Propionate, from threonine

The a-ketobutyric acid formed from threonine is decarboxylated to propionic acid, as shown in reaction 5. The latter is further metabolized as discussed under valine below. 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

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. 

This enzyme s role in humans is to assist the detoxification of propionate derived from the degradation of the amino acids methionine, threonine, valine, and isoleucine. Propionyl-CoA is carboxylated to (5 )-methylmalonyl-CoA, which is epimerized to the (i )-isomer. Coenzyme Bi2-dependent methylmalonyl-CoA mutase isomerizes the latter to succinyl-CoA (Fig. 2), which enters the Krebs cycle. Methylmalonyl-CoA mutase was the first coenzyme B -dependent enzyme to be characterized crystallographically (by Philip Evans and Peter Leadlay). A mechanism for the catalytic reaction based on ab initio molecular orbital calculations invoked a partial protonation of the oxygen atom of the substrate thioester carbonyl group that facilitated formation of an oxycyclopropyl intermediate, which connects the substrate-derived and product-related radicals (14). The partial protonation was supposed to be provided by the hydrogen bonding of this carbonyl to His 244, which was inferred from the crystal structure of the protein. The ability of the substrate and product radicals to interconvert even in the absence of the enzyme was demonstrated by model studies (15). 

This reaction is involved in the production of succinyl CoA from valine, isoleucine, threonine, methionine, thymine, and the propionate formed by oxidation of fatty adds with an odd number of carbons. 

Fig. 1.8 Asaccharolytic fermentation produces ammonia and short-chain fatty acids. This group of fermentations by oral bacteria utilizes proteins, which are converted to peptides and amino acids. The free amino acids are then deaminated to ammonia in a reaction that converts nicotinamide adenine dinucleotide (NAD) to NADH. For example, alanine is converted to pyruvate and ammonia. The pyruvate is reduced to lactate, and ammonium lactate is excreted into the environment. Unlike lactate from glucose, ammonium lactate is a neutral salt. The common end products in from plaque are ammonium acetate, ammonium propionate, and ammonium butyrate, ammonium salts of short chain fatty acids. For example, glycine is reduced to acetate and ammonia. Cysteine is reduced to propionate, hydrogen sulfide, and ammonia alanine to propionate, water, and ammonia and aspartate to propionate, carbon dioxide, and ammonia. Threonine is reduced to butyrate, water, and ammonia and glutamate is reduced to butyrate, carbon dioxide, and ammonia. Other amino acids are involved in more complicated metabolic reactions that give rise to these short-chain amino acids, sometimes with succinate, another common end product in plaque.

Propionate is not a quantitatively significant gluconeogenic precursor in humans, but it is a major source of glucose in ruminants. It is derived from the catabolism of isolecucine, valine, methionine, and threonine from jd-oxidation of odd-chain fatty acids and from the degradation of the side chain of cholesterol. Propionate enters gluconeogenesis via the TCA cycle after conversion to succinyl-CoA (Chapter 18). 

JH but, at the same time, the incorporation of acetate, propionate, glucose, alanine, leucine, isoleucine, threonine and fractions furnished by methionine can be demonstrated. Ajami concludes from this that JH is biosynthesised via a fatty acid route, according to Scheme 1.19... 

Extensive studies have been performed to disclose the biosynthetic pathway of microcystin and their lower mass analogs, the nodularins (53,85). One of the major questions was the origin of the Adda residue. The methyl substimtion pattern was indicative of incorporation of either propionate or acetate followed by methylation via S-adenosylmethionine. Although both propionate and methionine were found to be incorporated, the pattern of labelled metabolites was clearly indicative of an acetate-plus-methionine sequence for Cl through C8. The remainder of Adda presumably derives from phenylalanine via phenylacetic acid. The other subunits are for the most part derived from predictable pathways. According to the biosynthetic intermediates isolated the assembly of the linear penta- and octapeptides occurs with the Adda unit as N-terminal residue and Arg as C-terminus. Cyclization apparently represents the last step, since conversion of N-methyl-serine and -threonine to Mdha and Mdhb, respectively, occurs in earlier steps. 

The enzyme threonine dehydratase (EC 4.2.1.16) has been shown to dehydrate both L-threonine 128a and L-allothreonine 129 in to yield (3R)-[3- H,]-a-ketobutyrate 124 (131) (Scheme 40), the configuration of which was proven by conversion to (2R)-[2- H,]propionate and comparison of the ORD with that of an authentic sample. This implies either that the bound substrates 128a and 129 dehydrate with different stereochemistries and protonate from the same side or that they dehydrate in identical fashion and protonate from different sides. Threonine dehydratase has an important role in the biosynthesis of valine, as we shall see in Section VIII. 

The enzyme catalyzing reaction 1 is threonine dehydratase. As described above for serine dehydratase, an enzyme having activity towards both serine and threonine has been found in spinach leaves (Sharma and Mazumder, 1970). Dougall (1970) has also reported a threonine dehydratase in extracts from Paul s Scarlet Rose tissue cultures. The oxidative decarboxylation of the 2-oxobutyrate would lead to propionate (reaction 2) which could then be oxidized via the pathway demonstrated by Giovanelli and Stumpf (1958). 

L-lsoieucine, lie L-a-amino-P-methylvaleric acid, CH3-CH2-CH(CH3)-CH(NH2)-C00H, an aliphatic, neutral amino acid found in proteins. He is found in relatively large amounts in hemoglobin, edestin, casein and serum proteins, and in sugar beet molasses, from which it was first isolated in 1904 by F. Ehrlich. It is an essential dietary amino acid, and is both glu-coplastic (degradation via propionic acid) and keto-plastic (formation of acetate) (see Leucine), The biosynthesis of He starts with oxobutyrate and pyruvate. Oxobutyrate is synthesized by deamination of L-threonine by threonine dehydratase (threonine de-... 

Propionic acid fermentation is not limited to propionibacteria it functions in vertebrates, in many species of arthropods, in some invertebrates imder anaerobic conditions (Halanker and Blomquist, 1989). In eukaryotes the propionic acid fermentation operates in reverse, providing a pathway for the catabolism of propionate formed via p-oxidation of odd-numbered fatty acids, by degradation of branched-chain amino acids (valine, isoleucine) and also produced from the carbon backbones of methionine, threonine, thymine and cholesterol (Rosenberg, 1983). The key reaction of propionic acid fermentation is the transformation of L-methylmalonyl-CoA(b) to succinyl-CoA, which requires coenzyme B12 (AdoCbl). In humans vitamin B deficit provokes a disease called pernicious anemia. 

Of these only the methylmalonyl-CoA mutase (E.C. 5.4.99.2) reaction takes place in mammalian metabolism and forms the link between the metabolism of odd-chain fatty acids, cholesterol, isoleucine, valine, threonine, methionine, and propionic acid on the one hand, and the tricarboxylic acid cycle through succinyl-CoA on the other (Fig. 5). The reaction is of special importance for ruminants in which propionate, arising from cellulose degradation, forms a major source of energy. The enzyme involved is located in the mitochondria and is composed of two nonidentical subunits, one of which binds adenosylcobalamin. A deficiency of adenosylcobalamin or the apoenzyme results in the accumulation of methylmalonic acid, which is secreted by the kidneys and gives rise to methylmalonic aciduria (42). 

Poly-3-hydroxybutyrate-co-3-hydroxyvalerate [P(3HB-co-3HV)] copolymers have a variety of uses as single use, bulk-commodity plastics, in the marine environment and in biomedical applications (2/). Normally, P(3HB-co-3HV) is synthesized in bacteria grown on a mixture of glucose and propionate (22). Although demonstrated in plants. Figure 1C shows a pathway which could potentially be used in bacteria for the conversion of threonine (derived from the TCA cycle) to 3-hydroxyvalerate by threonine deaminase, IlvA, to 2-ketobutyrate, followed by reduction to propionyl-CoA by pyruvate dehydrogenase. BktB then catalyzes the formation of the 3-(7 )-hydroxyvaleryl-CoA substrate which can be polymerized into a P(3HB-co-3HV) copolymer (23). 

Robins et al. (246) demonstrated that L-threonine and L-isoleucine are specific precursors for monocrotalic acid (46), the C -necic acid component of monocrotaline (44), present in several Crotalaria species. Degradation of the monocrotalic acid produced gave results which were consistent with the incorporation of isoleucine into C-1, C-2, C-3, C-6, and C-7 of monocrotalic acid (Scheme 25). The remaining three carbon atoms may be derived from propionate. 

---