Cystathionase activity

A number of enzymes involved in cysteine metabolism have been described in the tapeworm Hymenolepis diminuta (48). In addition to a high cystathionine /3-synthase activity it has low y-cystathionase activity, and contains cysteine aminotransferase, cysteine dioxygenase and cysteine sulphinate aminotransferase the latter two could be involved in the oxidation of cysteine. 

Since methionine has several pathways open to it, it is essential to know what factors control the direction that its metabolism takes. Studies in young adults have shown that the utilization of methyl groups is normally accounted for chiefly by creatinine formation. This reaction consumes more 5-adenosylmethionine than all other transmethylations together. However, examination of enzyme activities from these two pathways in fetal animals leads to the conclusion that remethylation preponderates over transsulfuration. Indeed, since y-cystathionase activity is immeasurable in human fetal liver and brain, not only is the remethylation sequence favored, but also cysteine then becomes an essential amino acid for the fetus and infant. 

The metabolism of methionine, shown in Figure 11.22, includes two pyridoxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionase activity falls markedly in vitamin deficiency, and as a result there is an increase in the urinary excretion of homocysteine and cystathionine, both after a loading dose of methionine and under basal conditions. However, as discussed below, homocysteine metabolism is affected more by folate status than by vitamin status, and, like the tryptophan load test, the methionine load test is probably not reliable as an index of... 

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... 

Gaull et al., 1972 Pascal et al., 1972). Thus for the human fetus, cysteine is an essential amino acid, and must be supplied by the mother. The same is true for the prematurely bom and full term human infant since the available data indicate that development of cystathionase activity is a postnatal phenomenon whether the gestation time is shortened or is of normal length(Table 1). In the... 

Table 1. Cystathionase Activity in Developing Hunan Liver...

Cystathionase activity correlates significantly with time of death after birth (r 0.776), but not with weight at birth. Furthermore, correlation of cystathionase activity with time of death after birth and weight at birth as two independent variables does not add to the significance of the correlation with time of death after birth. 

Heinonen, K., 1973, Studies on cystathionase activity in rat liver and brain during development, Biochem. J., 136 1011-1015. 

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. 

Activity toxicity M. is a powerful inhibitor of cystathionine synthase and cystathionase. The growth of shoots of Phaseolus aureus is inhibited by 3,4-dihy-droxypyridine and mimosine with equal activity. The inhibitory activity is neutralised by addition of pyri-doxal phosphate. M. causes loss of hair in sheep, horses, and pigs goats and cattle, in contrast, are not affected in this way. M. effects growing hair, impairs the estrogen cycle in rats, and DNA synthesis. ... 

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. 

Cystathioninuria, a deficiency of cystathionase, is a much rarer and less clearly defined disorder . While the disease has frequently been associated with mental retardation, this may only refiect the type of individual with which testing most frequently occurs. Patients with normal mental function are also known. Nonetheless, the high levels of cystathionine in brain and the mental defects associated with its faulty metabolism, have led to speculation that this thioether has some special role in nervous function. In tissues from at least one patient, there was evidence that the defect was in pyridoxal phosphate binding by cystathionase and that normal enzyme activity could be achieved at abnormally high levels of coenzyme. This is often quoted as the classical example of a binding or K mutant, but not all patients with the disorder give the same effect. 

Cystathionase also has a low level of direct cysteine desulphydrase activity. Tryptophanase and tryptophan synthetase are other enzymes capable of carrying out the cysteine desulphydrase reaction. Such considerations have cast doubt on this biological significance of this reaction, although strong arguments have been presented for a true cysteine desulphydrase in SalmonellcP. 

Effects of 3- and i4.-mercapto-2-amino acids. It has long been known that 1,2- and 1,3-aminothiols, and especially the substrate-like mercapto-amino acids - penicillamine, homocysteine et al. - strongly inhibit many PLP-enzymes(transaminases, c<-decarboxylases, y cystathionase, and others) by condensing with the carbonyl group of PLP in the active site to stable heterocyclic compounds (thiazolidines, resp., thiazanes), see Pefs. 5 ... 

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