferase (COASY; PPAT; CoaD)
# Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme
dephosphocoenzyme A kinase (COASY, DPCK; CoaE). This final step requires ATP.
Enzyme nomenclature abbreviations in parentheses represent mammalian, other eukaryotic, and prokaryotic enzymes respectively. In mammals steps 4 and 5 are catalyzed by a bifunctional enzyme called
COASY
Bifunctional coenzyme A synthase is an enzyme that in mammals is encoded by the ''COASY'' gene that catalyses the synthesis of coenzyme A from 4'-phosphopantetheine.
Function
COASY is an enzyme that catalyzes the last two steps in the synthesis ...
.
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.
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 pathway allows for 4′-phosphopantetheine to be replenished in the cell and allows for the conversion to coenzyme A through enzymes, PPAT and PPCK.
Commercial production
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.
Function
Fatty acid synthesis
Since coenzyme A is, in chemical terms, a
thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
, it can react with
carboxylic acids to form
thioesters, thus functioning as an
acyl
In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
group carrier. It assists in transferring
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s from the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
to
mitochondria. 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
Phosphopantetheine, also known as 4'-phosphopantetheine, is a prosthetic group of several acyl carrier proteins including the acyl carrier proteins (ACP) of fatty acid synthases, ACPs of polyketide synthases, the peptidyl carrier proteins (PCP), ...
group that is added as a
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
to proteins such as
acyl carrier protein
The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...
and
formyltetrahydrofolate dehydrogenase.
Energy production
Coenzyme A is one of five crucial coenzymes that are necessary in the reaction mechanism of the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
. 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
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or m ...
s,
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s, and
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
s.
Regulation
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 and
glucagon 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
Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.
Pyruvate dehydrogenase is u ...
.
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 organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl g ...
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
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...
or
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
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
Dithiothreitol (DTT) is the common name for a small-molecule redox reagent also known as Cleland's reagent, after W. Wallace Cleland. DTT's formula is C4H10O2S2 and the chemical structure of one of its enantiomers in its reduced form is shown o ...
or
2-mercaptoethanol
2-Mercaptoethanol (also β-mercaptoethanol, BME, 2BME, 2-ME or β-met) is the chemical compound with the formula HOCH2CH2SH. ME or βME, as it is commonly abbreviated, is used to reduce disulfide bonds and can act as a biological antioxidant by s ...
.
Non-exhaustive list of coenzyme A-activated acyl groups
*
Acetyl-CoA
*
fatty acyl-CoA (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
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
esterification
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
)
**
Propionyl-CoA
Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain (without the coenzyme, it is a 3 carbon structure) and its production and metabolic fate depend on which organism it is present in. Several diffe ...
**
Butyryl-CoA
Butyryl-coenzyme A (or butyryl-CoA) is the coenzyme A-containing derivative of butyric acid. It is acted upon by butyryl-CoA dehydrogenase and an intermediary compound of ABE fermentation.
Butyryl-CoA is a precursor to and converted from crotonyl- ...
**
Myristoyl-CoA
**
Crotonyl-CoA
*
Acetoacetyl-CoA
*
Coumaroyl-CoA
Coumaroyl-coenzyme A is the thioester of coenzyme-A and coumaric acid. Coumaroyl-coenzyme A is a central intermediate in the biosynthesis of myriad natural products found in plants. These products include lignols (precursors to lignin and ligno ...
(used in
flavonoid and
stilbenoid
Stilbenoids are hydroxylated derivatives of stilbene. They have a C6–C2–C6 structure. In biochemical terms, they belong to the family of phenylpropanoids and share most of their biosynthesis pathway with chalcones. Most stilbenoids are prod ...
biosynthesis)
*
Benzoyl-CoA
Benzoyl-CoA is a molecule implied in the activity of the different enzymes 4-hydroxybenzoyl-CoA reductase, benzoyl-CoA reductase, benzoyl-CoA 3-monooxygenase, benzoate-CoA ligase, 2alpha-hydroxytaxane 2-O-benzoyltransferase, anthranilate N-be ...
*
Phenylacetyl-CoA
* Acyl derived from
dicarboxylic acids
**
Malonyl-CoA (important in chain elongation in
fatty acid biosynthesis and
polyketide
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
biosynthesis)
**
Succinyl-CoA
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
(used in
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
biosynthesis)
**
Hydroxymethylglutaryl-CoA (used in
isoprenoid biosynthesis)
**
Pimelyl-CoA (used in
biotin biosynthesis)
References
Bibliography
*
{{Enzyme cofactors
Coenzymes
Metabolism
Thiols