Cystathionine accumulation

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. 

L-Cystathionine (accumulated by mutant 2 supports growth of mutant 1)... 

Figure 9-5. Pathway for formation of cysteine from methionine. Only the enzymes involved in known diseases of this pathway are shown. Cystathionase is deficient in cysthioninuria, which leads to accumulation of cystathionine without producing frank symptoms. Cystathionine p-synthase deficiency causes homocystinuria.

The major type is caused by cystathionine fi-synthase deficiency, leading to accumulation of upstream intermediates in the pathway, especially homocysteine. 

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

Correct answer = B. Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), a-ketoisovalerate (due to branched-chain a-ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening of the urine. 

Homocystinuria may result from one or several abnormalities in the mechanism whereby homocysteine is methylated to form methionine. About half of the patients respond to treatment with pyridoxine and it is thought that the vitamin overcomes a block at the homocysteine/cystathionine level by mass action (C23). However, Schuh et al. (S22) have recently described a patient who responded to vitamin B12. The infant presented with severe developmental delay, homocystinuria, and a megaloblastic anemia. Treatment with cyanocobalamin was without effect but treatment with hydroxocobalamin resulted in a rapid clinical improvement, and the homocystinuria disappeared. Methionine synthetase activity in cell extracts was normal, while cultured fibroblasts showed an absolute growth requirement for methionine. The defect appeared to be limited to methyleobalamin accumulation and an inability to transfer the methyl group from 5-methyltetrahydrofolate to homocysteine. 

In homocystinuria, cystathionine synthase is defective. Therefore, homocysteine does not react with serine to form cysteine (see Figure 7-10). The homocysteine that accumulates is oxidized to homocystine and excreted in the urine. Some cases respond to increased doses of vitamin B6, which forms pyridoxal phosphate, the cofactor for the synthase enzyme. 

Several inherited disorders of methionine metabolism (Chapter 17) give rise to exeessive production of homocysteine, HS-CH2-CH2CH(NH3 )COO , and its excretion in urine. The most common form of homocystinuria is due to a deficiency of cystathionine synthase (Chapter 17). A major clinical manifestation of homocystinuria is connective tissue abnormalities that are probably due to the accumulation of homocysteine, which either inactivates the reactive aldehyde groups or impedes the formation of polyfunctional cross-links. 

Homocystinurla A deficiency of the enzyme cystathionine synthase leads to the accumulation of sulphur-containing amino acids. Affected children are normal at birth but develop eye problems, osteoporosis and mental retardation... 

Homocysteine also accumulates in the blood if a mutation is present in the enzyme that converts N, methylene FH4 to N -methyl FH4. When this occurs, the levels of N -methyl FH4 are too low to allow homocysteine to be converted to methionine. The loss of this pathway, coupled with the feedback inhibition by cysteine on cystathionine formation, will also lead to elevated homocysteine levels in the blood. 

A third way in which serum homocysteine levels can be elevated is by a mutated cystathinone-(3-synthase or a deficiency in vitamin B6, the required cofactor for that enzyme. These defects block the ability of homocysteine to be converted to cystathionine, and the homocysteine that does accumulate cannot all be accommodated by conversion to methionine. Thus, an accumulation of homocysteine results. 

Fig. 40.10. Reaction pathways involving homocysteine. Defects in numbered enzymes (1 = methionine synthase, 2 = N, methylene FH4 reductase, 3 = cystathionine-(3-synthase) lead to elevated homocysteine. Recall that as cysteine accumulates, there is feedback inhibition on cystathionine-P-synthase to stop further cysteine production.

Homocystinuria is a biochemical abnormality caused either by a deficiency of cystathionine P-syn-thase or impaired activity of N -methyltetrahydrofolate-homocysteine methyltransferase. The classical homocystinuria occurs when the conversion of homocysteine to cystathionine is limited by a deficiency of cystathionine P-synthase, with accumulation of methionine and homocysteine and a decrease in cysteine. 

More recently, similar results were obtained in studies with L. paucico-stata (P. M. Macnicol, A. H. Datko, J. Giovanelli, and S. H. Mudd, unpublished). Again, the inorganic sulfate pool(s) of the plants were depleted by steady-state growth at a very low but constant concentration of sulfate in the medium. The S originating in [ S]04 accumulated initially in cysteine plus cystathionine. Once more, cysteine appeared to be compartmentalized and the rapid turnover time of the relatively small precursor pool required... 

Homocysteine lies at a metabolic crossroad it may condense with serine to form cystathionine, or it may undergo remethylation, thereby conserving methionine. There are two pathways for remethylation in humans. In one, betaine provides the methyl groups, while in the other 5-methyltetrahydrofolate is the methyl donor. This latter reaction is catalyzed by a Bj -containing enzyme, 5-methyltetrahydrofolate homocysteine methyltransferase. Two defects in this latter mechanism may account for the inability to carry out remethylation. In one of them, patients are unable to synthesize or accumulate methylcobalamin, while others cannot produce the second cofactor, 5 -methyltetrahydrofolate, because of adefect in 5,10-methylenetrahydrofolate reductase. 

Fibroblasts from each patient had markedly reduced levels of the above enzyme. The defect results in an inability to synthesize 5-methyltetrahydrofolate in amounts sufficient for the remethylation of homocystine to methionine. Homocystine accumulates in plasma, and the plasma methionine is decreased. As in the other remethylation defect, there is accumulation of cystathionine. Treatment with high doses of folic acid has been beneficial in several patients (Mudd et al., 1989). 

Homocystinuria is caused by a deficiency in the enzyme, cystathionine-P-synthase (CBS), and results in the accumulation of homocysteine and methionine. 

Homocyslinuiia is an autosomal recessive condition caused by a deficiency of the enzyme, cystalhionine-p-synthase (CBS), which results in the accumulation of homocysteine and methionine and a deficiency of cystathionine and cysteine. There are other disorders to consider when an elevated homocysteine concentration is identified. These disorders include vitanun Bn uptake or activation defects, which may or may not have associated elevated methylmalonic acid, severe 5,10-methylenetetrahydrofolate reductase deficiency, and 5-methyl-THF-homocysteine meth-yltransferase deficiency. The latter two are typically associated with an elevated homocysteine, but low methionine concentrations, so it is relatively easy to disaiminate these conditions from homocystinuria. It is also important to consider that nongenetic causes of hyperhomocyste-inemia exist, such as dietary deficiencies, end-stage renal disease, and administration of several drugs [6]. 

Smolin L. A. and Benevenga N. J. (1982) Accumulation of homocysteine in vitamin B-6 deficiency A model for the study of cystathionine p-synthase deficiency / Nutr 112, 1264 1272. 

A second metabolic system similar to the first is shown in Figure 1, panel ii. In this schematic, the emphasis is a metabolite one or two steps proximal to the primary enzyme deficiency. For example, in normal individuals, metabolite C is converted by enzyme Y to metabolite A, which is subsequently converted by enzyme X to metabolite B. As described above, in individuals with an inherited deficiency of enzyme X, metabolite A accumulates. In this particular scenario, compounds that are converted to metabolite A, namely metabolite C, will increase as enzyme Y is inhibited by basic kinetics. An example of this enzyme system is homocystinuria. In this disorder, the metabolism of homocysteine to cystathionine by cystathionine S-synthase is blocked. An increase in homocysteine causes an accumulation of S-adenosyl homocysteine and S-adenosyl methionine. Due to an increase in these metabolites, the metabolism of methionine to S-adenosyl methionine by methionine adenosyl transferase is decreased. Hence, methionine increases in the blood of individuals with homocystinuria. Note that in this example there were two enzymatic steps before the metabolism of homocysteine. 

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). 

These data indicate that methionine, or a derivative thereof, controls vivo assimilation of sulfate into cystathionine and its products, and therefore that the regulatory locus is at cystathionine synthesis. Furthermore, since regulation at this step did not cause an accumulation of cysteine and its products, regulation of sulfate assimilation into cysteine is also indicated. It has not yet been firmly established whether methionine also controls novo synthesis of the carbon moieties of methionine. Such regulation of the 4-carbon moiety would be expected if exogenous methionine regulates the cystathionine synthesis step, since it is at this step that both the sulfur and 4-carbon moieties become committed to methionine. 

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. 

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...

A number of inborn errors of metabolism are due to an enzyme deficiency which leads to the accumulation of the precursor of that particular pathway. This type of clinical expression was among the first to be described, since simple clinical screening tests often uncovered the increased excretion in the urine, or accumulation in the blood, of early metabolites of the pathway which had been blocked. An important example of such a defect is homocystinuria, where both methionine and homocystine accumulate as the result of the deficiency of activity of cystathionine synthase (Mudd and Levy, 1978). A variant of the foregoing occurs when both the precursor of the main pathway and metab-... 

Type II Methylmalonic acid, homocystine, cystathionine Failure of cellular cobalamin accumulation and/or retention with secondary failure of both methyl-cobsdamin and 5 -deoxyadenosyl-cobalamin synthesis 11.1... 

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