Cystathionine, biosynthesis

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... 

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

Homocysteine. A sulfur-containing amino acid, a homologue of cysteine, produced by the demethylation of methionine, and an intermediate in the biosynthesis from methionine via cystathionine. 

Beta replacement is catalyzed by such enzymes of amino acid biosynthesis as tryptophan synthase (Chapter 25),184 O-acetylserine sulfhydrylase (cysteine synthase),185 186a and cystathionine (3-synthase (Chapter 24).187 188c In both elimination and (3 replacement an unsaturated Schiff base, usually of aminoacrylate or aminocrotonate, is a probable intermediate (Eq. 14-29). Conversion to the final products is usually assumed to be via hydrolysis to free aminoacrylate, tautomerization to an imino acid, and hydrolysis of the latter, e.g., to pyruvate and ammonium ion (Eq. 14-29). However, the observed stereospecific addition of a... 

Figure 18.5. GSH biosynthesis and the cystathionine pathway for cysteine biosynthesis in liver and the protective functions of GSH.

CyslAlhionine synthase Biosynthesis of cystathionine from homocysteine and serine... 

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 y-synthase (CGS) is a rather unique PLP-enzyme that catalyzes a transsulfuration reaction important in microbial methionine biosynthesis. It is the only known enzyme whose function is the catalysis of a PLP-dependent replacement reaction at the y-carbon of the amino acid substrate the succinyl moiety of O-succinyl-L-homoserine is replaced by i-Cys to give the thioether linkage of L,/.-cystathionine (scheme II). In the absence of L-Cys, the enzyme catalyzes a net y-elimination reaction from OSHS (scheme II). Because both reactions require the elimination of succinate, the catalytic pathways must diverge from a common reaction intermediate. It was originally hypothesized that a vinylglycine quinonoidal intermediate (structure 11)... 

CGS catalyzes the 7-replacement reaction of an activated form of L-homoserine with L-cysteine, leading to cystathionine. 0-Succinyl-L-homoserine (l-OSHS), 0-acetyl-L-homoserine (OAHS), and 0-phospho-L-homoserine (OPHS) are substrates for CGS ftom bacteria, fungi, and plants, respectively. The plant enzyme is also able to convert the microbial substrates, albeit at much higher values. This reaction is the first step in the transsulfuration pathway that converts L-Cys into L-homocysteine, the immediate precursor of L-methionine. The 0-activated L-homoserine substrate is situated at a metabolic branch point between L-Met and L-Thr biosynthesis, and which substrate is used by CGS depends on the species. In analogy with TS, CGS is tightly regulated by SAM concentration in plants. ... 

Cystathionine y-synthase is the best studied enzyme catalyzing both y-replacement and /3,y-elimination reactions. The enzyme is found in plants and bacteria and normally functions to catalyze the formation of cystathionine from 0-acylhomoserine and cysteine during the biosynthesis of methionine (66) [Eq. (57)] ... 

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. 

Cystathionine-y-synthase isolated from Salmonella typhimurium is a tetramer (molecular weight 160000) and catalyses, in vivo, the y-replacement of O-suc-cinylhomoserine with cysteine [79] to yield cystathionine. The latter, by way of homocysteine, is involved in the biosynthesis of methionine. In other species of bacteria and plants the succinyl moiety may be replaced by acetyl, phosphoryl, or malonyl moieties [80]. In the absence of cysteine the enzyme catalyses an abnormal reaction resulting in the formation of a-oxobutyrate. The latter reaction has been utilised for mechanistic investigations pertinent to the y-eUmination-deamination process (vide infra). 

The more complex sulphur requirements of the marine animals are met largely by cysteine, cystine, methionine, biotin, and thiamine (Young and Maw, 1958) (Fig. 4). Cysteine is a component of the tripeptide glutathione and a precursor of taurine. Methionine is as an essential amino acid involved in biosynthesis of proteins, creatine and adrenaline. Adenosylmethionine is considered to be the active part in transmethylation, e.g. of choline. Methionine is part of the pathways to homocysteine, cystathionine and methylthioadenosine (Young and Maw, 1958). Various organisms convert cysteine and/or cystine into mercapturic acids, cysteine sulphinic acid, and thiazolidine derivatives (Zobell, 1963). 

Protein and amino add Alfalfa [12] (animal feed) Increases in cysteine and methionine by overexpression of an enzyme (cystathionine y-synthase) involved with the biosynthesis of sulfur amino adds... 

Toxicity Causes neurolathyrism and cystathionuria by inhibition of cystathionine y-lyase (EC 4.4.1.1). Biosynthesis metabolism From serine or cysteine and cyanide catalyzed by 3-cyanoalanine synthase (EC 4.4.1.9). 3-Cyanoalanine hydratase (EC 4.2.1.65) hydrates C. to asparagine. ... 

Biosynthesis metabolism In plants from O-acetyl-serine in animal tissue, on the other hand, by cleavage of cystathionine formed fium 5-adenosylmethi-onine. Since methionine is an essential amino acid, Cys may also be considered as essential. C. can be converted by several routes to pyruvic acid and is metabolized in the citric acid cycle. Cys is a component of glutathione. 

Biosynthesis H. is formed from aspartic acid semialdehyde by homoserine dehydrogenase (EC 1.1.1.3). H., in turn, is converted either to threonine via 0-phospho-homoserine or to methionine through O-succinylho-moserine, cystathionine, and homocysteine. 

Biosynthesis Thr belongs biogenetically to the Asp group and is formed from Asp. The direct precursor is L- homoserine, which also forms Met via cystathionine and homocysteine. Homoserine is first converted to 0-phosphohomoserine by ATP under the action of homoserine kinase (EC 2.7.1.39) and then by threonine synthase (EC 4.2.99.2) to Thr. Thr is a component of glycoproteins. It frequently occurs in the free form, see also L-serine. 

A number of amino acids act as intermediates in the biosynthesis of various protein amino acids and are thus present in plants, although often in low concentrations. These include homoserine (III), homocysteine (IV), cystathionine (V), ornithine (VI), and citrulline (VII). The properties of these... 

In fungi, AdoMet regulates methionine biosynthesis by feedback inhibition of cystathionine synthase (see Umbarger, 1978) no such effect of AdoMet on cystathionine synthetic activity in extracts of sugar beet leaves was observed (Madison and Thompson, 1976). In bacteria, AdoMet and methionine synergistically inhibit homoserine succinyltransferase (see Umbarger, 1978). 

A similar enzyme has recently been purified 277-fold from turnip (R. rapa) roots (Anderson and Thompson, 1979). The properties of this enzyme appear to be very similar to those of the rutabaga except the purified enzyme had some activity towards DL-cystathionine and several other substituted cysteines. Even though the activity towards cystathionine is only 22% that of L-cystine and the A , for cystathionine was 4 mM as compared to 0.94 mM for L-cystine, these authors consider that this may have a j8-cystathionase function in methionine biosynthesis. 

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