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Skip to main content Thank you for visiting nature. Subjects Metabolism. Abstract The consensus has been that intracellular coenzyme A CoA is obtained exclusively by de novo biosynthesis via a universal, conserved five-step pathway in the cell cytosol. Access through your institution. Buy or subscribe. Change institution. Rent or Buy article Get time limited or full article access on ReadCube.
References 1 Lipmann, F. Google Scholar 4 Leonardi, R. Acknowledgements The authors thank S. Sibon View author publications. View author publications. Ethics declarations Competing interests The authors declare no competing financial interests.
Supplementary information. The insulating blubber of this sperm whale is composed mainly of fats made from triglycerides, each of which was made by acetyl-CoA. Acetyl-CoA is also used in the synthesis of isoprenoid molecules, esters and amides e. In animals, both sugars carbohydrates and fats can be metabolised to produce energy, and acetyl-CoA is central to keeping the balance between these two.
If the body takes in more sugar or fat than it needs, the excess is stored as fat, as described above. But when the body requires this energy again, the fat is metabolised with the help of acetyl-CoA. The stored triglycerides are cleaved to give 3 fatty acid chains and 1 glycerol molecule in a process called lipolysis. The glycerol is converted to glucose, and gives cells energy. And the 3 fatty acids provide an extra source of energy, as the long chains are cleaved 2-carbons at a time to form acetyl-CoA, which can then be fed into the Citric Acid Cycle.
In cases of starvation, or where the person has a low carbohydrate diet such as the Atkins Diet , this process can occur more readily and extensively. This can produce an unusually large amount of ketones from the breakdown of fatty acids to acetyl groups. In this situation, the person is said to exhibit ketosis , and the ketones are excreted in the breath and urine giving the person's breath a characteristic sweet, fruity smell, that has been likened to the smell of nail varnish remover acetone or sometimes pear drops ethyl ethanoate.
Back to Molecule of the Month page. A The conventional de novo and alternative pathways of CoA biosynthesis are shown. B CoA degradation involves phosphodiesterases, phosphatases and pantetheinases. The biosynthesis and homeostasis of CoA is controlled at different levels: transcription of genes encoding biosynthetic enzymes, regulation of enzymatic activities by a feedback mechanism, signalling pathways, degradation of CoA and interconversion between CoA and its thioester derivatives.
Various extracellular stimuli, such as nutrients, hormones of metabolic homeostasis, intracellular metabolites and stress, were found to regulate the total level of CoA in mammalian cells. It is reduced in to insulin, glucose, pyruvate and fatty acids, whereas glucagon, glucocorticoids and oxidative stress have an opposite effect [ 4 — 8 ]. The expression and activity of the PANK proteins are governed by multiple mechanisms.
The total cellular CoA content is also controlled by degradation, involving phosphodiesterases, phosphatases and pantetheinases Figure 1B [ 15 ]. The degradation of CoA results in the generation of products which are known intermediates in the biosynthetic pathway. Produced pantothenate may re-enter the CoA biosynthetic pathway or be excreted. The estimated CoA levels in mammalian cells and tissues span more than a fold range.
Liver, heart and brown adipose tissue have the highest CoA levels, followed by kidney and brain. The subcellular distribution of CoA in mammalian cells reflects the variety of processes in which it is implicated.
The concentration of CoA in mitochondria and peroxisomes are in the range of 2—5 and 0. CoA is a large and charged molecule, therefore, it must be distributed to subcellular organelles via dedicated transporters.
High-affinity transporters for CoA and dephospho-CoA were identified on mitochondrial and peroxisomal membranes [ 20 , 21 ].
CoA and its thioester derivatives play important roles in numerous biosynthetic and degradative pathways of cellular metabolism, allosteric interactions and the regulation of gene expression. These include synthesis and oxidation of fatty acids, the Krebs cycle, ketogenesis, biosynthesis of cholesterol and acetylcholine, degradation of amino acids, regulation of gene expression and cellular metabolism via protein acetylation and others Figure 2 [ 1 , 22 , 23 ].
Abnormal biosynthesis and homeostasis of CoA and its derivatives are associated with various human pathologies, including diabetes, Reye's syndrome, cancer, vitamin B12 deficiency and cardiac hypertrophy [ 24 — 26 ]. Genetic studies in human and animal models revealed the importance of the CoA biosynthetic pathway for the development and functioning of the nervous system [ 27 , 28 ].
CoA thioester derivatives are implicated in diverse cellular functions, including the Krebs cycle, ketogenesis, biosynthesis of cholesterol and acetylcholine, the degradation of amino acids, the synthesis and oxidation of fatty acids, biosynthesis of neurotransmitters and the regulation of gene expression. Protein CoAlation is a novel, unconventional function of CoA in redox regulation and antioxidant defence.
Although de novo CoA biosynthesis is an evolutionary conserved biochemical process, significant structural and regulatory differences between microbial and human biosynthetic enzymes make the CoA biosynthetic pathway an attractive target for the development of novel antibiotics.
The role of the CoA thiol group in the production and function of various thioester derivatives has been extensively studied since the discovery of this coenzyme in the middle of last century. In contrast, the contribution of the CoA thiol moiety towards redox regulation and antioxidant defence has yet to be established. Mammalian cells contain high levels of low-molecular-weight LMW thiols that provide protection against a variety of reactive oxygen, nitrogen and electrophilic species ROS, RNS and RES generated inside cells by incomplete reduction of molecular oxygen, dysregulation of metabolic processes or produced during the detoxification of xenobiotic and endobiotic compounds.
In contrast, low levels of reactive chemical species can act as second messengers and key regulators in signal transduction and metabolic pathways [ 30 ]. GSH is also the most studied and best characterised thiol that functions to protect cellular macromolecules from oxidative damage and detoxify xenobiotics and toxic endogenous products, such as aldehydes, quinones, epoxides or alkyl hydroperoxides.
Other biologically relevant LMW thiols include cysteine, homocysteine, taurine, lipoic acid and CoA [ 29 ]. The wide variety in structures of LMW thiols allows them to participate in diverse biochemical reactions, and it is not surprising that their cellular functions vary widely.
The redox functions of CoA in mammalian cells under physiological and pathophysiological conditions are not well understood.
To perform a nucleophilic attack, the p K a of the CoA thiol needs to be decreased. The reactivity of CoA in cellular redox processes can be enhanced by complexing with the enzyme s which can reduce the p K a value of its thiol and facilitate covalent modification of cellular targets by CoA, as reported for GSH in complex with glutathione transferases [ 33 ].
The enzyme s possessing this activity has yet to be identified. Eukaryotic CoA disulfide reductase remains to be identified. The CoA-GSH CoASSG mixed disulfide was identified as a renal vasoconstrictor and found to stimulate the proliferation of cultured vascular smooth muscle cells in a dose-dependent manner [ 36 ].
The existence of CoA mixed disulfides with cysteine residues in proteins has been known for many years. They were reported in several biochemical and crystallographic studies, and a number of CoA-modified proteins identified as acetyl CoA acetyltransferase, glutamate dehydrogenase flavodoxin, phenol sulfotransferase and peroxide sensor OhrR organic hydroperoxide resistance repressor [ 39 — 42 ].
However, the extent of covalent protein modification by CoA, its regulation by oxidative and metabolic stress and the proteome-wide identification of CoA-modified proteins in prokaryotes or eukaryotes have not been investigated until recently.
Cysteine is one of the most evolutionarily constrained amino acids and the least commonly used in human proteome [ 43 ]. Despite this rare usage in protein synthesis, cysteine residues serve critical roles in defining protein structure and function by forming inter- and intramolecular disulfide bonds, coordinating metal ions and participating in catalytic reactions. Furthermore, protein cysteines are targets for numerous post-translational modifications PTMs that serve to modulate the activity, regulatory interactions and localisation of diverse proteins.
These include S-acylation, oxidation, S-nitrosation, persulfhydration and S-thiolation [ 44 ]. The diverse functionality of cysteine residues in proteins is due to the high reactivity of its side chain sulfhydryl group, especially in a biologically oxidative environment.
During oxidative stress, the thiol group of cysteine can become progressively oxidised to sulfenic, sulfinic or sulfonic states [ 44 ]. Mitochondrial acyl-CoA concentrations are 10 fold higher than in the cytoplasm.
Six such proteins have been characterized in Arabidopsis that vary in their subcellular distribution, tissue-specificity, stress-responsiveness and ligand selectivity. They have also been studied intensively in oil seed crops. One class of ACBPs is specific for very-long-chain acyl-CoAs, which it transports from the endoplasmic reticulum to and across the plasma membrane for the biosynthesis of surface lipids such as wax and cutin. These proteins are not simply transporters but are also important regulators in the synthesis of various signalling lipids that include phosphatidic acid, sterols, oxylipins, and sphingolipids, and in the responses to abiotic and biotic stress.
Pathological conditions: Impaired metabolism can lead to accumulation of CoA and acyl-CoA within cells and trigger a sequence of reactions that give rise to chronic illness. This is a factor in some neurodegenerative diseases, and for example, ACOT7 in the brain is critical for preventing neuronal lipotoxicity, but can also be a problem in cancer, myopathies, and infectious diseases.
Pantethine, which can be converted in tissues to pantothenic acid and cysteamine, is used pharmacologically for the treatment of hyperlipidemia. Catabolism: At high concentrations, acyl-CoA are non-specific inhibitors of innumerable enzyme systems, and they must be removed from cells in part as their acyl-carnitine derivatives.
In addition, there is a super-family of acyl-CoA thioesterases ACOTs of two main types 12 in total in humans , which are located in most cells and cellular compartments in plants and animals and catalyse the hydrolysis of acyl-CoAs to the free fatty acids and coenzyme A.
In animals, Type I acyl-CoA thioesterases have a molecular mass of approximately 40 kDa, while that of the Type II enzymes is approximately — kDa, with no sequence homology nor common structural features between them. Of these, the best characterized is ACOT8, which is located in peroxisomes in humans, mice and rats, and is believed important for the catabolism of long-chain and branched-chain fatty acids. CoA per se is degraded by intra- and extracellular pathways that involve a sequence of reactions involving dephosphorylations and the removal of the nucleotide moiety.
For example, pantetheinase enzymes in peroxisomes hydrolyse the pantetheine moiety to 4'-phosphopantetheine, eventually releasing pantothenate into the bloodstream, where it is available for cellular uptake and re-synthesis of CoA. The 4-phosphopantetheine moiety, linked via its phosphate group to the hydroxyl group of serine, is the active component in another important molecule in lipid metabolism, Acyl Carrier Protein ACP.
This is a small 8. It is a ubiquitous and highly conserved carrier of acyl groups from active site to active site in polyketide and fatty acid synthases see the web page on synthesis of fatty acids. A defining feature of an ACP is its flexibility in terms of its structure, substrate and enzyme partners. Thus, in animals, the ACPs are tethered covalently to the type I mega-synthase by flexible linkers in the peptide chain, which permit the intermediates to remain in an energy-rich linkage with access to spatially distinct enzyme-active sites in a manner that resembles an assembly line.
However, the final step in fatty acid synthesis with type I synthases is transfer of the fatty acyl group from ACP to CoA. The pool of ACP is regenerated for further fatty acid biosynthesis. ACPs protect their cargo of reactive intermediates in the cytosol by sequestration within a hydrophobic cleft, which protects the thioester linkage from premature hydrolysis and other side reactions.
In contrast, in type II fatty acid synthases in prokaryotes and plants, ACP-intermediates are diffusible discrete proteins. The Arabidopsis genome, for example, encodes eight ACP isoforms, five of which are believed to be located in plastids and three in mitochondria.
These must deliver intermediates to the independent catalytic partners of the synthase in a concerted manner. In the chloroplast, the chain elongation process is terminated by acyl-ACP—dependent acyltransferases, which provide acyl groups for lipid biosynthesis, or by thioesterase reactions, which release a non-esterified fatty acid from the ACP for export to other cellular organelles. ACPs can also be used for production of other important cellular constituents, such as the octanoate moiety of lipoic acid and other biosynthetic products of acyl transfer, including rhamnolipids , for example.
Molecules related structurally to ACP are utilized in non-ribosomal peptide and depsipeptide biosynthesis. A family of thioesterases is responsible for hydrolysis of acyl-ACPs in plants and animals. ACP has an essential function role in shuttling substrates between appropriate enzymes in metabolic pathways. It sequesters fatty acyl moieties differing in chain length in such a manner within the four-helical bundle that partner enzymes can distinguish allosterically between chain lengths via protein-protein interactions.
Acyl-phosphates: It has become apparent that most bacteria, including such important human Gram-positive pathogens as Streptococcus pneumoniae , Bacillus subtilis and Staphylococcus aureus , lack the glycerophosphate acyl transferase enzymes that make use of CoA. Instead, a fatty acyl-phosphate is the reactive acyl donor and can be produced by two routes both from fatty acids synthesised de novo and those of exogenous origin. In the first mechanism, the acyl-phosphate is produced by reaction of acyl-ACP with phosphate catalysed by an acyl-ACP:phosphate acyltransferase designated PlsX in the cell membrane, and the product then requires a specific acyl-transferase, designated PlsY, so that it can be utilized in the first step for the synthesis of phosphatidic acid by acylation of position sn -1 of glycerolphosphate; acyl-ACP is the donor for esterification of position sn -2 via an enzyme designated PlsC.
In these species, PlsX is key regulatory enzyme that synchronizes fatty acid synthesis with that of phospholipids, and interacts with PlsY in the membrane to channel the substrate towards glycerolipid synthesis. Although acyl-phosphates are less stable than thio esters in vitro , this is obviously not a problem in vivo.
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