Hyperhomocysteinemia Molecular Basis of Disease

Homocysteine is a non-protein-forming, sulfhydryl amino acid that is an intermediary between methionine and cysteine (Figure 12-9). Homocysteine is formed by intra-cellular demethylation of dietary methionine. Homocys-teine is converted to cysteine in a two-step transsulfuration pathway that requires initial condensation of homocysteine with serine to form cystathionine. The latter reaction is catalyzed by cystathionine-ß-synthase (CBS) and requires the essential cofactor pyridoxal 5'-phosphate (vitamin B6). In the second step, catalyzed by cystathionine y-lyase, cystathionine is hydrolyzed to a-ketobutyrate and cysteine. Homocysteine can be remethylated to methionine via two

Tetrahydrofoiate Methyi-cobaiam S, 1O-methyienetetra-hydrofoiate reductase ydrofoia 4

S-methyienetetra hydrofoiate

Tetrahydrofoiate Methyi-cobaiam S, 1O-methyienetetra-hydrofoiate reductase


Methionine Methionine




S-adenosylmethionine 3 h CH3


['"Adenosine Homocysteine Serine Pyridoxal phosphate

Cystathionine 1. Cystathionine synthase

2. Betaine homocysteine methyltransferase

3. N3-methyltetrahydrofolate homocysteine methyltrasferase

4. 5, 10-methylenetetrahydrofolate reductase

Pyridoxai phosphate

Figure 12-9. Homocysteine metabolism pathway.

pathways. In the first, a methyl group is donated by methyl-tetrahydrofolate in a reaction catalyzed by methyltetrahy-drofolate-homocysteine methyltransferase and requiring cobalamin (vitamin B12). Tetrahydrofolate (folic acid) is remethylated to methyltetrahydrofolate in a reaction that includes the intermediary 5,10-methylenetetrahydrofolate and requires the enzyme methylenetetrahydrofolate reductase (MTHFR). In the second pathway, betaine (trime-thyl-glycine) donates a methyl group to remethylate homocysteine to methionine in a reaction requiring betaine-homocysteine methyltransferase. Remethylation is primarily responsible for regulation of fasting homocys-teine levels, while transsulfuration mainly regulates higher homocysteine levels as occur in the postprandial state or after methionine loading.29

Homocystinuria is a rare inherited disorder affecting 3 to 5 per million of the general population, and usually is caused by severe deficiency of CBS. Most patients are homozygous or compound heterozygous for one or more of three mutations (833T^C, 919G^A, or 1224A^C) within the CBS gene located in the subtelomeric region of chromosome 21 (21q22). Heterozygotes often have normal basal plasma homocysteine levels but develop hyperhomocysteinemia after a methionine load.29 Although rare, severe MTHFR deficiency also can cause homocystinuria. Homozygotes for the common MTHFR 677C^T mutation who become folate deficient may develop mild hyperhomocysteinemia. This mutation encodes for substitution of a valine for alanine at amino acid position 223.Approximately 12% of the U.S. population is homozygous for this mutation.

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