Methionine carbon catabolism

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. 

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-... 

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

Answer The catabolism of the carbon skeletons of valine, isoleucine, and methionine is impaired because of the absence of a functional methylmalonyl-CoA mutase. This enzyme requires coenzyme B12 as a cofactor, and a deficiency of this vitamin leads to elevated methylmalonic acid levels (methylmalonic acidemia). The symptoms and effects of this deficiency are severe (see Table 18-2 and Box 18-2). 

The carbon skeleton of methionine is converted to a-ketobutyrate (Figure 20.17), which is catabolized to propionyl-CoA and then to succinate. The sulfur atom is transferred to serine in the cystathionase reaction to yield cysteine. Cysteine is nonessential, because it can be derived from serine and methionine. 

Preliminary results99 indicated that 11-demethyltomaymycin (118) had a similar genesis to anthramycin (116) from tryptophan and tyrosine, and these results have now been published in full.100 Tryptophan has been shown to provide ring A, presumably by catabolism through anthranilic acid. The results99,100 are summarized in Scheme 12. It is to be noted that methionine provides only the aromatic O-methyl group [in anthramycin there is an extra carbon present in the unit related to (119) which derives from methionine see above]. Further evidence from incorporation of labelled tyrosine indicates that the C7 unit (119) derives from seven tyrosine carbon atoms. The incorporation of L-[l-14C,2,3-3H2]tyrosine (tritium distribution H-2, 50% H-3-pro-S, 41.5% H-3-pro-R, 8.5%) with loss of half the tritium label was interpreted reasonably as involving loss only of the C-2... 

FIGURE a.27 Pathway for methionine cataboLsm and cysteine synthesis. Methionine is the source of the sulfur atom of cysteine. Serine is the source of the carbon skeleton of serine. In methionine catabolism, the carbon skeleton of methionine is converted to propionyl-CoA, which eventually enters the Krebs cycle at the point of succinyl-CoA. BCAA dehydrogenase catalyzes the oxidation of a ketobutyrate to propionyXloA-... 

The concept of sparing of one nutrient by another was introduced earlier, where it was demonstrated that dietary carbohydrate can spare protein. Similarly, cysteine can spare methionine and tyrosine can spare phenylalanine. A certain proportion of dietary methionine is converted to cysteine. Mediionine normally supplies part of the body s needs for cysteine. With cysteine-free diets, methionine can supply all of the body s needs for cysteine. The methionine catabolic pathway that leads to cysteine production is shown in Figure 8.27. Only the sulfur atom of methionine appears in the molecule of cysteine serine supplies the carbon skeleton of cysteine. a-Ketobutyrate is a byproduct of the pathway. a-Ketobutyrate is further degraded to propionyl-CoA by BCKA dehydrogenase or pyruvate dehydrogenase. Propionyl-CoA is then converted to succinyl-CoA, an intermediate of the Krebs cycle. 

What common feature is shared by the catabolism of fatty acids having an odd number of carbon atoms and the catabolism of the amino acids isoleucine, methionine, and valine ... 

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. 

Homoserine also has been detected in filtrates of liver preparations incubated with methionine. Cantoni provisionally identified homoserine as a product of the acid hydrolysis of active methionine (S-adeno-sylmethionine). Beyond homoserine, the postulated reactions 2 and 3 are still more speculative. It might be presumed that homoserine is oxidized to aspartic acid, in analogy to the observations on the catabolism of lysine, in which the analogous a-amino adipic acid is an intermediate. If aspartic acid is formed, the subsequent reaction sequence is readily apparent. Evidence favorable to the proposed reaction pathway is the finding of Marshall and Friedberg, of the occurrence of a small amount of fumaric acid, labeled in the methine carbons, from the livers of mice injected with DL-methionine-2-C. ... 

Trimble KC, Molloy AM, Scott JM, Weir DG. The effect of ethanol on one-carbon metabolism increased methionine catabolism and lipotrope methyl-group wastage. 

In summary, the biochemical function of folate coenzymes is to transfer and use these one-carbon units in a variety of essential reactions (Figure 2), including de novo purine biosynthesis (formylation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide), pyrimidine nucleotide biosynthesis (methylation of deoxyuridylic acid to thy-midylic acid), amino-acid interconversions (the interconversion of serine to glycine, catabolism of histidine to glutamic acid, and conversion of homocysteine to methionine (which also requires vitamin B12)), and the generation and use of formate. 

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