Propionyl CoA

Glncose-6-phosphatase Biotin (biocytin) CO, Propionyl-CoA carboxylase... 

Oxidation of Odd-Carbon Fatty Acids Yields Propionyl-CoA... 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

FIGURE 24.26 Branched-chain fatty acids are oxidized by o -oxidation, as shown for phytanic acid. The product of the phytanic acid oxidase, pristanic acid, is a suitable substrate for normal /3-oxidation. Isobutyryl-CoA and propionyl-CoA can both be converted to suc-cinyl-CoA, which can enter the TCA cycle. 

Most fatty acids have an even number of carbon atoms, so none are left over after /3-oxidation. Those fatty acids with an odd number of carbon atoms yield the three-carbon propionyl CoA in the final j3-oxidation. Propionyl CoA is then converted to succinate by a multistep radical pathway, and succinate enters the citric acid cycle (Section 29.7). Note that the three-carbon propionyl group should properly be called propnnoyl, but biochemists generally use the non-systematic name. 

Biotin is involved in carboxylation and decarboxylation reactions. It is covalently bound to its enzyme. In the carboxylase reaction, C02 is first attached to biotin at the ureido nitrogen, opposite the side chain in an ATP-dependent reaction. The activated C02 is then transferred from carboxybiotin to the substrate. The four enzymes of the intermediary metabolism requiring biotin as a prosthetic group are pyruvate carboxylase (pyruvate oxaloacetate), propionyl-CoA-carboxylase (propionyl-CoA methylmalonyl-CoA), 3-methylcroto-nyl-CoA-carboxylase (metabolism of leucine), and actyl-CoA-carboxylase (acetyl-CoA malonyl-CoA) [1]. 

The acetyl-CoA used as a primer forms carbon atoms 15 and 16 of palmitate. The addition of all the subsequent C2 units is via malonyl-CoA. Propionyl-CoA acts as primer for the synthesis of long-chain fatty... 

Fatty acids with an odd number of carbon atoms are oxidized by the pathway of P-oxidation, producing acetyl-CoA, until a three-carbon (propionyl-CoA) residue remains. This compound is converted to succinyl-CoA, a constiment of the citric acid cycle (Figure 19-2). Hence, the propionyl residue from an odd-chain frtty acid is the only part of a frtty acid that is glucogenic. 

Methionine. Methionine reacts with ATP forming 5-adenosylmethionine, active methionine (Figure 30-17). Subsequent reactions form propionyl-CoA (Figure 30-18) and ultimately succinyl-CoA (see Figure 19-2). 

Methylmalonyl CoA mutase, leucine aminomutase, and methionine synthase (Figure 45-14) are vitamin Bj2-dependent enzymes. Methylmalonyl CoA is formed as an intermediate in the catabolism of valine and by the carboxylation of propionyl CoA arising in the catabolism of isoleucine, cholesterol, and, rarely, fatty acids with an odd number of carbon atoms—or directly from propionate, a major product of microbial fer-... 

Carboxylation of propionyl-CoA is accomplished by propionyl-CoA carboxylase (biotin, which is the carboxyl group carrier, serves as a coenzyme for this enzyme) the presence of ATP is also required. The methylmalonyl-CoA formed is converted by methylmalonyl-CoA mutase (whose coenzyme, deoxyadenosylcobalamin, is a derivative of vitamin B]2) to succinyl-CoA the latter enters the Krebs cycle. 

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

Figure 13.8 De novo synthesis of 2-methyl hutanoyl CoA and 2-methyl propionyl CoA...

The following examples, found in R. eutropha, illustrate the formation of copolymers (cf. [37]). With propionic acid as an additional carbon source, the 3-ketothiolase catalyzes the condensation of the propionyl-CoA unit with acetyl-CoA to form 3-ketovaleryl-CoA, which is reduced to 3-hydroxyvalerate moieties and polymerized by the synthase [27]. 

In Rhodococcus ruber and Nocardia corallina the polymers composed of 3-hydroxybutyryl and 3-hydroxyvaleryl residues are synthesized from sugars by methyl-malonyl-CoA. Succinyl-CoA is decarboxylated via methyl-malonyl-CoA to propionyl-CoA as the precursor of 3-hydroxyvaleryl-CoA [40]. 

Fig. 1. Modification of plant metabolic pathways for the synthesis of poly(3HB) and poly(3HB-co-3HV). The pathways created or enhanced by the expression of transgenes are highlighted in bold, while endogenous plant pathways are in plain letters. The various transgenes expressed in plants are indicated in italics. The ilvA gene encodes a threonine deaminase from E. coli. The phaARe, phaBRe, and phaCRe genes encode a 3-ketothiolase, an aceto-acetyl-CoA reductase, and a PHA synthase from R. eutropha, respectively. The btkBRe gene encodes a second 3-ketothiolase isolated from R. eutropha which shows high affinity for both propionyl-CoA and acetyl-CoA [40]. PDC refers to the endogenous plant pyruvate dehydrogenase complex...

Production of poly(3HB-co-3HV) co-polymer in plants has recently been demonstrated by the PHA group of Monsanto [27], which acquired the PHA business of Zeneca in 1996. In the commercial production of poly(3HB-co-3HV) from R. eutropha, propionate is added to the growth media in order to create an intracellular pool of propionyl-CoA which can be condensed to acetyl-CoA to form 3-ketovaleryl-CoA. The 3-ketovaleryl-CoA is then reduced by the aceto-acetyl-CoA reductase to give 3-hydroxyvaleryl-CoA, which is co-polymerized with 3-hydroxybutyryl-CoA to synthesize poly(3HB-co-3HV) (Fig. 1). For the synthesis of poly(3HB-co-3HV) in plants, it was thus necessary to create an endogenous pool of propionyl-CoA which could be used by the PHA pathway. 

In the synthesis of propionyl-CoA, the PDC competes with the enzyme of the isoleucine biosynthetic pathway for 2-ketobutyrate (Fig. 3). Since the PDC has a... 

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