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

HOOC C CH2 CH2 S CH3 NH2

Methionine Methionine

Betaine

N1N-dimethygiycine

Betaine

S-adenosylmethionine 3 h CH3

S-adenosylmethionine

['"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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Keep Your Weight In Check During The Holidays

Keep Your Weight In Check During The Holidays

A time for giving and receiving, getting closer with the ones we love and marking the end of another year and all the eating also. We eat because the food is yummy and plentiful but we don't usually count calories at this time of year. This book will help you do just this.

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