Propionate metabolism pathways

Bramer CO, A Steinbuchel (2001) The methylcitrate acid pathway in Ralstonia eutropha new genes identified involved in propionate metabolism. Microbiology (UK) 147 2203-2214. 

Several mutant strains of R. eutropha that were made to possess defective competing metabolic pathways with the PHA biosynthetic pathway were developed for the enhanced PHA production. The isocitrate dehydrogenase leaky mutant of R. eutropha accumulated P(3HB) more favorably at a lower car-bon/nitrogen molar ratio and at a lower carbon concentration than the parent strain [82]. In batch culture, the final cell and P(3HB) concentrations, and P(3HB) yield on glucose were slightly increased. Also, in the P(3HB-co-3HV) biosynthesis, the molar fraction of 3HV and the 3HV yield on propionic acid increased due to the enhanced conversion of propionic acid to 3-hydroxyvaleryl-CoA rather than to acetyl-CoA and C02 in this mutant. Another mutant R. eu-... 

Fig. 9. Pathway duplication the methyl citrate cycle and the glyoxylate shunt. A pathway for acetate metabolism in E. coli that uses the glyoxylate shunt is depicted on the right. Part of the methyl citrate cycle, a pathway for propionate metabolism, is depicted on the left. The pathways are analogous furthermore, three of the four steps are catalyzed by homologous enzymes. PrpE (propionyl-CoA synthase) is homologous to AcsA (acetyl-CoA synthase). PrpC (2-methyl-citrate synthase) is homologous to GltA (citrate synthase). PrpB (2-methyl-isocitrate lyase) is homologous to AceA (isocitrate lyase). The third step in the methyl citrate cycle has been suggested to be catalyzed by PrpD the second half of the reaction (the hydration) can be catalyzed by aconitase.

Valine, methionine, isoleucine, and threonine are all metabolized through the propionic acid pathway (also used for odd-carbon fatty acids). Defidency of either enzyme results in neonatal ketoacidosis from failure to metabolize ketoacids produced from these four amino adds. The defidendes may be distinguished based on whether meth)dmalonic adduria is present. A diet low in protein or a semisynthetic diet with low amounts of valine, methionine, isoleudne, and threonine is used to treat both deficiencies. 

Figure 13.7 Metabolic pathway for production of propionic acid by propi-onibacteria.

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

Insects utilize propionate and methylmalonate in the biosynthesis of ethyl branched juvenile hormones and methyl branched cuticular hydrocarbons. The sources of propionate and methylmalonate in some insects appear to differ from those in mammals. Succinate is the precursor of propionate and methylmalonate in a termite, whereas valine and probably other amino acids are the sources of propionate and methylmalonate in several other species. An unusual pathway for propionate metabolism has been shown to occur in insects and it may be related to the absence or low levels of vitamin B found in many species. Propionate is converted directly to acetate with carbon 1 of propionate lost as C02> carbon 2 of propionate becoming the methyl carbon of acetate and carbon 3 of propionate becoming the carboxyl carbon of acetate. This pathway suggested the possibility that 2-fluoropropionate might be selectively metabolized in insects to the toxic 2-fluoro-acetate. However, preliminary data indicate that 2-fluoropropionate is not toxic to the housefly or the American cockroach. 

Insects have an unusual pathway for catabolizing propionate which may be related to the absence or low levels of vitamin found in many species. The propionate to acetate pathway is present in all insects which have been studied, including the termite, which has high levels of vitamin B1 . The presence of this unusual metabolic pathway for propionate metabolism offered the potential for selectivity in developing insect control... 

T. Haller, T. Buckel, J. Reteyand, and J. A. Gerit, Discovering new enzymes and metabolic pathways conversion of succinate to propionate by Escherichia coli, Biochemistry, 39 (2000) 4622-4629. 

MCM plays an essential role in propionate metabolism. Propionate and propionyl-CoA are intermediates in the catabolism of leucine and isoleucine and are further metabolized by carboxylation of propionyl-CoA to methylmalonyl-CoA. Isomerization to succinyl-CoA feeds the carbon chain into the tricarboxylic acid pathway of oxidative metabolism. For this reason, MCM is an important enzyme in bacterial and mammalian metabolism. It is one of the two vitamin Bj2-dependent enzymes known to be important in human metabolism. 

The substances in this group that have been evaluated at this meeting and at the fifty-third and sixty-first meetings are predicted to be metabolized by a variety of metabolic pathways. Because of the diverse structures, there are few common metabolites. Examples are 3-(methylthio)propionic acid (from Nos 476 and 468) and thioacetic acid (from Nos 482, 483, 485 and 491). The combined intakes of substances with a common metabolite were below the relevant threshold of toxicological concern (TTC) value. 

The incorporation of 3HV into the copolymer increases proportionally with the concentration of sodium valerate or sodium propionate added to the culture medium (Ishihara et al. 1996 Shang et al. 2004 Abdelhad et al. 2009). With higher concentration of precursors (3.36 and 4.32 g/L), more residual oil was present in the culture medium, indicating that the jatropha oil was less utilized. The 3HV monomer composition in P(3HB-co-3HV) produced from sodium valerate addition was higher (3-41 mol%) compared to that produced using sodium propionate (2-27 mol%) (Lee et al. 2008). The biosynthesis of P(3HB-co-3HV) from sodium valerate is more effective because the metabolic pathway is more exclusive for the biosynthesis of 3HV monomer. Sodium valerate can be converted via /3-oxidation cycle into 3-hydroxyvaleryl-CoA intermediate to be incorporated directly into P(3HB-co-3HV) without catabolism (Doi et al. 1988b). A 3HV composition as high as 90 mol% had been achieved from valeric acid in some studies (Mitomo et al. 1999 Khanna and Srivastava 2007). 

BaUhausen D, et al. Evidence for catabolic pathway of propionate metabolism in CNS expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain. Neuroscience. 2009 164(2) 578-87. 

The metabolic pathway for propionic acid use in mammals involves the carboxylation of propionyl CoA in the presence of a specific carboxylase and ATP. The products of the reaction are methylmalonyl CoA and ADP. The ultimate product of propionate metabolism is succinate, which is oxidized via the Krebs cycle. These reactions all occur in the mitochondria. The ability of the mitochondria of biotin-deficient animals to use propionic acid is reduced. This metabolic defect of the deficient mitochondria cannot be corrected by adding biotin in vitro, but the rate of propionic acid use by mitochondria is restored to normal if the deficient animals are fed a normal diet containing biotin. 

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