Cystathionine Cystathionase

The major developmental change which takes place In both brain and liver is the postnatal activation of the transsulfuration pathway of methionine metabolism. The net result of this pathway is the transfer of the sulfur atom from homocysteine to the carbon skeleton of serine to form cysteine. This conversion is mediated by two enzymes cystathionine synthase (L-serine hydro-lyase adding homocysteine, EC 4.2.1.22) which catalyzes the 3-activation of serine and the addition of homocysteine to form the thio-ether, cystathionine cystathionase (EC 4.4.1.1) which catalyzes the y-cleavage of cystathionine to form cysteine (Fig. 1). Both of these enzymes catalyze reactions other than those described above although their importance vivo is uncertain (Tallan et al., 1974). In mature mammals, activities both of cystathionine synthase and of cystathionase are present in brain and liver, although cystathionase activity in... 

This pyridoxal-phosphate-dependent enzyme [EC 4.4.1.8], also referred to as /3-cystathionase and cystine lyase, catalyzes the hydrolysis of cystathionine to yield homocysteine, pyruvate, and ammonia. 

Gonversion of homocysteine to Gys occurs in two reactions catalyzed by two pyridoxal phosphate-requiring enzymes, cystathionine p-synthase and y-cystathionase. 

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.

Cystathionine (3-lyase (cystathionase) O-Acetylserine sulfhydrylase (cysteine synthase)... 

The subsequent cleavage of cystathionine to yield cysteine, a-ketobutyrate and NH4+ is catalyzed by y-cystathionase, a pyridoxal-phosphate-containing enzyme. This transsulfura-tion pathway is one of the routes used for methionine catabolism. 

The vitamin B6-dependent enzyme CBS catalyzes the first step, in which homocysteine reacts with serine to form L-cystathionine. In the second step, L-cystathionine is converted to L-cysteine, a-ketobutyrate, and ammonia by the vitamin B6-dependent enzyme cystathionase (7). 

There are two pyridoxal phosphate-requiring enzymes in the homocysteine degradation pathway, which are associated with genetic diseases. In homo-cystinuria, cystathionine synthase is defective, and large amounts of homocystine are excreted in the urine. Some homocystinurics respond to the administration of large doses of vitamin B6. In cystathioninuria, cystathionase is either defective or absent. These patients excrete cystathionine in the urine. Cystathionase is often underactive in the newborns with immature livers, and cysteine and cystine become essential amino acids. Human milk protein is especially rich in cysteine, presumably to prepare the newborn for such a contingency. 

Studies on the / ,-/-elimination reaction catalyzed by y-cystathionase showed that in the conversion of homoserine to a-ketobutyrate one atom of deuterium from the solvent is incorporated at C-/ , where it occupies the pro-S position [156]. The stereochemistry of protonation at C-/ in this reaction is thus the same as in the / -/-elimination catalyzed by cystathionine-y-synthase. 

Trapping of the aminoacrylate intermediate in the reactions catalyzed by cystathionine-y-synthase and y-cystathionase produced the same diastereomer of KEDB which was different from the one formed with bacterial L-threonine dehydratase. Unfortunately, this experiment has apparently not been done with threonine synthetase. 

Figure 9.5. Methionine load test for vitamin Be status. Methionine synthetase, EC 2.1.1.13 (vitamin Bi2-dependent) 2.1.1.5 (betaine as methyl donor) cystathionine synthetase, EC 4.2.1.22 and cystathionase, EC 4.4.1.1. Relative molecular masses (Mr) methionine, 149.2 homocysteine, 135.2 cystathionine, 222.3 and cysteine, 121.2.

The metabolism of methionine, shown in Figure 9.5, includes two pyri-doxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionine synthetase is litde affected by vitamin Bg deficiency,... 

As discussed in Section 10.3.4.2, the metabolic fate of homocysteine arising from methionine is determined not only by the activity of cystathionine synthetase and cystathionase, hut also the rate at which it is remethylated to methionine (which is dependent on vitamin B12 and folate status) and the requirement for cysteine. 

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. ... 

A third sulfurtransferase, cystathionase (cystathionine y-lyase EC 4.4.1.1), which is a cytosohc enzyme, may play a role in CN detoxification in the kidney and rhombencephalon (Wrobel et al., 2004). A product of the cystathionase reaction, bis(2-amino-2-carboxylethyl)trisulfide (thiocystine), may serve as a sulfur substrate donor for rhodanese. Another reaction product, 3-(thiosulpheno)-alanine (thiocysteine), may be an additional link between cystathionase and CN biodetoxification. In addition, cystathionase also functions as a sulfane sulfur carrier. 

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. 

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