Methionine synthase deficiency

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

Methionine synthase deficiency (cblC, cblD, cblF, cblE, cblG defects) 100-250... 

Classical homocystinuria is caused by defective activity of cystathionine P-synthase. However, methionine synthase deficiency causes hyperhomocysteinaemia. 

Table 10>7J. Methionine synthase deficiency (cblG) (approx. 20 patients)...

Table 10.8.2. Functional rnethylmalonyl CoA mutase and methionine synthase deficiency (cblD) (2 patients)...

Methionine synthase deficiency (incl. methylmalonyl CoA mutase def.) 7.9/10.8 Methionine synthase reductase deficiency 10.7.2... 

B Eowler, RBH Schutgens, DS Rosenblatt, GPA Smit, J Lindemans. Folate-responsive homocystinuria and megaloblastic anaemia in female patient with functional methionine synthase deficiency (CblE disease). J Inher Metab Dis 10 731-741,... 

EA Kvittingen, S Spangen, J Lindemans, B Eowler. Methionine synthase deficiency without megaloblastic anemia. Eur J Pediatr 156 925-930, 1997. 

Homocysteine is markedly elevated in different inborn errors of homocysteine metabolism such as cystathionine p-synthase, methionine synthase deficiencies,... 

Fohc acid is a precursor of several important enzyme cofactors required for the synthesis of nucleic acids (qv) and the metaboHsm of certain amino acids. Fohc acid deficiency results in an inabiUty to produce deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and certain proteins (qv). Megaloblastic anemia is a common symptom of folate deficiency owing to rapid red blood cell turnover and the high metaboHc requirement of hematopoietic tissue. One of the clinical signs of acute folate deficiency includes a red and painhil tongue. Vitamin B 2 folate share a common metaboHc pathway, the methionine synthase reaction. Therefore a differential diagnosis is required to measure foHc acid deficiency because both foHc acid and vitamin B 2 deficiency cause... 

Figure 45-14. Homocysteinuria and the folate trap. Vitamin 6,2 deficiency leads to inhibition of methionine synthase activity causing homocysteinuria and the trapping of folate as methyltetrahydrofolate.

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. 

Answer C Only methionine is degraded via the homocysteine/cystathionine pathway and would be elevated in the plasma of a cystathionine synthase-deficient patient via activation of homocysteine methyl-transferase by excess substrate. 

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

In a totally different field, studies were being carried out on children who had a deficiency of methionine synthase and an impaired ability to convert homocysteine to methionine, so that they had increased blood levels of homocysteine. It was noted that these children had an increased incidence of thrombosis in cerebral and coronary arteries. This led to a study which eventually showed that an increased level of homocysteine was a risk factor for coronary artery disease in adults. Since methionine synthase requires the vitamins, folic acid and B12, for its catalytic activity, it has been suggested that an increased intake of these vitamins could encourage the conversion of homocysteine to methionine and hence decrease the plasma level of homocysteine. This is particularly the case for the elderly who are undernourished (see Chapter 15 for a discussion of nutrition in the elderly). 

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.

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

A large elevation of Hey in body fluids and tissues is found in several genetic enzyme deficiencies, the homocystinurias. These include cystathionine /3-synlhase deficiency [9], the remethylation defects due to deficiency of MTHF reductase [10], methionine synthase and methionine synthase reductase deficiencies, as well as defects of intracellular cobalamin metabolism [11], namely the cblF, cblC and cblD defects. It is noteworthy that low levels of total Hey (tHcy) have been described in sulphite oxidase deficiency [12]. 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Answer The vegan diet lacks vitamin Bi2, leading to the increase in homocysteine and methylmalonate (reflecting the deficiencies in methionine synthase and methylmalonic acid mutase, respectively) in individuals on the diet for several years. Dairy products provide some vitamin B12 in the lactovegetarian diet. 

Fig. 6 Methyl trap hypothesis 5,10-Methylenetetrahydrofolate is reduced to 5-methyltetiahy-drofolate in an irreversible reaction. When vitamin Bn is deficient, methyl groups are trapped as 5-methyltetrahydrofolate, resulting in decreased substrates for DNA synthesis and neural lipid methylation. MTHFR, methylenetetrahydrofolate reductase DHFR, dihydrofolate reductase MS, Methionine synthase TS, thymidylate synthase SAM, S-adenosyl-methionine dUMP, deoxyuridine 5 -monophosphate dTTP, deoxythymidine 5 -monophosphate...

E-S) Hypermetbioninuria (decrease in methionine adenosyl transferase) at this step. The condition is relatively benign, whereas cystathionine synthase deficiency (see above) is not benign. 

The inability to absorb Vitamin B12 occms in pernicious anemia. In pernicious anemia intrinsic factor is missing. The anemia results from impaired DNA synthesis due to a block in purine and thymidine biosynthesis. The block in nucleotide biosynthesis is a consequence of the effect of vitamin B12 on folate metabolism. When vitamin B-12 is deficient essentially all of the folate becomes trapped as the N -methyltetrahydrofolate derivative as a result of the loss of functional methionine synthase. This trapping prevents the synthesis of other tetrahydrofolate derivatives. required for the purine and thymidine nucleotide biosynthesis pathways. 

Vitamin 13]2 deficiency induces deficiency in folate, because vitamin Bn is required for the conversion of folate from a form that has limited use (5-melhyl H.tfolate) to a form (H folate) that can be readily assimilated and used in a variety of reactions. Vitamin is the cofactor of methionine synthase, the enzyme required for conversion of 5-methyl-H4folate to H4folate. The metabolism of folate and that of vitamin B12 are, in part, intimately related. Because of this relationship, the symptoms of deficiencies in both of these vitamins are shared. 

Vitamin B]2 deficiency results in impairment in the activities of the Bj2-re< iJiring 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 tetrahydrofolatc. 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 Hjfolate from S-methyl-Hjfolate. The major effect of B 2 deficiency is an impairment of growth, particularly of rapidly growing cells such as immature red blood cells. Bu deficiency also results in the buildup of homocy steine in the cell and bloodstream. 

Methyl trap The sequestering of tetrahydrofolate as N -methyl THF because of decreased conversion of homocysteine to methionine as a result of a deficiency of methionine synthase or its cofactor, cobalamin (vitamin B ). 

E. Vitamin is a cofactor in two biochemical reactions, the conversion of homocysteine to methionine by the enzyme methionine synthase and the conversion of L-methylmalonyl-CoA to succinyl-CoA by methytmalonyl-CoA mutase. N -methyl THF is a methyl donor in the methionine synthase reaction. A folate deficiency would result in decreased methionine synthase activity and decreases in methionine and cystathionine concentrations, while homocysteine levels would be increased. A vitamin deficiency would also yield these same results, but in addition methytmalonate levels would increase as a consequence of a decrease in the activity of methylmalonyl-CoA mutase activity. 

One form of methionine synthase common in bacteria uses lV -methyltetrahydrofolate as a methyl donor. Another form of the enzyme present in some bacteria and mammals uses A/ -methyltetrahydro-folate, but the methyl group is first transferred to cobalamin, derived from coenzyme B12, to form methylcobalamin as the methyl donor in methionine formation. This reaction and the rearrangement of L-methyl-malonyl-CoA to succinyl-CoA (see Box 17-2, Fig. la) are the only known coenzyme Bi2-dependent reactions in mammals. In cases of vitamin B12 deficiency, some symptoms can be alleviated by administering not only vitamin B12 but folate. As noted above, the methyl group of methylcobalamin is derived from W -methyltetrahy-drofolate. Because the reaction converting the methylene form to the 7V -methyl form of tetrahydrofo-... 

Because methionine synthase is the only mammalian enzyme known to act on 5-methyltetrahydrofolate, the decreased intracellular activity of this enzyme causes 5-methyltetrahydrofolate to accumulate, at the expense of depleted pools of the other tetrahydrofolate coenzymes. Thus, even though total folate levels may seem ample, there is a functional folate deficiency, with insufficient levels of the formyl and methylene derivatives needed for synthesis of nucleic acid precursors. 

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