Cystathionase defect

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. 

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 genetic disease cystathioninuria, the enzyme cystathionase is defective or missing. In this case, cystathionine accumulates and is excreted in the urine. Thus, almost all of the equivalent of methionine intake is put out as cystathionine. If cystathionase is missing, an individual cannot make cysteine from methionine or homocysteine. 

If the blood levels of methionine and homocysteine are very elevated and cystine is low, cystathionine p-synthase could be defective, but a cystathionase deficiency is also a possibility. With a deficiency of either of these enzymes, cysteine could not be synthesized, and levels of homocysteine would rise. Homocysteine would be converted to methionine by reactions that require B12 and tetrahydrofolate (see Chapter 40). In addition, it would be oxidized to homocystine, which would appear in the urine. The levels of cysteine (measured as its oxidation product cystine) would be low. A measurement of serum cystathionine levels would help to distinguish between a cystathionase or cystathionine p-synthase deficiency. 

Homocystinuria is caused by deficiencies in the enzymes cystathionine p-synthase and cystathionase as well as by deficiencies of methyltetrahy-drofolate (CH3-FH4) or of methyl-B12. The deficiencies of CH3-FH4 or of methyl-B12 are due either to an inadequate dietary intake of folate or B12 or to defective enzymes involved in joining methyl groups to tetrahy-drofolate (FH4), transferring methyl groups from FH4 to B12, or passing them from B12 to homocysteine to form methionine (see Chapter 40). 

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. 

In some premature as well as term infants cystine may be an essential amino acid (Sturman, J. A., al., 1970). Infants for whom this is true lack one of the enzymes responsible for the conversion of methionine to cystine (i,.. , cystathionase). The exact number of infants having this defect is not known, but it is thought to be significant. Therefore, it would seem to be desirable to add cystine to the infusate. Because of its low solubility, however, this is not possible. Thus alternate ways of providing cystine (perhaps as a soluble metabolizable compound) must be explored. 

Fig. 10.1. Defects of transmethylation (methioninehomocysteine), transsulfuration (methionine sulfate), and remethylation (homocysteine - methionine) enzymes of sulfur amino acid metabolism 10.1, methionine adenosyltransferase 10.2, cystathionine ) -synthase 10.3, y-cystathionase 10.4, sulfite oxidase 10.5, molybdenum cofactor 10.6, methylenetetrahydrofolate reductase 10.7 and 10.8, methionine synthase.

Corticosterone methyl oxidase II deficiency Costeff optic atrophy syndrome Coupling state defect Creatine deficiency Creatine transporter deficiency Cu-binding P-type ATPase deficiency y-Cystathionase deficiency Cystathionine gamma-lyase deficiency Cystathionine y -synthase deficiency Cystathioninuria... 

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