Cystathionine, cysteine from

Cyclopentenones. from 1.4-diketones. 886-887 Cyclopropane, angle strain in, 115 bent bonds in. 115 from alkenes. 227-229 molecular model of, 111. 115 strain energy of, 114 torsional strain in, 115 Cystathionine, cysteine from. 1177 Cysteine, biosynthesis of, 1177 disulfide bridges from, 1029 structure and properties of, 1018 Cytosine, electrostatic potential map of, 1104... 

Figure 9-5. Pathway for formation of cysteine from methionine. Only the enzymes involved in known diseases of this pathway are shown. Cystathionase is deficient in cysthioninuria, which leads to accumulation of cystathionine without producing frank symptoms. Cystathionine p-synthase deficiency causes homocystinuria.

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

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. 

Homocysteine—A homolog of cysteine, produced by the demethy-lation of methionine, and an intermediate in the bios5mthesis of 1-cysteine from 1-methionine via 1-cystathionine. Elevated levels of homocysteine have been associated with certain forms of heart disease. 

Methionine. Methionine degradation begins with the formation of S-adeno-sylmethionine, which is followed by a demethylation reaction, as described (Figure 14.16). S-Adenosylhomocysteine, the product of the latter reaction, is hydrolyzed to adenosine and homocysteine. Homocysteine then combines with serine to yield cystathionine. Cysteine, a-ketobutyrate, and NH4 result from... 

In the genetic disease cystathioninuria, the enzyme cystathionase is defective or missing. In this case, cystathionine accumulates and is excreted in the urine. Thus, almost all of the equivalent of methionine intake is put out as cystathionine. If cystathionase is missing, an individual cannot make cysteine from methionine or homocysteine. 

C HjNOjS mol wt 135.19. C 35.53%, H 6.71%, N 10,36%. O 23.67%, S 23.72%. HSCH,CHjCH(NH,)COOH. A sulfur containing amino acid, produced by the demethylation of methionine and an intermediate in the biosynthesis of cysteine from methionine. Originally obtained from the liver of mammals. Has also been obtained from cystathionine Binkley, Methods EnzymoL 2, 314 (1955). D-Homocysteine may be prepd from 5-benzyl -D-homocysteine, while L-homocysteine is best obtained from L-homocystrre du... 

Cystathionine (made by cystathionine synthase from homocysteine and serine) plays a central role both in the biosynthesis of methionine in plants and bacteria and in the biosynthesis of cysteine in animals. In humans, deficiency of cystathionine synthase leads to a condition called homocystinuria, in which homocysteine overaccumulates. The condition results in severe mental retardation and dislocation of the lens of the eye. 

Tkanssulfuration exch ge of sulfur between l-homocysteine and L-cysteine, with L-cystathionine as an intermediate (Fig.). Strictly speaking, T. is not a group transfer reaction, because the sulfur bond formed in the synthesis of cystathionine is different from that broken in the formation of L-cysteine. T. operates in the biosynthesis of L-cysteine from L-me-thionine, and in the biosynthesis of L-methionine. The methionine precursor, L-homocysteine, is formed by T. as follows ... 

L-Methionine originates from L-homoserine, a product of L-aspartic acid metabolism (D 16). Key intermediates are 0-phospho-L-homoserine (plants) and 0-acyl-L-homoserine (microorganisms). Cystathionine is formed with L-cysteine as sulfur donor. It may be degraded to L-homocysteine, which, however, may also directly be formed with the participation of sulfide, a reaction resembling the formation of L-cysteine from 0-acetyl-L-serine (D 11). 5-Methyltetrahydrofolic acid acts as donor of the L-methionine methyl group (C 3.2). 

Binkley and Okeson purified the enzyme system that cleaves cystathionine and found that neither phosphate nor ATP was required for activity, thus correcting the previous report that ATP was required. In addition to splitting cystathionine, this enzyme preparation also produced H2S from cysteine. The authors suggest that their enzyme may be identical with cysteine desulfhydrase. Binkley also reported that he had been able to synthesize cystathionine enzymatically from homocysteine and serine by a fractionated liver preparation which had been freed from the cystathionine cleavage enzyme, serine dehydrase and homoserine deaminase. The activity of the enzyme synthesizing cystathionine was either inhibited or unaffected by ATP, DPN, AMP, and various metal ions. 

These results are consistent with the hypothesis that the sulfur atom of DCS is derived from cysteine and carbon atoms 1 and 2 are derived from serine. Biosynthesis of DCS would then follow the well known [8]serine palmityol CoA pathway with introduction of the sulfur atom into sphingosine or ceramide by a cystathionine-type reaction with cysteine followed by oxidation of the SH group to a sulfonic acid group The role of cysteic acid is not clear, since it cannot participate in a cystathionine-type reaction, but it may be a more effective donor of sulfur than sulfate for synthesis of cysteine from serine. 

The amino acid cysteine, C3H7NO2S, is biosynthesized from a substance called cystathionine by a multistep pathway. 

Cysteine is synthesized by two consecutive reactions in which homocysteine combines with serine, forming cystathionine, which, in turn, is hydrolyzed to a-ketobutyrate and cysteine (see Figure 20.8). Homocysteine is derived from methionine as described on p. 262. Because methionine is an essential amino acid, cysteine synthesis can be sustained only if the dietary intake of methionine is adequate. 

In some organisms sulfur incorporation involves homocysteine as an intermediate. In such cases cysteine formation occurs by a transsulfuration reaction, with the intermediate formation of L,L-cystathionine (fig. 21.86). Cystathionine is formed in a simple condensation reaction from serine and homocysteine by cystathionine-jS synthase. 

Our findings in this study are in harmony with the concept that L-cystathionine is an intermediate in the formation of cystine from methionine in man. Direct evidence for the existence of cystathionine in man was provided by the demonstration by Tallan, Moore, and Stein (13) of the occurrence of L-cystathionine in extracts of human brain. Moreover, cases of human cystathioninuria have been reported by Harris, Penrose, and Thomas (9) and by Frimpter, Haymovitz, and Horwith (8). The latter authors have also stated that an increased renal clearance of cystathionine is not observed in cystinuria. It is of considerable interest, however, that the mixed disulfide of L-cysteine and L-homo-... 

A /3,y-elimination of succinylhomoserine to a-ketobutyrate is also catalyzed by cystathionine-y-synthase from Salmonella in the absence of L-cysteine. 

---