Cystathionine synthesis

Together, these data strongly suggest that O-phosphohomoserine is the physiologically important a-aminobutyryl donor for synthesis of both cystathionine and homocysteine in plants. This finding is consistent with the in vivo experiments of Dougall and Fulton (1967), which showed that neither O-succinyl nor 0-acetylhomoserine was utilized in preference to homoserine for cystathionine synthesis by cells of Paul s Scarlet Rose. 

Cystathionine y-synthase of N. crassa has an absolute requirement for N -methyltetrahydrofolate (Selhubef al., 1971). Addition of this cofactor did not stimulate cystathionine synthesis with O-acetyl, O-malonyl, or O-phosphohomoserine by extracts of spinach leaves, even when the extracts were subjected to treatments designed to remove traces of the cofactor (Datkoefa/., 1974b). 

These data indicate that methionine, or a derivative thereof, controls de novo assimilation of sulfate into cystathionine and its products and therefore that the locus of the regulatory effect is at cystathionine synthesis. 

While the studies of Dougall (1965) are suggestive, it has not yet been firmly established whether or not methionine also controls de novo synthesis of the carbon moieties of methionine. Of course such regulation of the four-carbon portion would be expected if the effect of exogenous methionine is exerted upon the cystathionine synthesis step, since it is at this step that both the sulfur and the four-carbon moieties become committed to methionine formation. 

In those plants in which it has been determined, O-phosphohomoserine is present in concentrations of less than 25 ixM (Datko et al., 1974b, 1977). Since the for O-phosphohomoserine in threonine synthesis (in the absence of AdoMet) is approximately 2 mM (Madison and Thompson, 1976 Thoen et al., 1978), and for cystathionine synthesis approximately 7 mM (Madison and Thompson, 1976), it follows that (unless compartmentation is very extreme) each of these enzymes will be operating below its for O-phosphohomoserine, and the two enzymes will therefore compete for the available supply of this substrate. 

A hypothesis has been proposed to explain all known causes of hyperho-mocysteinemia by a single, biochemical principle (Selhub and Miller 1992). The hypothesis emphasizes the existence of coordinate regulation by AdoMet of the partitioning of homocysteine between methionine synthesis and catabolism through cystathionine synthesis Elevated homocysteine levels in blood can be caused by a number of factors, including folate and B vitamin (B12, Bg) deficiency and pre-existing diseases such as atherosclerotic disease, diabetes and by various drugs. 

While plants are unique in using 0-phosphohomoserine as the physiological substrate, crude plant extracts can also use other homoserine esters. For cystathionine synthesis, in general... 

Sturman, d.A., Gaull, G.E., and Niemann, W.H., 1976, Cystathionine synthesis and degradation in brain, liver and kidney of the developing monkey, J. Neurochem., 26 457-463. 

Scheme 10 Orthogonally Protected Cystathionine Derivatives as Intermediates for Peptide Synthesis...

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 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. 

JJR Coque, JL de la Fuente, P Liras, J Martin. Overexpression of the Nocardia lactamdurans alpha-aminoadipyl-cysteinyl-valine synthetase in Streptomyces lividans. The purified multienzyme uses cystathionine and 6-oxopiperidine 2-carboxylate as substrates for synthesis of the tripeptide. Eur J Biochem 242 264-270, 1996. 

In addition to being a precursor of methionine in the activated methyl cycle, homocysteine is an intermediate in the synthesis of cysteine. Serine and homocysteine condense to form cystathionine. This reaction is catalyzed hy cystathionine -synthase. Cystathionine is then deaminated and cleaved to cysteine and a-ketohutyrate hy cystathioninase. Both of these enzymes utilize PLP and are homologous to aspartate aminotransferase. The net reaction is... 

S,S-(L,L)-Cystathionine (S-2-amino-2-carboxyethyl-L-homocysteine, L-2-amino-4[(2-amino-2-carboxyethyI)thio]butyric acid) [56-88-2] M 222.3, m >300°, dec at 312° with darkening at 270°, [ajp +23.9° (c 1, M HCI). Could be converted to the HCl salt by dissolving in 20% HCl and carefully basifying with aqueous NH3 until separation is complete. Filter off and dry in a vacuum. It forms prisms from H2O. The dibenzoyl derivative has m 229° (from EtOH). [IR Greenstein and Winitz Chemistry of the Amino Acids (J Wiley) Vol 3 2690 7967 and Tallan et al. J Biol Chem 230 707 1958 Synthesis du Vigneaud et al. J Biol Chem 143 59 1942 Anslow et al. J Biol Chem 166 39 7946.]... 

B. Homocystine is produced when two homocysteine molecules form a disulfide bond. Homocysteine is produced when S -adenosylhomocysteine (SAH) releases adenosine. It is used in the synthesis of cystathionine. Homocysteine accepts a methyl group (from FH4 via vitamin B12) to form methionine. If the enzyme that cleaves adenosine from SAH is deficient, homocysteine levels will decrease. The other deficiencies would lead to increased levels of homocysteine. 

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