Brain cystathionine synthase

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... 

Fig. 3 Specific activity of cystathionine synthase (A) and concentration of cystathionine (B) in rhesus monkey brain during development. From Sturman et al., 1976.

Reaction 4 is catalysed by cystathionine synthase (EC 4.2.1.13), an enzyme widely distributed in the tissues. In homocystinuria, cystathionine synthase is virtually completely absent or inactive in all tissues examined liver, brain and fibroblasts grown in tissue culture [33]. In some cases 1 to 2% of the normal enzymic activity can be demonstrated, in others no enzymic activity has been found [34]. As a result of the metabolic block, homocysteine accumulates and is partly converted to homocystine, partly to homocysteine-cysteine mixed disulphide and partly S-methylated to methionine by reactions 6 and 7 with, respectively, N -methyltetrahydrofolic acid and betaine as methyl donors. In infancy methionine and homocysteine are present in high concentrations in the plasma while homocystine and homocysteine-cysteine mixed disulphide are excreted in the urine later the concentration of methionine in the plasma drops. Cystathionine is normally present in highest concentration in the cells of the brain, though traces are found elsewhere and in the urine in homocystinuria no cystathionine can usually be demonstrated in the brain or urine [35]. The body s cysteine and cystine are also largely biosynthesized from methionine, though some is obtained from cysteine and cystine in dietary proteins in homocystinuria, cysteine/cystine becomes an essential amino acid. 

Cystathionine is the first intermediate metabolite in transsulfuration, formed from HCY and serine by cystathionine-fi-synthase, a redox-sensitive, heme-containing enzyme (Banerjee et al., 2003), whose activity is lower in males vs. females (Vitvitsky et al., 2007). The higher levels of cystathionine in human brain reflect a strong diversion of HCY to transsulfuration (i.e., low methionine synthase activity and high cystathionine-f)-synthase activity), in conjunction with a decreased conversion of cystathionine to cysteine. As illustrated in Fig. 1, this indicates impaired transsulfuration in human brain. Low transsulfuration activity relative to other tissues has been described in rat or mouse brain (Finkelstein, 1990), although a... 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

Eto et al. (2002) showed that the levels of H2S were severely decreased in the brains of Alzheimer s disease patients (76.4 2.3 years) compared with the brains of the age matched normal individuals (71.5 7.2 years). In addition to HjS production cystathionine P-synthase also catalyses another metabolic pathway in which cystathionine is produced from the substrate homocysteine. S-adenyl-L-methionine, a cystathionine P-synthase activator, is much reduced in Alzheimer s disease brains (Morrison et al. 1996, Eto et al. 2002) and homocysteine accumulates in the serum of Alzheimer s disease patients (Clarke etal. 1998, Eto etal. 2002). 

The gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator and is also active in the brain, where it increases the response of the NMD A receptor and facilitates long term potentiation, which is involved in the formation of memory. 

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