Homocysteine conversion from methionine

Other compounds involved in one-carbon metabolism are derived from degradation products of choline. Choline, an essential component of certain phospholipids, is oxidized to form betaine aldehyde, which is further oxidized to betaine (trimethylglycine). In the liver, betaine can donate a methyl group to homocysteine to form methionine and dimethyl glycine. This allows the liver to have two routes for homocysteine conversion to methionine. Under conditions in which SAM accumulates, glycine can be methylated to form sarcosine (N-methyl glycine). This route is used when methionine levels are high and excess methionine needs to be metabolized. 

Figure 28-9. Conversion of homocysteine and serine to homoserine and cysteine. The sulfur of cysteine derives from methionine and the carbon skeleton from serine.

The route from methionine to homocysteine is described in more detail in Figure 18-18 the conversion of homocysteine to a-ketobutyrate in Figure 22-14 the conversion of propionyl-CoA to succinyl-CoA in Figure 17-11. 

Cysteine is formed in plants and in bacteria from sulfide and serine after the latter has been acetylated by transfer of an acetyl group from acetyl-CoA (Fig. 24-25, step f). This standard PLP-dependent (3 replacement (Chapter 14) is catalyzed by cysteine synthase (O-acetylserine sulfhydrase).446 447 A similar enzyme is used by some cells to introduce sulfide ion directly into homocysteine, via either O-succinyl homoserine or O-acetyl homoserine (Fig. 24-13). In E. coli cysteine can be converted to methionine, as outlined in Eq. lb-22 and as indicated on the right side of Fig. 24-13 by the green arrows. In animals the converse process, the conversion of methionine to cysteine (gray arrows in Fig. 24-13, also Fig. 24-16), is important. Animals are unable to incorporate sulfide directly into cysteine, and this amino acid must be either provided in the diet or formed from dietary methionine. The latter process is limited, and cysteine is an essential dietary constituent for infants. The formation of cysteine from methionine occurs via the same transsulfuration pathway as in methionine synthesis in autotrophic organisms. However, the latter use cystathionine y-synthase and P-lyase while cysteine synthesis in animals uses cystathionine P-synthase and y-lyase. 

There may be an added benefit for adults. N 5-methyltetrahydrofolate is required for the conversion of homocysteine to methionine (Figure 33-1 Figure 33-2, reaction 1). Impaired synthesis of N 5-methyltetrahydrofolate results in elevated serum concentrations of homocysteine. Data from several sources suggest a positive correlation between elevated serum homocysteine and occlusive vascular diseases such as ischemic heart disease and stroke. Clinical data suggest that the... 

Although numerous enzymatic reactions requiring vitamin B12 have been described, and 10 reactions for adenosylcobalamin alone have been identified, only three pathways in man have so far been recognized, one of which has only recently been identified (PI). Two of these require the vitamin in the adenosyl form and the other in the methyl form. These cobalamin coenzymes are formed by a complex reaction sequence which results in the formation of a covalent carbon-cobalt bond between the cobalt nucleus of the vitamin and the methyl or 5 -deoxy-5 -adenosyl ligand, with resulting coenzyme specificity. Adenosylcobalamin is required in the conversion of methylmalonate to succinate (Fig. 2), while methylcobalamin is required by a B12-dependent methionine synthetase that enables the methyl group to be transferred from 5-methyltetrahydrofolate to homocysteine to form methionine (Fig. 3). 

A. Pernicious anemia occurs when the stomach does not produce adequate intrinsic factor for absorption of vitamin B12, which is required for the conversion of methylmalonyl CoA to succinyl CoA and homocysteine to methionine. A vitamin B12 deficiency results in the excretion of methylmalonic acid and an increased dietary requirement for methionine. The methyl group transferred from vitamin B12 to homocysteine to form methionine comes from 5 -methyl tetrahydrofolate, which accumulates in a vitamin B12 deficiency, causing a decrease in folate levels and symptoms of folate deficiency, including increased levels of FIGLU and decreased purine biosynthesis. 

Cysteine synthesis is a primary component of sulfur metabolism. The carbon skeleton of cysteine is derived from serine (Figure 14.7). In animals the sulfhydryl group is transferred from methionine by way of the intermediate molecule homocysteine. (Plants and some bacteria obtain the sulfhydryl group by reduction of SOj to S2 as H2S. A few organisms use H2S directly from the environment.) Both enzymes involved in the conversion of serine to cysteine (cystathionine synthase and y-cystathionase) require pyridoxal phosphate. 

The remethylation cycle allows the conversion of homocysteine back to methionine by two pathways. The first and major pathway is catalyzed by the enzyme, methionine synthase, and links the folate cycle with homocysteine metabolism. Methionine synthase requires the cofactor, meth-ylcobalamin. The second pathway utilizes the enzyme, betaine-homocysteine methyltransfer-ase [8]. This pathway remethylates homocysteine using a methyl group derived from betaine, formed via oxidation of choline, and is presumably responsible for up to 50 % of homocysteine remethylation [10]. Both methionine and homocysteine play important roles in protein synthesis, folding, and function. 

Caffeine synthase, the majority of SAH hydrolase activity, and parts of the adenine-salvage pathway are localized to chloroplasts. In coffee SAM synthase is confined to the cytosol and SAM synthase genes fi-om tobacco and parsley lack a transit peptide. However, SAM synthase from tea is a chloroplastic enzyme, encoded by a nuclear gene (Koshiishi et al. 2001). The proposed model for the subcellular localization of caffeine biosynthesis begins with the production of homocysteine and its conversion to methionine in the chloroplasts. Methionine is then converted to SAM in the cytosol and transported back into the chloroplast to serve as the methyl donor in caffeine biosynthesis. Purine alkaloids are stored in vacuoles where they are thought to form complexes with chlorogenic acids (Mosli-Waldhauser and Baumann 1996). 

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. 

In animal metabolism, derivatives of cobalamine are mainly involved in rearrangement reactions. For example, they act as coenzymes in the conversion of methylmalonyl-CoA to succinyl-CoA (see p. 166), and in the formation of methionine from homocysteine (see p. 418). In prokaryotes, cobalamine derivatives also play a part in the reduction of ribonucleotides. 

Difluorocysteine, like 3,3-difluoroserine, is unstable. However, a protected derivative has been described. Conversely, 3,3-difluoro-L-homocysteine and 3, 3-difluoro-L-methionine are much more stable. They are prepared from difluoro-homoserine. This latter is prepared through a multistep synthesis starting from isoascorbic acid (Figure 5.24). ... 

Two essential enzymatic reactions in humans require vitamin B12 (Figure 33-2). In one, methylcobalamin serves as an intermediate in the transfer of a methyl group from /V5-methyltetrahydrofolate to homocysteine, forming methionine (Figure 33-2A Figure 33-3, section 1). Without vitamin B12, conversion of the major dietary and storage folate, N5-... 

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

The second reaction requiring vitamin B12 catalyzes the conversion of homocysteine to methionine and is catalyzed by methionine synthase. This reaction results in the transfer of the methyl group from N -methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate and methylcobalamin during the process of the conversion. 

Vitamin B12 (2 a) participates in the aqueous-phase biosynthesis of purine and pyrimidine bases, the reduction of ribonucleotide triphosphates, the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A, the biosynthesis of methionine from homocysteine, and the formation of myelin sheath in the nervous systems. 

Animals - Mammals require methionine (Met) in their diets (i.e.. Met is an essential amino acid) and Cys can be made from Met, as shown in Figure 2L7. Thus, Cys is nonessential as long as sufficient Met is present in the diet. Mammals make Met from homocysteine, as shown in the reaction here. Figure 2L8 shows the pathway from Met to Cys and reveals that it is quite similar to the reverse of the methionine synthesis pathway in bacteria shown in Figure 21.5. Plants and bacteria also use the pathway shown in Figure 2L8 so they can synthesize one from the other, depending on their immediate needs. Methionine can also be made by conversion of choline, as shown here. 

METABOLIC FUNCTIONS The active coenzymes methylcobalamin and 5-deoxyadeno-sylcobalamin are essential for cell growth and replication. Methylcobalamin is required for the conversion of homocysteine to methionine and its derivative, SAM. In addition, when concentrations of vitamin Bj are inadequate, folate becomes trapped as methyltetrahydrofolate, causing a functional deficiency of other required intracellular forms of folic acid (see Figures 53-6 and 53-7 and discussion above). The hematological abnormalities in vitamin Bj -deficient patients result from this process. 5-Deoxyadenosylcobalamin is required for the isomerization of L-methylmalonyl CoA to succinyl CoA (Figure 53-6). 

An enzyme preparation from jack bean meal will transfer a methyl group from S-methylmethionine 167 to homocysteine 148 to yield 2 mol of methionine 149. Use of the doubly labeled compounds 166a and 166b, separated by the method of Cornforth et al. (160), conversion to the (Cs, Sj)- and (Cj, Ss)-isomers of methylmethionine 167a and 167b, and incubation with the enzyme, allowed mass spectrometry to be used to show that the pro-R methyl group of S-methylmethionine is transferred to L-homocysteine 148 (161,162), as shown in Scheme 52. 

So, the biosynthesis of methionine (Met, M), the first of the essential amino adds to be considered (Scheme 12.13), begins by the conversion of aspartate (Asp, D) to aspartate semialdehyde in the same way glutamate (Glu, E) was converted to glutamate semialdehyde (vide supra. Scheme 12.6). Phosphorylation on the terminal carboxylate of aspartate (Asp, D) by ATP in the presence of aspartate kinase (EC 2.7.2.4) and subsequent reduction of the aspart-4 yl phosphate by NADPH in the presence of aspartate semialdehyde dehydrogenase (EC 1.2.1.11) yields the aspartate semialdehyde. The aspartate semialdehyde is further reduced to homoserine (homoserine oxoreductase, EC 1.1.1.3) and the latter is succinylated by succinyl-CoA with the liberation of coenzyme A (CoA-SH) in the presence of homoserine O-succinyl-transferase (EC 2.3.1.46). Then, reaction with cysteine (Cys, C) in the presence of cystathionine y-synthase (EC 2.5.1.48) produces cystathionine and succinate. In the presence of the pyridoxal phosphate protein cystathionine P-lyase (EC 4.4.1.8), both ammonia and pyruvate are lost from cystathionine and homocysteine is produced. Finally, methylation on sulfur to generate methionine (Met, M) occurs by the donation of the methyl from 5-methyltetrahydrofolate in the presence of methonine synthase (EC 2.1.1.13). 

Fig. 29.1 The biosynthetic pathways of caffeine from xanthosine. The major pathway that consists of four steps is shown with solid arrows. Conversion of 7-methylxanthosine to 7-methylxanthine is catalyzed by nucleosidase activity involved in 7-methylxanthosme synthase or a specific Af-methyl nncleosidase. Minor pathways, shown with dotted arrows, are theoretically possible. They may occur because of the broad substrate specificity of caffeine synthase or other Ai-methyltransferases. Enzymes 7mXS 7-methylxanthosine synthase, CS caffeine synthase, TS theobromine synthase, SAM 5-adenosyl-L-methionine, SAH S-adenosyl-L-homocysteine...

A cobalt-containing vitamin which is required for normal haemopoiesis. It participates as a cofactor in certain enzymic reactions, including the synthesis of methionine from homocysteine, the conversion of methyl malonyl CoA to suc-cinyl CoA, and the methylation of RNA. Its role as a cofactor in the synthesis of nucleic acids is closely liked to that of folate. 

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