Methyl cycle

Fig. 2.4 The S-methylmethionine cycle and its interaction with the activated methyl cycle. The SMM cycle operates within the activated methyl cycle, and in effect short-circuits it. The reactions mediated by MMT and HMT are shown in bold. THF, tetrahydrofolate CH2-THF, 5,10-methylenetetrahydrofolate,...

FIGURE 18-18 Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle. The steps are described in the text. In... 

Transfer of the methyl group from 5,-adenosylmethi-onine to an acceptor yields S -adenosylhomocysteine (Fig. 18-18, step (2)), which is subsequently broken down to homocysteine and adenosine (step (3)). Methionine is regenerated by transfer of a methyl group to homocysteine in a reaction catalyzed by methionine synthase (step (4)), and methionine is reconverted to 5-adenosyl-methionine to complete an activated-methyl cycle. 

S-Adenosyl methionine is the major methyl donor in biological reactions. It is regenerated via the intermediates S-adenosyl homocysteine, homocysteine and methionine in the activated methyl cycle. 

In addition to being a precursor of methionine in the activated methyl cycle, homocysteine is an intermediate in the synthesis of cysteine. Serine and homocysteine condense to form cystathionine. This reaction is catalyzed hy cystathionine -synthase. Cystathionine is then deaminated and cleaved to cysteine and a-ketohutyrate hy cystathioninase. Both of these enzymes utilize PLP and are homologous to aspartate aminotransferase. The net reaction is... 

Figure 24.14. Activated Methyl Cycle. The methyl group of methionine is activated by the formation of S-adenosylmethionine.

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

The methylation cycle proceeds as follows. Methionine can be converted to S-adenosylmethionine (SAM). SAM is a universal methyl donor and is required in most or alJ methylation events occurring in the body. For example, SAM is used in the synthesis of creatine and carnitine and in the methylation of nucleic acids and proteins. With the donation of the methyl group, SAM is converted to S-ade-nosylhomocystcine (SAH), as shown in Figure 9-4. SAH is finally broken down to homocysteine, completing the methylation cycle. The point of departure of the 1-carbon unit, derived from serine, from the methylation cycle is indicated by the section symbol (g). 

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. 

Methionine challenge lest, 553 Methionine synthase, 498, 502,507 Methotrexate (M ITt), 499-500 Methylation cycle, folate metabolism and, 496-497... 

FIGURE 9.4 The methylation cycle and its relationship to folate metabolism. 

Methionine, homocysteine, and cysteine are linked by the methylation cycle and transsulfuratlon pathway (Figure 55-9). Conversion of methionine into homocysteine proceeds via the formation of S-adenosyl intermediates including S-adenosylmethionine, die methyl group donor in a wide range of transmethylation reactions. Homocysteine is further condensed with serine by cystathionine 3-synthase to form cystathionine. 

In a classic paper, Snapper synthesized an ilimaquinone-agarose-affinity resin (30), which was incubated with homogenized bovine liver and then washed extensively.93 Proteins retained by the resin were separated by gel electrophoresis, yielding six main protein bands. Amino acid sequencing of these bands revealed three proteins involved in the activated methyl cycle — SAHase, S-adenosylmethionine synthetase (SAM synthetase), and catechol-O-methyltransferase (COMT) — as well as three unrelated proteins. Subsequent enzymatic assays established that ilimaquinone is a competitive inhibitor of SAHase, but has little effect on the activity of SAM synthetase or COMT. The authors noted that a consequence of SAHase inhibition would be the intracellular accumulation of SAH, which is a potent feedback inhibitor of methyltransferases. These results support the assertion that methylation events play an important role in cellular secretory events and vesicle-mediated processes. The study also highlighted the problem of nonspecific interactions as only one of the six isolated proteins was shown to interact in any way with the natural product. 

SeMet, TMSe and AdoSeMet. The identification of AdoSeMet seems to confirm that SeMet enters the metabolic pathway of its sulfur analog in the activated methylation cycle... 

Outline the activated methyl cycle and describe the roles of methylcobalamin and ATP in the cycle. Give examples of important derivatives from 5-adenosylmethionine. 

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