Phosphoribosyl5aminoimidamle4 carboxamide AICAR

GAR Transformylase

N10-Formyl-THF DHF NADPH + H

NADP+

OH OH

5-Phosphoformylribosylglycinamide (FGAR)

Dihydrofolate reductase

AICAR Transformylase

N10-Formyl THF DHF NADPH +

Dihydrofolate reductase

5'-Phosphoribosyl -5-formamidoimidazole-4-carboxamide (AlCAR)

Figure 8.50. Coenzyme roles for 10-formyl THF.

OH H

Deoxyuiidylic acid

Dihydrofolate reductase

OH H

Deoxythymidylic acid

N5,N10-Methvlene THF DHF

NADPH +

NADP+^ THF

Figure 8.51. Methylation of deoxyuridylic acid forming deoxythymidylic acid.

Figure 8.51. Methylation of deoxyuridylic acid forming deoxythymidylic acid.

and/or an inflamed mucosa inhibits folate transport. Finally, anticonvulsants such as phenytoin somehow interfere with folic acid uptake or utilization.

The dihydrofolate reductase inhibitor, methotrexate (Fig. 8.47), was developed as an anticancer drug, whose inhibition of formation of folic acid coenzymes would block purine synthesis. In other words, it was designed to induce a folic acid deficiency. Notice in Figs. 8.50 and 8.51 that formation of dTMP, FGAR, and AICAR also causes the oxidation of tetra-hydrofolate to dihydrofolate. The latter must be reduced by dihydrofolate reductase to tet-rahydrofolate before active coenzyme can form again. Thus, not only does methotrexate inhibit the initial formation of the tetrahydro-folate moiety, it blocks regeneration of the co-enzyme form.

3.11.5 Hypervitaminosis Folic Acid. This apparently is not a problem. Transport across the intestinal mucosa may be regulated by a feedback mechanism or the rate of hydrolysis of the polyglutamate chain or a combination of both. What is very important is that taking the vitamin in doses above 400 jug (800 ยกig in pregnant and lactating women) can mask the macrocytic anemia seen with pernicious anemia caused by a cyanocobalamin deficiency (Fig. 8.53). The Tolerable Upper Limit is based on trying to avoid this masking. Therefore, the UL to RDA ratio is low (2-2.5) in adults.

3.1 1.6 Dietary Reference Intakes.

Infants EAR

Children (1-8 years) Children (9-13years) Adolescents (14-18 years) Adults (19-50+years) Pregnancy Lactation RDA

Children (1-8 years) Children (9-13 years) Adolescents (14-18 years) Adults (15-50+ years) Pregnancy Lactation UL (from fortified food or supplements) Children (1-3 years) Children (4-8 years) Children (9-13 years) Adolescents (14-18 years) Adults (19+ years) Pregnancy (14-18 years) Pregnancy (19+ years) Lactation (14-18years) Lactation (19+ years)

120-160 /xg/day 250 /xg/day 330 /xg/day 320 /xg/day 520 /xg/day 450 /xg/day

150-200 /xg/day 300 /xg/day 400 pglday 400 /xg/day 600 jxg/day 500 /xg/day

300 jutg/day 400 jxg/day 600 /xg/day 800 pglday 1000 /xg/day 800 /xg/day 1000 pglday 800 /xg/day 1000 /xg/day

3.12 Vitamin B12 (Cobalamin) (72)

This chemically very complex vitamin is required for two reactions, the methylation of ho-

Methione

Succinyl CoA

Methionine adenosyl transferase

"methyl transferases"

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