Liver cystathionine synthase

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. 

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 ]. 

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... 

The data obtained suggest that the increase in SAH content in liver of vitamin Bs-deficient mice and rats is not due only to decrease in cystathionine synthase activity. Molecular basis for SAH metabolic disturbances under condition of vitamin B5-deficency remain to be clarified. 

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. 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

A biopsy specimen from Homer Sistine s liver was sent to the hospital s biochemistry research laboratory for enzyme assays. Cystathionine p-synthase activity was reported to be 7% of that found in normal liver. 

Metabolism In a prospective controlled study in 74 patients taking isotretinoin for cystic acne, blood concentrations of homocysteine, vitamin B12, and folate were assessed before and after 45 days of isotretinoin therapy [39 ]. The control group consisted of 80 individuals. Homocysteine concentrations were significantly higher in those who took isotretinoin. The vitamins were unaffected, but serum lipids and liver enzymes increased significantly. These effects may have been due to inhibition of cystathionine-beta-synthase, an enzyme required for the metabolism of homocysteine by either the drug or liver dysfunction. Daily supplementation with vitamin B12 and folate can lower plasma concentrations of homocysteine, and the authors therefore recommended the use of these vitamins in patients taking isotretinoin. 

A.E. Braunstein, E.V. Goryachenkova, E.A. Tolosa, I.H. Wileha-rdt and Yefremova. Specificity and some other properties of liver serine sulfhydrase evidence for its identity with cystathionine /3-synthase. Biochim. Biophys. Acta, 1971, 242 247. 

Fig. 17.5 Effect of nitric oxide on the synthesis of methionine and S-adenosylmethionine and methylation reactions. NO inhibits methyltetrahydrofolate reductase (MTR). This results in a decrease in tetrahydrofolate (FH4) and methionine. Additional reduction in the FH4 level may occur by the NO-induced oxidation of ferritin, a compound that inhibits the proteasomal degradation of FH4. NO affects SAM synthesis not only by inducing a decrease in methionine synthesis but also by directly inhibiting the liver-specific methyl-thioadenosyltransferase I/III (MATI/III) isozymes. The fall in SAM level cannot be fully compensated by an increase in the extrahepatic isozyme MATH, since this enzyme is inhibited by its reaction product. The reduction in homocysteine utilization for methionine synthesis may result in homocysteine accumulation. This probably does not lead to a consistent rise in cystathionine and reduced glutathione synthesis, dne to a reduced stabilization of cystathionine P-synthase (CBS) by SAM. Consequently, an inciea.se in SAH, associated with a decrease in the SAM/SAH ratio, inhibits methyltransferases (MT) and DNA methylation. The reduction in SAM level may decrease IicBa activation, thus favoring NF-kB activity...

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