Serine methionine, transsulfuration

The transsulfuration pathway (Fig. 40-4) entails the transfer of the sulfur atom of methionine to serine to yield cysteine. The first step is activation of methionine, which reacts with ATP to form S-adenosylmethionine (Fig. 40-4 reaction 1). This compound is a key methyl donor and plays a prominent role in the synthesis of several... 

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. 

In the biosynthesis of cysteine, the sulfur comes from methionine by transsulfuration, and the carbon skeleton and the amino group are provided by serine (Figure 17-16). Cysteine regulates its own formation by functioning as an allosteric inhibitor of cystathionine y-lyase, a-Ketobutyrate is metabolized to succinyl-CoA by way of propionyl-CoA and methylmalonyl-CoA. 

Cystathionine is the first intermediate metabolite in transsulfuration, formed from HCY and serine by cystathionine-fi-synthase, a redox-sensitive, heme-containing enzyme (Banerjee et al., 2003), whose activity is lower in males vs. females (Vitvitsky et al., 2007). The higher levels of cystathionine in human brain reflect a strong diversion of HCY to transsulfuration (i.e., low methionine synthase activity and high cystathionine-f)-synthase activity), in conjunction with a decreased conversion of cystathionine to cysteine. As illustrated in Fig. 1, this indicates impaired transsulfuration in human brain. Low transsulfuration activity relative to other tissues has been described in rat or mouse brain (Finkelstein, 1990), although a... 

As noted above, cystathionine formation is the other major fate of methionine. The condensation of homocysteine with serine is catalyzed by the vitamin requiring enzyme cystathionine P-synthase. In the last step of the transsulfuration sequence, cystathionine undergoes cleavage to cysteine and a-ketobutyrate in yet another enzyme reaction that requires pyridoxal phosphate. 

Synthesis of Sulfur Amino Acids. Of the many oxidation states of sulfur, only sulfite has been shown to be utilized by cell-free systems in the net synthesis of compounds with carbon-sulfur bonds, although mutant studies have indicated that more reduced forms can be incorporated. The formation of cysteinesulfinic acid from sulfite has been demonstrated in extracts of acetone-dried rabbit kidney it is possible that this reaction participates in the principal mechanism of sulfur incorporation. In many organisms that require preformed sulfur amino acids, cysteine may be formed from methionine. Only the sulfur of methionine is transferred to cysteine the carbon skeleton of cysteine is derived exclusively from serine. Transsulfuration appears to require the formation of homocysteine from methionine. Homocysteine and serine condense to form a thioether, cystathionine (V). Pyridoxal phosphate has been... 

The transsulfuration reaction by which cysteine is formed depends upon the condensation of homocysteine, the demethylated product of methionine, with serine to form the intermediate cystathionine (see p. 152). 

Besides the suggestion that serine is involved in the transsulfuration reaction, this theory has taken on new interest in view of Cantoni s evidence for the formation of the analogous S-adenosylmethionine as the activated form of methionine in the transmethylation reaction. 

The transsulfuration reaction from methionine to cysteine presupposes the formation of the compound cystathionine from methionine (or homocysteine) and serine as an intermediate. 

The metabolic relationship of methionine and cysteine was clarified by the now classic in vivo studies of du Vigneaud and his co-workers 99). The work of Tarver and Schmidt 34), who showed earlier the transfer of methionine sulfur to cysteine, was confirmed and extended by these workers. The in vivo conversion of methionine to cysteine, a process often referred to as transsulfuration proceeds through an intermediate cystathionine, formed by a loss of H2O from cysteine and serine. The biologically active forms of cystathionine are ... 

The major developmental change which takes place In both brain and liver is the postnatal activation of the transsulfuration pathway of methionine metabolism. The net result of this pathway is the transfer of the sulfur atom from homocysteine to the carbon skeleton of serine to form cysteine. This conversion is mediated by two enzymes cystathionine synthase (L-serine hydro-lyase adding homocysteine, EC 4.2.1.22) which catalyzes the 3-activation of serine and the addition of homocysteine to form the thio-ether, cystathionine cystathionase (EC 4.4.1.1) which catalyzes the y-cleavage of cystathionine to form cysteine (Fig. 1). Both of these enzymes catalyze reactions other than those described above although their importance vivo is uncertain (Tallan et al., 1974). In mature mammals, activities both of cystathionine synthase and of cystathionase are present in brain and liver, although cystathionase activity in... 

The action of cysteine desulfhydrase is inhibited by hydrogen cyanide. Binkley and du Vigneaud (15) have observed that the production of hydrogen sulfide, which appears in the comrse of the reaction due either to homocysteine desulfhydrase or to cysteine desulfhydrase, is arrested in the presence of hydrogen cyanide, without however diminishing appreciably the yield of cysteine. This observation shows that the mechanism in question does not come into play in the experiments of Binkley and du Vigneaud, but the re.sults do not show that this mechanism plays no role in the animal. The theory of Toennies (121) assumes the existence of a direct transsulfuration between methionine and serine. This theory is based on the ability of methionine sulfur to form sulfonium derivatives... 

---