Cysteine synthesis

F Albericio, E Nicolas, J Rizo, M Ruiz-Gayo, E Pedroso, E Giralt. Convenient syntheses of fluorenylmethyl-based side chain derivatives of glutamic, aspartic, lysine and cysteine. Synthesis 119, 1990. 

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. 

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. 

As already noted the serine family includes three amino acids Serine, glycine, and cysteine (see fig. 21.1). We focus on cysteine synthesis, which funnels sulfur into the biochemical world and supplies the cysteine needed for biosynthesis. 

When cucurbit cells are fed O-acetylserine or its metabolic precursors the rate of hydrogen sulfide emission in response to sulfate declines, and the incorporation of labeled sulfur from 35S-sulfate into cysteine increases (18). Inhibition of the synthesis of the O-acetylserine precursor acetyl coenzyme A by 3-fluoropyruvate (22) enhances hydrogen sulfide emission, but inhibits cysteine synthesis (1 ). These observations indicate that the availability of O-acetylserine is the rate limiting factor in cysteine synthesis. Hydrogen sulfide may be emitted to the extent the amount of sulfate reduced exceeds the synthesis of O-acetylserine. Therefore, direct release of sulfide from carrier-bound sulfide appears to be responsible for the emission of hydrogen sulfide in response to sulfate (Figure 1, pathway 1). 

Neuwald, A.F., Krishnan, B.R., Brikun, I., Kulakauskas, S., Suziedelis, K., Tomcsanyi, T., Leyh, T.S., and Berg, D.E., 1992, CysQ, a gene needed for cysteine synthesis in Escherichia coli K-12 only during aerobic growth. J. Bacteriol. 174 415—425. 

J. Vina, A. Gimenz, I. Puertes, E. Gasco and J. Vina, Impairment of Cysteine Synthesis From Methionine in Rats Exposed to Surgical Stress, British J Nutrition 68 (1992) 421-429. 

FIGURE a.27 Pathway for methionine cataboLsm and cysteine synthesis. Methionine is the source of the sulfur atom of cysteine. Serine is the source of the carbon skeleton of serine. In methionine catabolism, the carbon skeleton of methionine is converted to propionyl-CoA, which eventually enters the Krebs cycle at the point of succinyl-CoA. BCAA dehydrogenase catalyzes the oxidation of a ketobutyrate to propionyXloA-... 

Methionine is utilized primarily in protein synthesis, providing sulfur for cysteine synthesis, and is the body s principal methyl donor. In methylation reactions, S-adenosylmethionine (SAM) is the methyl group donor. SAM is a sulfonium compound whose adenosyl moiety is derived from ATP as follows ... 

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 other two nonessential amino acids, tyrosine and cysteine, require an essential amino acid for their synthesis (phenylalanine for tyrosine, and methionine for cysteine). The carbons for cysteine synthesis come from glucose the methionine only donates the sulfur. 

The carbons and nitrogen for cysteine synthesis are provided by serine, and the snlfur is provided by methionine (Fig. 39.7). Serine reacts with homocysteine (which is prodnced from methionine) to form cystathionine. This reaction is catalyzed by cystathionine 3-synthase. Cleavage of cystathionine by cystathionase prodnces cysteine and a-ketobntyrate, which forms snccinyl CoA via propionyl CoA. Both cystathionine 3-synthase ( 3-eliminaiion) and cystathionase (y-elimination) require PLP. 

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. 

Homocysteine provides the sulfur atom for the synthesis of cysteine (see Chapter 39). In this case, homocysteine reacts with serine to form cystathionine, which is cleaved, yielding cysteine and a-ketobutyrate. The first reaction in this sequence is inhibited by cysteine. Thus, methionine, via homocysteine, is not used for cysteine synthesis unless the levels of cysteine in the body are lower than required for its metabolic functions. An adequate dietary supply of cysteine, therefore, can spare (or reduce) the dietary requirement for methionine. 

This evidence is consistent with, but does not provide definitive proof for OAS being the physiologically important precursor of cysteine. Only a limited number of O-esters of serine have been tested for activity with cysteine synthase (Section II,B,2), and no systematic studies have been made to determine whether serine O-esters other than OAS are synthesized by plants, or to identify the physiologically important a-aminopropionyl donor for cysteine synthesis. Experiments analogous to those used to identify the a-aminobutyryl donor for cystathionine and homocysteine synthesis (Section III,A,3) and the physiological carrier in sulfate reduction in Chlorella (Section IV,D,3) should be informative in this respect. 

Cysteine synthesis in bacteria proceeds via a-aminoacrylic acid bound to the enzyme as a Schiff base with pyridoxal phosphate (Cook and Wedding, 1976). Partially purified cysteine synthase from spinach (Schmidt, 1977a) and Chlorella (Schmidt, 1977b) catalyzes an exchange of sulfide into cysteine, consistent with the above mechanism. The exchange of acetate into OAS that would be expected due to formation of the proposed enzyme intermediate was not tested. 

Two separate pathways converge in the reaction catalyzed by cysteine synthase the reductive assimilation of sulfate to sulfide, and the synthesis of OAS. All the reactions of reductive sulfate assimilation are present in chloroplasts, but the quantitative significance of these organelles in providing the sulfur precursor for cysteine synthesis is not clear (see Anderson, this volume. Chapter 5). A recent review (Givan and Harwood, 1976) indicates that serine is formed in chloroplasts fairly directly from intermediates of the carbon reduction pathway, but that this synthesis also requires extrachloro-plastic factors yet to be defined. Serine acetyltransferase has been reported in a fraction consisting mainly of mitochondria (Smith and Thompson, 1%9 ... 

The other system for sulphide assimilation involves a coupled hydrolysis of acetyl coenzyme A. This enzyme system can only operate in the direction of cysteine synthesis and would ensure the effective trapping of... 

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