 | |
| Names | |
|---|---|
| IUPAC name 3′-O-Phosphonoadenosine 5′-{(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-[(3-oxo-3-{[2-(propanoylsulfanyl)ethyl]amino}propyl)amino]butyl dihydrogen diphosphate} | |
| Systematic IUPAC name O1-{[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]methyl}O3-{(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-[(3-oxo-3-{[2-(propanoylsulfanyl)ethyl]amino}propyl)amino]butyl} dihydrogen diphosphate | |
| Other names Propionyl Coenzyme A; Propanoyl Coenzyme A | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChemSpider |
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| ECHA InfoCard | 100.005.698 |
| MeSH | propionyl-coenzyme+A |
| UNII | |
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| Properties | |
| C24H40N7O17P3S | |
| Molar mass | 823.60 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Propionyl-CoA is acoenzyme A derivative ofpropionic 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.[1] Several different pathways can lead to its production, such as through the catabolism of specificamino acids or theoxidation ofodd-chain fatty acids.[2] It later can be broken down bypropionyl-CoA carboxylase or through the methylcitrate cycle.[3] In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation.[4] Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.[5]
There are several different pathways through which propionyl-CoA can be produced:
Themetabolic (catabolic fate) of propionyl-CoA depends on what environment it is being synthesized in. Therefore, propionyl-CoA in ananaerobic environment could have a different fate than that in anaerobic organism. The multiple pathways, either catabolism by propionyl-CoA carboxylase or methylcitrate synthase, also depend on the presence of various genes.[7]
Within the citric acid cycle in humans, propionyl-CoA, which interacts with oxaloacetate to form methylcitrate, can also catalyzed into methylmalonyl-CoA throughcarboxylation bypropionyl-CoA carboxylase (PCC). Methylmalonyl-CoA is later transformed tosuccinyl-CoA to be further used in thetricarboxylic acid cycle. PCC not only catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA, but also acts on several differentacyl-CoAs. Nevertheless, its highest binding affinity is to propionyl-CoA. It was further shown that propionyl-CoA transformation is inhibited by the absence of severalTCA markers, such asglutamate. The mechanism is shown by the figure to the left.[2]
In mammals, propionyl-CoA is converted to (S)-methylmalonyl-CoA bypropionyl-CoA carboxylase, abiotin-dependent enzyme also requiring bicarbonate andATP.
This product is converted to (R)-methylmalonyl-CoA bymethylmalonyl-CoA racemase.
(R)-Methylmalonyl-CoA is converted tosuccinyl-CoA, an intermediate in thetricarboxylic acid cycle, bymethylmalonyl-CoA mutase, an enzyme requiring
cobalamin to catalyze the carbon-carbon bond migration.
Themethylmalonyl-CoA mutase mechanism begins with the cleavage of the bond between the 5'CH
2- of 5'-deoxyadenosyl and the cobalt, which is in its +3 oxidation state (III), which produces a 5'-deoxyadenosyl radical and cobalamin in the reduced Co(II) oxidation state.
Next, this radical abstracts a hydrogen atom from the methyl group of methylmalonyl-CoA, which generates a methylmalonyl-CoA radical. It is believed that this radical forms a carbon-cobalt bond to the coenzyme, which is then followed by the rearrangement of the substrate's carbon skeleton, thus producing a succinyl-CoA radical. This radical then goes on to abstract a hydrogen from the previously produced 5'-deoxyadenosine, again creating a deoxyadenosyl radical, which attacks the coenzyme to reform the initial complex.
A defect in methylmalonyl-CoA mutase enzyme results inmethylmalonic aciduria, a dangerous disorder that causes a lowering of blood pH.[8]
Propionyl-CoA accumulation can prove toxic to different organisms. Since different cycles have been proposed regarding how propionyl-CoA is transformed into pyruvate, one studied mechanism is themethylcitrate cycle. The initial reaction isbeta-oxidation to form the propionyl-CoA which is further broken down by the cycle. This pathway involves the enzymes both related to the methylcitrate cycle as well as thecitric acid cycle. These all contribute to the overall reaction to detoxify the bacteria from harmful propionyl-CoA. It is also attributed as a resulting pathway due to the catabolism of fatty acids in mycobacteria.[3] In order to proceed, the prpC gene codes for methylcitrate synthase, and if not present, the methylcitrate cycle will not occur. Instead, catabolism proceeds through propionyl-CoA carboxylase.[7] This mechanism is shown below to the left along with the participating reactants, products, intermediates, and enzymes.
The oxidation of propionyl-CoA to form pyruvate is influenced by its necessity inMycobacterium tuberculosis. Accumulation of propionyl-CoA can lead to toxic effects. InMycobacterium tuberculosis, it has been suggested that the metabolism of propionyl-CoA is involved in cell wallbiogenesis. A lack of suchcatabolism would therefore increase the susceptibility of the cell to various toxins, particularly tomacrophageantimicrobial mechanisms. Another hypothesis regarding the fate of propionyl-CoA, inM. tuberculosisis, is that since propionyl-CoA is produced by beta odd chain fatty acid catabolism, the methylcitrate cycle is activated subsequently to negate any potential toxicity, acting as a buffering mechanism.[11]
Propionyl-CoA has can have many adverse and toxic affects on different species, includingbacterium. For example, inhibition ofpyruvate dehydrogenase by an accumulation of propionyl-CoA inRhodobacter sphaeroides can prove deadly. Furthermore, as withE. coli, an influx of propionyl-CoA inMyobacterial species can result in toxicity if not dealt with immediately. This toxicity is caused by a pathway involving the lipids that form thebacterialcell wall. Using esterification of long-chain fatty acids, excess propionyl-CoA can be sequestered and stored in the lipid,triacylglycerol (TAG), leading to regulation of elevated propionyl-CoA levels. Such a process of methyl branching of the fatty acids causes them to act as sinks for accumulating propion[4]
In an investigation performed by Luo et al.,Escherichia coli strains were utilized to examine how the metabolism of propionyl-CoA could potentially lead to the production of3-hydroxypropionic acid (3-HP). It was shown that a mutation in a key gene involved in the pathway,succinate CoA-transferase, led to a significant increase in 3-HP.[7] However, this is still a developing field and information on this topic is limited.[12]
Amino acid metabolism in plants has been deemed a controversial topic, due to the lack of concrete evidence for any particular pathway. However, it has been suggested that enzymes related to the production and use of propionyl-CoA are involved. Associated with this is the metabolism ofisobutyryl-CoA. These two molecules are deemed to be intermediates invaline metabolism. As propionate consists in the form of propionyl-CoA, it was discovered that propionyl-CoA is converted toβ-hydroxypropionate through a peroxisomal enzymaticβ-oxidation pathway. Nevertheless, in the plantArabidopsis, key enzymes in the conversion of valine to propionyl-CoA were not observed. Through different experiments performed by Lucas et al., it has been suggested that in plants, throughperoxisomal enzymes, propionyl-CoA (andisobutyryl-CoA) are involved in the metabolism of many different substrates (currently being evaluated for identity), and not justvaline.[13]
Propionyl-CoA production through thecatabolism offatty acids is also associated withthioesterifcation. In a study concerningAspergillus nidulans, it was found that with the inhibition of a methylcitratesynthase gene,mcsA, of the pathway described above, production of distinctpolyketides was inhibited as well. Therefore, the utilization of propionyl-CoA through the methylcitrate cycle decreases its concentration, while subsequently increasing the concentration of polyketides. A polyketide is a structure commonly found in fungi that is made ofacetyl- andmalonyl-CoAs, providing a product with alternatingcarbonyl groups andmethylene groups. Polyketides and polyketide derivatives are often highly structurally complex, and several are highly toxic. This has led to research on limiting polyketide toxicity to crops in agriculture throughphytopathogenicfungi.[14]
Propionyl-CoA is also a substrate forpost-translational modification of proteins by reacting with lysine residues on proteins, a reaction called proteinpropionylation.[15][16] Due to structural similarities of Acetyl-CoA and Propionyl-CoA, propionylation reaction are thought to use many of the same enzymes used for protein acetylation.[16] Although functional consequences of proteinpropionylation are currently not completely understood, in vitropropionylation of thePropionyl-CoA Synthetase enzyme controls its activity.[17]
Similar to how plant peroxisomal enzymes bind propionyl-CoA and isobutyryl-CoA, Gen5, anacetyltransferase in humans, binds to propionyl-CoA andbutyryl-CoA. These specifically bind to the catalytic domain ofGen5L2. This conserved acetyltransferase is responsible for the regulation of transcription bylysineacetylation of thehistoneN-terminal tails. This function of acetylation has a much higher reaction rate thanpropionylation orbutyrylation. Because of the structure of propionyl-CoA, Gen5 distinguishes between differentacyl-CoA molecules. In fact, it was found that thepropyl group of butyrl-CoA cannot bind due to lack of stereospecificity to the active binding site of Gen5 due to theunsaturatedacyl chains. On the other hand, the third carbon of propionyl-CoA can fit into theactive site of Gen5 with the correct orientation.[18]
In theneonatal developmental stages,propionic acidemia, which is a medical issue defined as the lack of propionyl-CoA carboxylase, can cause impairment, mental disability, and numerous other issues. This is caused by an accumulation of propionyl-CoA because it cannot be converted tomethylmalonyl-CoA. Newborns are tested for elevatedpropionylcarnitine. Further ways of diagnosing this disease include urine samples. Medications used help to reverse and prevent recurring symptoms include using supplements to decreasepropionate production.[5]
