Cysteine conversion from methionine

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.

Cysteine. Cysteine, while not nutritionally essential, is formed from methionine, which is nutritionally essential. Following conversion of methionine to ho-... 

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. 

This interconversion is catalyzed by serine transhydroxymethylase, another PLP enzyme that is homologous to aspartate aminotransferase (Figure 24.11). The bond between the a- and P-carbon atoms of serine is labilized by the formation of a Schiff base between serine and PLP (Section 23.3.3). The side-chain methylene group of serine is then transferred to tetrahydrofolate. The conversion of serine into cysteine requires the substitution of a sulfur atom derived from methionine for the side-chain oxygen atom (Section 24.2.8). 

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 evidence given above for the key role of cystathionine in the transsulfuration reaction to form cystine from methionine would be measurably strengthened by proof of the occurrence of this compound as a product of the metabolism of methionine. In Neurospora cystathionine has been isolated from the culture medium of certain methionineless mutants and shown to be a step in the conversion of cysteine to methio-... 

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 ... 

When administered to subjects of the metabolic disease cystinuria, cysteine, homocysteine and methionine are excreted largely as additional cystine whereas administered cystine, homocystine and glutathione are almost completely oxidised. From these observations it is concluded that cystine can be metabolised without previous reduction to cysteine, and that glutathione can be meta-bobsed without previous hydrolysis, indicating that the metabolic history of an amino acid may depend on whether it is free or combined. Methionine, previous to its conversion into cysteine is demethylated to form homocysteine, which may undergo condensation to homocystine or degradation to simpler products. 

The gradual conversion into MMM results in the release of DMM from depots such as lipid-rich tissues and plasma proteins, and permits its movement through barriers such as the blood-brain and placenta. A cysteine complex of the monomethylated metabolite penetrates the endotheilial cells of the blood-brain barrier by mimicking methionine and using the large neutral amino acid transporter. 

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... 

Sulfite oxidase is a molybdoenzyme which catalyzes the conversion of sulfite derived from cysteine, methionine and related compounds to inorganic sulfate. Sulfite oxidase has been isolated from bovine, chicken, rat, and human liver. It is located in the intermembrane space of mitochondria, and its physiological electron acceptor is mitochondrial cytochrome c. The purified enzymes consist of two identical subunits with a molecular weight range of 55-60 kDa, containing each one atom Mo and one cytochrome b5-type heme. 

Cysteine inhibits cystathionine 3-synthase and, therefore, regulates its own production to adjust for the dietary supply of cysteine. Because cysteine derives its sulfur from the essential amino acid methionine, cysteine becomes essential if the supply of methionine is inadequate for cysteine synthesis. Conversely, an adequate dietary source of cysteine spares methionine that is, it decreases the amount that must be degraded to produce cysteine. 

The conversion of serine to cysteine involves some interesting reactions. The source of the sulfur in animals differs from that in plants and bacteria. In plants and bacteria, serine is acetylated to form O-acetylserine. This reaction is catalyzed by serine acyltransferase, with acetyl-GoA as the acyl donor (Figure 23.13). Conversion of O-acetylserine to cysteine requires production of sulfide by a sulfur donor. The sulfur donor for plants and bacteria is 3 -phospho-5 -adenylyl sulfate. The sulfate group is reduced first to sulfite and then to sulfide (Figure 23.14). The sulfide, in the conjugate acid form HS", displaces the acetyl group of the O-acetylserine to produce cysteine. Animals form cysteine from serine by a different pathway because they do not have the enzymes to carry out the sulfate-to-sulfide conversion that we have just seen. The reaction sequence in animals involves the amino acid methionine. 

Cytochrome c (see 2 and Fig. 2-7) in the mitochondria is part of the chain of electron carrier proteins that ultimately produce ATP from ADP (oxidative phosphorylation). In principle, the heme in cytochrome c is the same as that in hemoglobin. But in detail, the vinyl groups, after conversion to thioethers, are covalently linked to cysteine amino residues of the protein chain [2,5]. The fifth coordination site of iron is occupied again by the imidazole N-atom of a histidine, but the sixth position is now coordinated to the S-atom of a methionine (Figs. 2-7, 2-17). The redox potential of low-spin Fe(III)/Fe(II) with E°= +0.25 V vs. NHE is drastically altered compared to heme. Now this heme iron is much more able to act in the electron-transporting chain by redox cycling. The mechanisms of electron transfer are available in modem textbooks of biochemistry. It is interesting to note that the macromolecular protein chain... 

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). 

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... 

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