Homocysteine accumulation

Methionine synthase is a vitamin B 12-dependent enzyme that needs N -methyl tetrahydrofolate (THF) as a coenzyme (Fig. 47.1). It catalyses the transfer of the methyl group from A/ -methyl THF to homocysteine to form methionine. When methionine synthase activity is deficient homocysteine accumulates, causing hyperhomocysti-... 

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). 

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...

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

When acting as a methyl donor, 5-adenosylmethionine forms homocysteine, which may be remethylated by methyltetrahydrofolate catalyzed by methionine synthase, a vitamin Bj2-dependent enzyme (Figure 45-14). The reduction of methylene-tetrahydrofolate to methyltetrahydrofolate is irreversible, and since the major source of tetrahydrofolate for tissues is methyl-tetrahydrofolate, the role of methionine synthase is vital and provides a link between the functions of folate and vitamin B,2. Impairment of methionine synthase in Bj2 deficiency results in the accumulation of methyl-tetrahydrofolate—the folate trap. There is therefore functional deficiency of folate secondary to the deficiency of vitamin B,2. 

The question therefore arose about the fate of the methyl group from methionine. When minimal amounts of methionine were used to supplement the diet of rats given homocysteine as their main source of sulfur, the rats did not usually thrive, and at death had fatty accumulations in their livers. Best and his co-workers had earlier reported the efficacy of choline as a lipotropic agent, facilitating the mobilization of fat from the liver. Du Vigneaud therefore tried supplementing homcys-... 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Answer A. Homocysteine, the substrate for the enzyme, accumulates increasing the risk of deep vein thrombosis and disrupting the normal crosslinking of fibrillin. Deficiency of homocysteine methyl transferase would cause homocystinuria, but would also predispose to megaloblastic anemia. 

Furthermore, the two pathways that normally degrade homocysteine are absent from the neurone and glial cells and so homocysteine can accumulate in the brain (Chapter 8, Appendix 8.2). Consequently, the maintenance of adequate intake of folic acid and vitamin over many years, to ensure low levels of homocysteine, may help to protect neurones and reduce the risk of development Alzheimer s disease. 

Deficiency of this enzyme leads to the most common form of homocystinuria, a pediatric disorder characterized by accumulation of homocysteine and reduced activity of several sulfotransferase reactions that require this compound or its derivatives as substrate. 

Accumulation of homocysteine and reduced transsulfation of various compounds leads to abnormalities in connective tissue structures that cause altered blood vessel wall structure, loss of skeletal bone density (osteoporosis), dislocated optic lens (ectopia lentis), and increased risk of blood clots. 

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. 

The abnormal T- and B-cell functions in patients with SCID are the result of ADA dehciency. The ADA gene has been mapped to chromosome 20q.l3, and a number of point and deletion mutations have been identihed in SCID patients [5-7]. ADA catalyses the irreversible deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyi-nosine as a part of purine nucleoside metabolism. Adenosine and deoxyadeno-sine are suicide inachvators of S-adenosyl-homocysteine (SAH) hydrolase, and lead indirectly to intracellular accumulation of SAH, which is a potent inhibitor of methy-lation reactions. Cellular methylation function is essential for detoxihcation of adenosine and deoxyadenosine. As a result ADA dehciency leads to accumulation to... 

A deficiency of vitamin B12 causes the accumulation of homocysteine due to reduced formation of methylcobalamin, which is required for the conversion of homocysteine to methionine (Figure 33-3, section 1). The increase in serum homocysteine can be used to help establish a diagnosis of vitamin B12 deficiency (Table 33-2). There is concern that... 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

Evidence that a diet rich in fruits and vegetables may protect against coronary heart disease is accumulating. It is unclear exactly which substances in fruits and vegetables are responsible for the observed inverse association with cardiovascular disease. The inverse association may be attributed to folate, antioxidant vitamins, or other constituents such as fiber, potassium, fla-vonoids, or other phytochemicals. The protective effect of folate may be attributed to its role as a cosubstrate in homocysteine metabolism (Eichholzer et al., 2001). 

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. 

A wide variety of methylation reactions, including developmentaUy important methylation of DNA, may be inhibited by S-adenosyUiomo-cysteine, which accumulates because homocysteine is a product inhibitor of S-adenosyUiomocysteine hydrolase. 

McGregor DO, Dellow WJ, Lever M, George PM, Robson RA, and Chambers ST (2001) Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations. Kidney International 59,2267-72. 

Is there any relationship between folate status and methionine intake Methionine has a pro-folate effect, as revealed in the Folate section. In brief, dietary methionine spares the use of 1-carbon units that might otherwise be used for the conversion of homocysteine to methionine. Furthermore, methionine is converted in the cell to SAM, which in turn inhibits 5,i0-methylenc-H4folate reductase. This inhibition prevents the useless accumulation or trapping of 1-carbon units in the form of S-methyl-H folate, and allows the folate cofactors to be used for other purposes, such as the synthesis of thymidylate. 

Vitamin B12 deficiency results in impairment in the activities of the B -requiring enzymes. This impairment prevents synthesis of the enzyme s products and forces the accumulation of reactants in the cell. Inhibition of methionine synthase prevents the synthesis of methionine and the regeneration of tetrahydrofolate. This inhibition results in interruption of the methylation cycle, which involves S-ade-nosylmethionine. The inhibition also results in an impairment of folate-mediated metabolism, because of the failure to regenerate H4folate from 5-methyl-H4folate. The major effect of 6 2 deficiency is an impairment of growth, particularly of rapidly growing cells such as immature red blood cells. B12 deficiency also results in the buildup of homocysteine in the cell and bloodstream. 

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