Homocysteine methyltransferases

Methylcobalamin is involved in a critically important physiological transformation, namely the methylation of homocysteine (8) to methionine (9) (eq. 2) catalyzed by A/ -methyltetrahydrofolate homocysteine methyltransferase. The reaction sequence involves transfer of a methyl group first from... 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

Cya n ocobalamin (Bir) Homocysteine methyltransferase Methylmalonyi CoA mutase Methionine, SAM Odd-carbon fatty acids, Val, Met, He, Thr MCC pernicious anemia. Also in aging, especially with poor nutrition, bacterial overgrowth of terminal ileum, resection of the terminal ileum secondary to Crohn disease, chronic pancreatitis, and, rarely, vegans, or infection with D. latum Megaloblastic (macrocytic) anemia Progressive peripheral neuropathy. ... 

Important pathways requiring SAM include synthesis of epinephrine and of the 7-methylgua-nine cap on eukaryotic mRNA, Synthesis of SAM from methionine is shown in Figure T17-3. After donating the methyl group, SAM is converted to homocysteine and remethylated in a reaction catalyzed by N-methyl THF-homocysteine methyltransferase requirii both vitamin Bj2 and N-meth d-THF. The methionine produced is once again used to make SAM. 

Additional folate may be stored as the highly reduced JV -methyl-THF. This form is referred to as the storage pool as there is only one known enzyme that uses it, and in turn moves it back into the active pool. This enzyme is N-methyl THF-homocysteine methyltransferase, discussed above, which also requires vitamin and is involved in regenerating SAM as a methyl donor for reactions. 

The vitamin cobalamin (vitamin Bjj) is reduced and activated in the body to two forms, adeno-sylcobalamin, used by methylmalonyl CoA mutase, and methylcobalamin, formed from methyl-THF in the N-methyl THF-homocysteine methyltransferase reaction. These are the only two enzymes that use vitamin (other than the enzymes that reduce and add an adenosyl group to it). 

Cobalamin deficiency can create a secondary deficiency of active THF by preventing its release from the storage pool through the AT-methyl THF-homocysteine methyltransferase reaction, and thus also result in megaloblastic anemia. Progressive peripheral neuropathy also results from cobalamin deficiency. TTeating a cobalamin deficiency with folate corrects the megaloblastic anemia but does not halt the neuropathy. 

Researchers studying the metalloenzyme hydrogenase would like to design small compounds that mimic this enzyme s ability to reversibly reduce protons to H2 and H2 to 2H+, using an active center that contains iron and nickel. Cobalamins (vitamin and its derivatives) contain an easily activated Co-C bond that has a number of biological functions, one of which is as a methyl transferase, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). This enzyme converts homocysteine (an amino acid that has one more CH2 group in its alkyl side chain than cysteine see Figure 2.2) to methionine as methylcobalamin is converted to cobalamin. 

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.

This enzyme [EC 2.1.1.14], also known as 5-methyltet-rahydropteroyltriglutamate homocysteine 5-methyltrans-ferase and methionine synthase, catalyzes the reaction of 5-methyltetrahydropteroyltri-L-glutamate with L-homo-cysteine to produce tetrahydropteroyltri-L-glutamate and L-methionine. The reaction requires the presence of phosphate. The enzyme isolated from E. coli also requires a reducing system. See N -Methyltetrahydrofo-late. Homocysteine Methyltransferase... 

GLYCINE METHYLTRANSFERASE HISTAMINE N-METHYLTRANSFERASE HOMOCYSTEINE METHYLTRANSFERASE... 

Metabolism of homocysteine. Abbreviations BHMI betaine homocysteine methyltransferase ... 

Cobalamin is a complex molecule containing a Co atom. In the mamalian synthesis of methionine, cobalamin acts as a coenzyme by accepting the methyl group from N5-methyltetrahydrofolate and transferring it to homocysteine. The reaction is catalyzed by cobalamin-N%-methyl-THF homocysteine methyltransferase. The overall reaction is... 

N -Methyltetrahydrofolate-Homocysteine Methyltransferases Robert T. Taylor and Herbert Weissbach... 

There are two separate homocysteine methyltransferases in most tissues. One uses methyl-tetrahydrofolate as the methyl donor and has vitamin B12 (cohalamin Section 10.8.1) as its prosthetic group. This enzyme is also known as methionine synthetase it is the only homocysteine methyltransferase in the central nervous system. The other enzyme utilizes hetaine (an intermediate in the catabolism of choline Section 14.2.1) as the methyl donor and does not require vitamin B12. 

This functional deficiency of folate is exacerbated by the associated low concentrations of methionine and S-adenosyl methioitine, although most tissues (apart from the central nervous system) also have betaine-homocysteine methyltransferase that may be adequate to maintain tissue pools of methionine. Under normal conditions S-adenosyl methioitine inhibits methylene-tetrahydrofolate reductase and prevents the formation of further methyl-tetrahydrofolate. Relief of this inhibition results in increased reduction of one-carbon substituted tetrahydrofolates to methyl-tetrahydrofolate. 

Figure 14.4. Catabolism of choline. Choline dehydrogenase, EC 1.1.99.1 betaine aldehyde dehydrogenase, EC 1.2.1.8 and homocysteine methyltransferase, EC 2.1.1.5. Relative molecular masses (Mr) choline, 104.2 betaine, 117.2 dimethylglycine, 102.2 methylglycine, 88.2 and glycine, 74.2. THF, tetrahydrofolate.

Shapiro, S.K., Yphantis, D.A., Almenas, A., (1964). Biosynthesis of Methionine in Saccha-romyces cerevisiae. Rartial purification and properties of S-adenosylmethionine homocysteine methyltransferase. J. Biol. Chem., 239, 1551-1556. 

Serine-hydroxymethyl transferase, methylenetetrahydrofolate reductase, and methyltetrahydrofolate-homocysteine methyltransferase, mechanism of biological methylation with 90CRV1275. 

Methionine can be regenerated by the transfer of a methyl group to homocysteine fromTV -methyltetrahydrofolate, a reaction catalyzed by methionine synthase (also known as homocysteine methyltransferase). 

Carrow, T. A. (1996). Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine methyltransferase. /. Bio . Chem. 271,22831-22838. 

Betaire-homocysteine methyltransferase, 502 BHT (bulyiated hydrtmytoLuene), 628 Bicarbonate, 79,80, S2, 717 Bilayer sheet, 25 Bile, 58,331... 

Reduced serum folate concentrations have been demonstrated in patients with homocystinuria taking pyridoxine. The mechanism of this effect may involve removal of substrate inhibition of the enzyme, A5-methyltetrahydrofolate homocysteine methyltransferase, due to pyridoxine-induced reduction of the substrate, homocysteine (27). 

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