Homocystine enzymic methylation

Figure 28-5. The reaction catalyzed by methionine synthase, a vitamin B12-requiring enzyme. In this reaction, homocystine is converted to methionine, with the simultaneous production of tetrahydrofolate (THF) from 5-methyltetrahydrofolate.Methionine can then be converted to 5-adenosyhnethionine (SAM), the universal methyl-group donor.

B. Homocystine is produced when two homocysteine molecules form a disulfide bond. Homocysteine is produced when S -adenosylhomocysteine (SAH) releases adenosine. It is used in the synthesis of cystathionine. Homocysteine accepts a methyl group (from FH4 via vitamin B12) to form methionine. If the enzyme that cleaves adenosine from SAH is deficient, homocysteine levels will decrease. The other deficiencies would lead to increased levels of homocysteine. 

Since the coenzyme from vitamin is required in two distinct enzyme reactions, i.e., remethylation of homocystine and catabolism of methylmalonic acid, the fundamental defect must involve a step in converting to its coenzymes. Formation of both deoxyadenosyl B and methyl B requires a prior reductive step catalyzed by cobalamin reductase, which appears to be the defective enzyme in this variant (Hogervorst et al., 2002) (Fig. 20.4). 

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. 

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