Amino acid metabolism methionine

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. 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Crystals from selenium-methionine- and/ or selenium-cysteine-labeled proteins can be studied by multi-wavelength anomalous dispersion (MAD) phasing techniques that can facilitate the solution of an X-ray crystal structure from a single crystal form [11]. However, if in vivo expression systems are used to prepare selenium-labeled proteins, amino acid metabolism and the toxicity of Se-methionine can result in low protein yields and low incorporation rates. 

The biological cofactor S-adenosyl methionine can be converted metabolically into 5 -thiomethyladenosine, which is recycled via opening of the ribose ring to the amino acid L-methionine, as shown in Figure 38. An unusual transformation in this pathway is the oxidative cleavage of aci-reductone to 2-keto-4-... 

L-Homoserine is found in many tissues as a intermediate in amino acid metabolism, including threonine, isoleucine, and methionine. Catabolism of aspartate to homoserine is shown here. The biosynthetic pathway from homoserine to methionine is shown in Figure 21.6. 

See also Citric Acid Cycle Intermediates in Amino Acid Metabolism, Metabolism of Valine, Leucine, Isoleucine, and Lysine, Aspartate, Lysine, Homoserine, Methionine... 

In vitamin B22 deficiency methyltetrahydrofolate cannot donate its methyl group to homocysteine to regenerate methionine. Because the synthesis of methyltetrahydrofolate is irreversible (text, p. 675), the cell s tetrahydrofolate ultimately will be converted into this form. No formyl or methylene tetrahydrofolate will be left for nucleotide synthesis. Pernicious anemia illustrates the intimate connection between amino acid metabolism and nucleotide metabolism. The metabolism of fatty acids that have odd numbers of carbons also will be affected because methylmalonyl-CoA mutase requires vitamin B22 for the production of succinyl-CoA. A further connection is that methylmalonyl-CoA mutase also is involved in the degradation of valine and isoleucine. 

Amino acid metabolism A artate aminotransferase Alanine aminotransferase Cysteine aminotransferase Tyrosine aminotransferase Leucine aminotransferase Alanine-ketoacid aminotransfoase Ornithine-ketoacid aminotransferase A artate carbamoyl transferase Methionine adenosyl transferase Glutamate decarboxylase Glutamate dehydrogenase Serine hydroxymethyltransferase Aminoacyl-sRNA synthetases... 

Several laboratories have been concerned with the effect of ascorbic acid deficiency on amino acid metabolism. Two main aspects have been investigated (1) a rather unspecific effect on the amino acid content in muscle and in blood and (2) a more specific action of vitamin C on the hydroxylation of some amino acids or intermediates in amino acid biosynthesis. Vitamin C deficiency alters the ratio of the various amino acid concentrations in muscle and blood. In muscle, while glutamic acid, leucine, valine, and methionine levels increase, glutamine and aspartic acid concentrations decrease. In blood of scorbutic guinea pigs, the concentrations of most of the amino acids decrease, while phenylalanine, leucine, and histidine levels rise. There is no definite explanation for these changes they indicate only that ascorbic acid is directly or indirectly involved with amino acid metabolism. 

The sulfur amino acids are methionine, homocyst(e)ine, cystathionine, cyst(e)ine, and taurine. Defects in several of the enzymatic steps of their metabolism are known some, but not all, result in human disease. The re-methylation of homocysteine to methionine is closely dependent on folate and cobalamin cofactors, and relevant defects of their metabolism are therefore included in this chapter. Cystinuria and cystinosis, defects of renal tubular and lysosomal transport of cystine, respectively, are described in Chap. 13. 

Fig. 10.1. Defects of transmethylation (methioninehomocysteine), transsulfuration (methionine sulfate), and remethylation (homocysteine - methionine) enzymes of sulfur amino acid metabolism 10.1, methionine adenosyltransferase 10.2, cystathionine ) -synthase 10.3, y-cystathionase 10.4, sulfite oxidase 10.5, molybdenum cofactor 10.6, methylenetetrahydrofolate reductase 10.7 and 10.8, methionine synthase.

The origin of the majority of sulfur-containing aroma compounds formed by microorganisms is sulfate, which is initially incorporated into the sulfur amino acids (L-methionine and L-cysteine) and the peptide, glutathione [112]. These sulfur-containing precursors are metabolized to a variety of aroma compounds of sensory significance. Spinnler et al. [112] have provided a good discussion of this process. 

Moderate vitamin B deficiency results in a number of abnormalities of amino acid metabolism, and especially of tryptophan (section 11.9.5.1) and methionine (section 11.9.5.2). In experimental animals, a moderate degree of deficiency leads to increased sensitivity of target tissues to steroid hormone action. This may be important in the development of hormone-dependent cancer of the breast, uterus and prostate, and may therefore affect the prognosis. Vitamin B supplementation may be a useful adjunct to other therapy in these common cancers certainly, there is evidence that poor vitamin Bg nutritional status is associated with a poor prognosis in women with breast cancer. 

In vivo deuterium ( H) MRS has been used to characterize amino acid metabolism, body iron content, brain and kidney metabolism and body fat utilization rates in rodents. These studies rely on the use of deuterium labelling or the existence of natural-abundance deuterium in water or lipids. For example, deuterium-labelled methionine was used to confirm the dominant contribution of the glycine/ sarcosine shuttle to the metabolism of excess methionine, while deuterium-labelled glucose was used to show that systemic glucose level influences brain... 

Although some 80% of the total body pool of vitamin Bg is associated with muscle glycogen phos-phorylase, this pool turns over relatively slowly. The major metabolic role of the remaining 20% of total body vitamin Bg, which turns over considerably more rapidly, is in amino acid metabolism. Therefore, a priori, it seems likely that protein intake will affect vitamin Bg requirements. People maintained on (experimental) vitamin Bg-deficient diets develop abnormalities of tryptophan and methionine metabolism faster, and their blood vitamin Bg falls more rapidly, when their protein intake is high. Similarly, dming repletion of deficient subjects, tryptophan and methionine metabolism and blood vitamin Bg are normalized faster at low than at high levels of protein intake. 

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. 

Two amino acids—cysteine and tyrosine—can be synthesized in the body, but only from essential amino acid ptecutsots (cysteine from methionine and tyrosine from phenylalanine). The dietary intakes of cysteine and tytosine thus affect the requirements for methionine and phenylalanine. The remaining 11 amino acids in proteins are considered to be nonessential or dispensable, since they can be synthesized as long as there is enough total protein in the diet—ie, if one of these amino acids is omitted from the diet, nitrogen balance can stiU be maintained. Howevet, only three amino acids—alanine, aspartate, and glutamate—can be considered to be truly dispensable they ate synthesized from common metabolic intetmediates (pyruvate, ox-... 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

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