Methionine and the Methionine Homocysteine Cycle

As sulfur reduction does not occur in mammals, sulfide, at an oxidation state of -2, is a dietary requirement. This requirement is met with cysteine and methionine. A high availability of methionine "spares" cysteine, as it can be converted to cysteine by transsulfuration. Transsulfuration is irreversible in mammals, although not in fungi which can interconvert methion-

ine and cysteine in either direction. Enteric bacteria synthesize cysteine de novo and convert it to methionine. The main path of sulfur metabolism in mammals involves the four processes of transsulfuration, oxidation, transamination and decarboxylation (Figure 3).

Although dietary cysteine can lower the dietary requirement for methion-ine, there is an absolute requirement for methionine as it has functions in addition to transsulfuration and it is also needed for protein synthesis. These functions include methylation and polyamine synthesis. However, methionine is one of the most toxic amino acids7. It causes growth retardation, tissue damage and iron deposition in the spleen. Tissue levels must therefore be kept low, and a dietary load must be processed rapidly. A further problem with methionine is its similarity to a football mom, that overworked denizen of American suburbs. Methionine has too much to do and some of the responsibilities are mutually conflicting.

Adomet And Adohcy
Figure 4. Methionine metabolism and the methionine-homocysteine cycle. AdoHcy: S-Adenosylhomocysteine; AdoMet: S-Adenosylmethionine; Cys: Cysteine; Cysta: Cystathionine; Hcy: Homocysteine; 5-MeTHF: 5-Methyltetrahydro folate; THF: Tetrahydro folate.

The major metabolic activities of methionine involve the methionine-homocysteine cycle (Figure 4): Adenosylation of methionine activates both the methyl group for transmethylation and the aminopropyl moiety for transfer in polyamine synthesis. Transmethylation yields S-adenosylhomocysteine, which is further converted to homocysteine. This is a substrate for three processes: transsulfuration, methyl neogenesis (from the tetrahydrofolate path), and methyl recycling (from choline via betaine, di-methylglycine, sarcosine to glycine). The conflicting demands of these processes create a traffic control problem in the cycle. Polyamine synthesis and transsulfuration drain intermediates away from the cycle, although poly-amine synthesis is a quantitatively minor pathway for methionine. A given molecule of methionine survives only two turns of the cycle. Transsulfuration and remethylation compete for homocysteine. Transmethylation must occur for transsulfuration to occur, as that is the only source of homocys-teine.

Homocysteine is toxic, producing cardiovascular disease and neural tube defects. Despite the high flux through the homocysteine pool, therefore, the pool size must be kept small (i.e. there must be rapid remethylation or rapid movement into transsulfuration). Serious toxicity has not been reported for S-adenosylmethionine1. However, the current interest in S-adenosylhomocysteine as a dietary supplement is disturbing18 in light of the toxicity of the closely related compounds methionine and homocysteine. S-adenosylhomocysteine is being widely used as an antidepressant and in treatment of arthritis and liver disease in recommended doses of up to 1.6 g/day.

Guanidinoacetate Converts
Figure 5. Methylation and muscle contraction. The methyl group of creatine is not necessary for its function as a phosphokinase substrate.

The requirement that transmethylation precede transsulfuration may explain a mystery of muscle biochemistry. Quantitatively, the most significant methylation process is the conversion of guanidinoacetate to creatine (Figure 5). The methylated compound creatine is a phosphagen that maintains myofibrillar ATP levels. Muscle levels of creatine are around 3x higher than

ATP levels. Biosynthesis of this one compound accounts for 80% of mammalian methylation57. The other 20% is consumed in epinephrine synthesis, carboxymethylation of proteins and phospholipid methylation.

But why is the methyl group of creatine needed for muscle function? It probably is not. In invertebrates such as polychaetes (marine worms), various sponges and sea anemones, the unmethylated compound, guanidino-ethane sulfonate, serves as the phosphagen285576. Guanidinopropionate and guanidinoethane sulfonate are substrates for creatine phosphokinase. In mammals, creatine can be replaced by guanidinopropionate without major problems for muscle function25,68. In human males, there is a shortfall of around 5.1 mmol of methyl per day between methyl groups available from diet and methyl groups consumed in transmethylation or methyl oxidation. This shortfall is met by methyl neogenesis via 5,10-methylenetetrahydrofolate and 5-methyltetrahydrofolate (Figure 4). The use of guanidinoacetate as a phosphagen would alleviate the need for this expensive reductive neogenesis. However, it is only by the passage of methyl groups through the methionine-homocysteine cycle that transsulfuration can proceed. This process is required for the production of cysteine under conditions of low dietary intake of cysteine, and for the removal of toxic methionine under conditions of high dietary intake. The use of creatine, therefore, may be an inefficient biochemical way of producing homocysteine needed for transsulfuration: creatine simply provides a sink for the methyl groups that must be consumed in order for the methionine-homocysteine cycle to operate.

Transsulfuration

Transsulfuration is so called because the sulfur of homocysteine is transferred to the carbon chain of serine, yielding cysteine (Fig. 6). Transsulfura-tion serves the functions of removing toxic methionine and producing cys-teine required for GSH and protein synthesis. In the brain, for example, methionine levels are below 1 (M. Cerebral cortical synaptosomes from adult rats contain 0.2 (mol methionine/g protein compared with 25 (mol taurine/g protein53. In biopsied human brain, methionine and phenylalanine were present in the lowest concentration of all amino acids examined50. Both enzymes involved in transsulfuration are pyridoxal phosphate-dependent. The significance of transsulfuration is indicated by the consequences of genetic deficiency in cystathionine B-synthase deficiency. Deficiency is associated with homocystinuria, hypermethioninemia, and decreased conversion of me-thionine to sulfate. Clinically, there are vascular, mental, skeletal and visual abnormalities.

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