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 different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

Production There are several different pathways through which propionyl-CoA can be produced:

Propionyl-CoA, a three-carbon structure, is considered to be a minor species of propionic acid. Therefore, odd-number chains of fatty acids are oxidized to yield both propionyl-CoA as well as acetyl-CoA. Propionyl-CoA is later converted into succinyl-CoA through biotin-dependant propionyl-CoA carboxylase (PCC) and b12-dependant methylmalonyl-CoA mutase (MCM), sequentially. Propionyl-CoA is not only produced from the oxidation of odd-chain fatty acids, but also by the oxidation of amino acids including methionine, valine, isoleucine, and threonine. Furthermore, catabolism of amino acids can also be a result of the conversion of propionyl-CoA to methylmalonyl-CoA by propionyl-CoA carboxylase. Cholesterol oxidation, which forms bile acids, also forms propionyl-CoA as a side product. In an experiment performed by Suld et al., when combining liver mitochondria and propionic acid with the addition of coenzyme A, labeled isotopes of psionic acid were degraded. However, following 5β-cholestane-3α,7α,12α,26-tetrol-26,27-C14 incubation, propionyl CoA was able to be rescued along with the formation of bile.

Metabolic fate

The metabolic (catabolic fate) of propionyl-CoA depends on what environment it is being synthesized in. Therefore, propionyl-CoA in an anaerobic environment could have a different fate than that in an aerobic organism. The multiple pathways, either catabolism by propionyl-CoA carboxylase or methylcitrate synthase, also depend on the presence of various genes.

Reaction with propionyl-CoA carboxylase Within the citric acid cycle in humans, propionyl-CoA, which interacts with oxaloacetate to form methylcitrate, can also catalyzed into methylmalonyl-CoA through carboxylation by propionyl-CoA carboxylase (PCC). Methylmalonyl-CoA is later transformed to succinyl-CoA to be further used in the tricarboxylic acid cycle. PCC not only catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA, but also acts on several different acyl-CoAs. Nevertheless, its highest binding affinity is to propionyl-CoA. It was further shown that propionyl-CoA transformation is inhibited by the absence of several TCA markers, such as glutamate. The mechanism is shown by the figure to the left.

Mechanism In mammals, propionyl-CoA is converted to (S)-methylmalonyl-CoA by propionyl-CoA carboxylase, a biotin-dependent enzyme also requiring bicarbonate and ATP. This product is converted to (R)-methylmalonyl-CoA by methylmalonyl-CoA racemase. (R)-Methylmalonyl-CoA is converted to succinyl-CoA, an intermediate in the tricarboxylic acid cycle, by methylmalonyl-CoA mutase, an enzyme requiring

cobalamin to catalyze the carbon-carbon bond migration. The methylmalonyl-CoA mutase mechanism begins with the cleavage of the bond between the 5' CH2- 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 in methylmalonic aciduria, a dangerous disorder that causes a lowering of blood pH.

Methylcitrate cycle

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 the methylcitrate cycle. The initial reaction is beta-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 the citric 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. 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. This mechanism is shown below to the left along with the participating reactants, products, intermediates, and enzymes.

Bacterial metabolism

Mycobacterium tuberculosis metabolism The oxidation of propionyl-CoA to form pyruvate is influenced by its necessity in Mycobacterium tuberculosis. Accumulation of propionyl-CoA can lead to toxic effects. In Mycobacterium tuberculosis, it has been suggested that the metabolism of propionyl-CoA is involved in cell wall biogenesis. A lack of such catabolism would therefore increase the susceptibility of the cell to various toxins, particularly to macrophage antimicrobial mechanisms. Another hypothesis regarding the fate of propionyl-CoA, in M. 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.

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