METHIONINE METABOLISM

Methionine is an important donor of a methyl group in several single-carbon transfer reactions and of the sulfur atom in the synthesis of the non-essential amino acid cysteine. After donating its methyl group, methionine is converted to homocysteine, a compound that is associated with risk of cardiovascular disease and neurological disorders. The metabolism of homocyteine requires the vitamins B₆, B₁₂, and folate.

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Methionine Is A Methyl Group Donor

In addition to its function as a substrate for protein synthesis, methionine is also an important source of a methyl group in many single-carbon transfer reactions and of the sulfur atom in the synthesis of the non-essential amino acid cysteine.

S-Adenosylmethionine (SAM)

Methionine is activated for methyl donation by reacting with Adenosine Triphosphate (ATP). The methionine sulfur makes a nucleophilic attack on the ATP 5’ carbon catalyzed by Methionine Adenosyl Transferase, creating S-Adenosylmethionine (SAM) with a positively charged sulfonium center.

Methyl Transfer

The S-Adenosylmethionine methyl group is now available for transfer by a large number of Methyltransferases, each named for its specific methyl acceptor, e.g., C-5 cytosine-specific DNA methylase, also known as DNA (cytosine-5) Methyltransferase (Dnmt1), which methylates the C-5 carbon of cytosines in DNA to produce C5-methylcytosine. The reaction product is S-Adenosylhomocyateine (SAH — SAM absent its methyl group). SAH feedback inhibits methyltransferases.

Processing Of S-Adenosylhomocysteine

S-adenosylhomocysteine is hydrolyzed to Homocysteine and Adenosine by S-Adenosylhomocysteine Hydrolase, which is inhibited by Deoxyadenosine. Deoxyadenosine accumulation, which occurs, for example, in the autosomal recessive genetic disease Adenosine Deaminase Deficiency causes S-Adenosylhomocystein to accumulate and inhibit methyltransferases. Homocysteine can take either of two paths, Transsulfuration or Remethylation

Homocysteine On The Transsulfuration Pathway

Cystathionine Synthase and Cystathionase convert Serine and Homocysteine into the non-essential amino acid Cysteine and α-Ketobutyrate; Serine, another non-essential amino acid, provides the carbon skeleton, Homocysteine provides the sulfur. Both Cystathionine Synthase and Cystathionase require vitamin B₆ (Pyridoxine) as an essential co-factor. The Cystationase reaction releases NH₃ -> NH₄⁺

Metabolism of α-Ketobutyrate; Vitamin B12

α-Ketobutyrate is converted to propionyl CoA, the same molecule as the end-product of odd-chain fatty acid β-oxidation. The propionyl CoA is converted in three enzymatic steps, one of which is one of only two reactions in Humans that required vitamin B₁₂, to Succinyl CoA, an intermediate of the TCA cycle. More propionyl CoA is converted to succinyl CoA by this pathway from amino acid degradation than from odd-chain fatty acid β-oxidation.

Homocysteine On The Remethylation Pathway

Methionine is regenerated by Methionine Synthase, which remethylates homocysteine in one of only two reactions in Humans that require vitamin B^{12 as the immediate methyl donor}

N-5-Methyl Tetrahydrofolate Is The Primary Methyl Donor

Tetrahydrofolate (see “Folate” in the top menu) is a derived from the vitamin folate (vitamin B₉. It accepts and donates single carbons at the oxidation level of formaldehyde, and formic acid in many single-carbon transfer reactions. Serine is the major donor of a single carbon to tetrhydrofolate at the oxidation level of formaldehyde via Serine Transhydroxymethylase. The methylene carbon is reduced to the oxidation level of methanol, and donated to vitamin B₁₂, which then donates it for the remethylation of Homocysteine to Methionine.

Some Specific SAM Reactions

S-Adenosylmethiohine (SAM) participates in the synthesis of many compounds that contain methyl groups. It is used in reactions that add methyl groups to either oxygen or nitrogen atoms in the acceptor (in contrast to folate derivatives (see “Folate” in the top menu), which can add one-carbon groups to sulfur or to carbon). As examples, SAM is required for the conversion of phosphatidylethanolamine to phosphatidylcholine, guanidinoacetate to creatine, norepinephrine to epinephrine acetylserotonin to melatonin, and nucleotides to methylated nucleotides. It is also required for the inactivation of catecholamines and serotonin. More than 35 reactions in humans require methyl donation from SAM.

Hyperhomocysteinemia, increased levels of homocysteine, has been shown to be associated with cardiovascular and neurologic disease, although with respect to cardiovascular disease it is controversial as to whether hyperhomocystenimia is causative. It is known that increased homocysteine can damage the endothelial lining of blood vessels. Some of the presumed mechanisms include an increase in proliferation of vascular smooth muscle cells, endothelial dysfunction, oxidative damage, an increase is synthesis of collagen and deterioration of arterial wall elastic material. Men with plasma homocysteine concentrations 12% above the upper limit of normal were determined to have approximately a threefold increase in the risk of myocardial infarction, as compared with those with lower levels. Treatment of hyperhomocysteinemia varies with the underlying cause. However, vitamin supplementation (folic acid, vitamin B₆ and vitamin B₁₂) is generally effective in reducing homocysteine concentrations. In most patients, 1 to 5 mg./day of folate rapidly decreases homocysteine concentrations. Folic acid alone, folic acid combined with vitamins B₁₂ and B₆, and vitamins _B6 and B₁₂ have all been shown to reduce homocysteine concentrations. The reduction in mortality from cardiovascular causes since 1960 has been correlated with the increase in vitamin B6 supplementation in the food supply. Genetic factors, including deficiencies in enzymes for methionine synthase, cystathionine synthase, cystathionase, enzymes involved in folate metabolism, and proteins required for folate, vitamin B₆ or vitamin B₁₂ (e.g.,intrinsic factor) absorption can all contribute to hyperhomocysteinemia, and to an increased risk of cardiovascular disease. The deficiencies of methyl tetrahydrofolate, or of methyl B₁₂ are due either to an inadequate dietary intake of folate or B₁₂, or to defective enzymes involved in joining methyl groups to tetrahydrofolate, transferring methyl groups from methyl tetrahydrofolate to B₁₂, or passing them from B₁₂ to homocysteine to form methionine.