Cystathione

M. Meier, M. Janosik, V. Kery, J.P. Kraus, and P. Burkhard, Structure of human cystathione beta-synthase a unique pyridozal 5 -phosphate-dependent heme protein. EMBO J. 20, 3910-3916 (2001). 

M. Nordstrom and T. Kjellstrom, Age dependency of cystathione beta-synthase activity in human fibroblasts in homocysteinemia and atherosclerotic vascular disease. Atherosclerosis 94, 213-221 (1992). 

Datko, A. H., S. H. Mudd, and J. Giovaneli. A sensitive and specific assay for cystathione cystathione content of several plant tissues. Ann... 

Iyase, ° cystathione y-Iyase, and tryptophan indole lyase are particularly... 

This rare disease has an autosomal recessive inheritance pattern. It is based on a deficiency of cystathion-P syn-... 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

Brattsrom, L Israelsson, B., Lindgarde, H, and Hultberg, B. (1988). Higher total plasma homocyteine in vitamin B,j deficiency than in heterozygosity for homocyteinuria due to cystathione p-synthase deficiency. MetabolKm 37,175-178,... 

Other examples of PLP-requiring enzymes are the amino acid decarboxylases that lead to formation of amines, including several that are functional in nervous tissue (e.g., epinephrine, norepinephrine, serotonin, and y-aminobutyrate) cysteine desulfhydrase and serine hydroxymethyltransferase, which use PLP to effect the loss or transfer of amino acid side chains phosphorylase, which catalyzes phosphorolysis of the a-1,4-linkages of glycogen and cystathione beta-synthase in the transsulfiiration pathway of homocysteine. Additionally the biosynthesis of heme depends on the early... 

There are several vitamin Bg-responsive inborn errors of metabolism that include (1) cases of infantile convulsions in which the apoenzyme for glutamate decarboxylase has a poor affinity for the coenzyme (2) a type of chronic anemia in which the number but not morphological abnormality of erythrocytes is improved by pyridoxine supplementation (3) xanthurenic aciduria in which affinity of the mutant kynureninase for PLP is decreased (4) primary cystathion-inuria caused by similarly defective cystathionase and (5) homocystinuria in which there is less of the normal cystathionine synthetase. In these cases increased levels (200 to lOOOmg/day) of administered vitamin Bg are required for life. Low vitamin Bg status (together with low vitamin B12 and folate status) in humans has been linked to hyperho-mocysteinemia and as an independent risk factor for cardiovascular disease. ... 

In the type of homocystinuria in which the patient is deficient in cystathione 13-synthase, the elevation in serum methionine levels is presumed to be the result of enhanced rates of conversion of homocysteine to methionine, caused by increased availability of homocysteine (see Fig. 39.14). In type II and type HI homocystinuria, in which there is a deficiency in the synthesis of methyl cobalamin and of N -methyltetrahydrofolate, respectively (both required for the methylation of homocysteine to form methionine), serum homocysteine levels are elevated but serum methionine levels are low (see Fig. 39.14). 

Further ) -replacement reactions of serine and its derivatives have also been found to proceed with retention of stereochemistry. Thus 0-acetylserine sulfydrase (EC 4.2.99.8) catalyzes the synthesis of cysteine 98 from O-acetylserine 97, as shown in Scheme 30 (84) (see also p414). Cystathione synthase (EC 4.2.1.22) catalyzes the condensation of serine 60c with homocysteine to yield cystathione 99 (106). Both enzymes have a requirement for PLP. 

The enzyme cystathione-y-synthase (EC 4.2.99.9) catalyzes y substitution of 0-succinyl-L-homoserine 122 by L-cysteine 98 to yield cystathione 99a by the mechanism shown in Scheme 3. It will also catalyze the dehydration to a-ketobutyrate 124 via vinylglycine 123 in the absence of L-cysteine. When the dehydration was conducted in and the [ H]-a-ketobutyrate was degraded to sodium propionate 125, the specific rotation was in keeping with that of an authentic sample of (2S)-[2- Hi]propionate 125, Hc = H (124, 125) (Scheme 37). The proton had added to the intermediate 123 to... 

Finally, synthetic samples of (4R)- and (4S)-[4- H,]-0-succinylhomoserine 122, Hg = H, and 122, H = H, respectively, were incubated with the enzyme in the presence of L-cysteine (128, 129), and the H NMR spectra of the resultant samples of cystathione 99a were compared with those of the samples from the vinylglycine incubations. It was evident from these that the /-substitution reaction had occurred with retention of configuration. 

Elucidation of the stereochemistry of the reactions catalyzed by cystathione- /-synthase has given a particularly detailed picture of the reactions. The /-substitution reaction, previously shown in Scheme 3, can now be shown to take place at the active site of the enzyme with the stereochemistry outlined in Scheme 38 if we assume a syn conformation for the PLP-Schiflf base. 

The enzyme homoserine dehydratase (EC 4.4.1.1) catalyzes the conversion of L-homoserine 104 to a-ketobutyrate 124. The stereochemistry of this reaction was shown (130) to be identical to that of the abnormal reaction of cystathione- /-synthase, H20 being added as the 2-pro-S hydrogen of the a-ketobutyrate 124. 

The amino acid homocysteine 148 is obtained on treatment of cystathione 99 with the enzyme / -cystathionase (EC 4.4.1.8). Chang and Walsh (128) used the samples of (4R)- and (4S)-[4- Hi]cystathione 99a, prepared as in Scheme 37, in this reaction and degraded the samples of homocysteine produced to labeled homoserinelactones. This indicated that, as expected, the chirally labeled center was not disturbed in the reaction. 

Classical homocystinuria is a rare inherited disorder, caused by the deficiency of cystathione beta-synthase resulting in accumulation of methionine it can cause mental retardation, eye problems and thrombosis. Dietary management aims to prevent accumulation of methionine by means of a low-methionine diet and by supplementing the diet with a methionine amino acid mixture. 

Fig. 2. The elution pattern of a standard mixture of OPA-derivatized primary amines, separated on a 5 (Jim Nucleosil C-18 column (200 X 4.6 mm id). The flow-rate was 1 mL/min employing the indicated gradient of metlianol and Na phosphate buffer (50 mA4, pH 5.25). Each peak represents 39 pmol except for those indicated below. 1, glutathione 2, cysteic acid 3, O-phosphoserine (19.5 pmol) 4, cysteine sulfinic acid 5, aspartic acid 6, asparagine (19.5 pmol) 7, glutamic acid 8, histidine 9, serine 10, glutamine 11, 3-methyl-histidine 12, a-aminoadipic acid (9.8 pmol) 13, citrulline (9.8 pmol) 14, carnosine 15, threonine,glycine 16, O-phosphoethanolamine 17, taurine (19.5 pmol) 18, p-alanine (19.5 pmol) 19, tyrosine 20, alanine 21, a-aminoisobutyric acid 22, aminoisobutyric acid 23, y-amino-ii-butyric acid 24, p-amino-u-butyric acid 25, a-amino-butyric acid 26, histamine 27, cystathione (19.5 pmol) 28, methionine 29, valine 30, phenylalanine 31, isoleucine 32, leucine 33, 5-hydroxytryptamine (5-H i ) 34, lysine. The chromatographic system consisted of a Varian LC 5000 chromatograph and a Schoeffel FS 970 fluorimeter.

Cystathioninuria increased levels of cystathione in tissues, additional abnormalities are usually associated with the cystatonuria Deficiency in cysta-thionase and homoserine Harris, H., Penrose, L.S., and Thomas, D.H.H. Cysthathioninuria. Ann. Human Genet. 23, 442-453 (1959) Perry, T.L., Robinson, G.C., Teasdale, J.M., and Hansen, S. Concurrence of cystathioninuria, nephrogenic diabetes insipidus and severe anemia. N. Engl. J. Med. 276, 721-725 (1967)... 

Some patients with methylmalonic aciduria also have increased levels of homocysteine and cystathione in the urine and decreased levels of methionine in tissues. Again, the defect can be overcome in fibroblasts by adding large amounts of hydroxycobalamin to the incubation mixture, suggesting that the defect results... 

Although it is possible to describe the clinicopatho-logical manifestations of pyridoxine deficiency and the metabolic role of pyridoxal phosphate, each pathological alteration cannot be explained by a specific metabolic alteration. Deficiency of a vitamin involved in several steps of the intermediary metabolism of amino acids is bound to be associated with severe clinicopath-ological changes, but the specific metabolic alterations responsible for the anemia and convulsions in pyridoxine deficiency have not been identified. y-Amino butyric acid, cystathione, sphingosine, and 5-hydroxy-tryptamine are compounds abundant in the brain. Pyridoxal phosphate is involved in their metabolic formation. Is there any correlation between the role of pyridoxal phosphate in the metabolism of these compounds and the development of convulsions and ataxia in pyridoxine deficiency Is the role of pyridoxine phosphate in the intermediary metabolism of sulfur amino acid related to the development of seborrheic dermatitis ... 

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