Human folate metabolism

Lin Y Dueker SR, Jones AD, et al. Quantitation of in vivo human folate metabolism, Am J Clin Nutr 2004 80 680-91. 

Lin YM, Dueker SR, Follett JR, Fadel JG, Aqomand A, Schneider PD, Miller JW, Green R, Buchholz BA, Vogel JS, Phair RD, Clifford AJ. Quantitation of in vivo human folate metabolism. Am J Clin Nutr 2004 80(3) 680 691. 

Human folate metabolism has recently been studied using accelerator mass spectrometry (AMS) by measuring the C-folate levels in plasma, urine and feces samples taken over a 150-day period after dosing a healthy adult volunteer (102). AMS avoids the need for high specific activities and pharmacological doses as needed with scintillation counting. The volunteer receives an effective radiation dose of only 1.1 mrem. 

Piper, J.R. et al. (1982) Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism, J. Med. Chem. 25, 182-187. Wright, J.E. et al. (1993) Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts, Biochem. Pharmacol. 46, 871-6. 

Grignani et al. (G14) studied several of the enzymes of folate metabolism in human epidermis—both normal and psoriatic. Increased levels of folate reductase were found in the psoriatic lesion, and further enzyme could be induced by treatment of the patients with amethopterin. By contrast, formate-activating enzyme, 5,10-methylenetetrahydrofolate dehydrogenase, serine hydroxylase, and cyclohydrolase were normal in the psoriatic lesion. Formiminotetrahydrofolate transferase could not be measured either in normal or psoriatic skin. The activities of the above enzymes as well as the absence of the transferase are similar to the findings for small bowel but not to other tissues studied. How these findings... 

Nzila, A., Ward, S. A., Marsh, K., Sims, P. F., and Hyde, J. E. (2005). Comparative folate metabolism in humans and malaria parasites (part II) Activities as yet untargeted or specific to Plasmodium. Trends Parasitol. 21, 334-339. 

It is, however, pertinent to mention here that the mammalian dihydrofolate reductase is approximately 1 10,000 to 1 50,000 as sensitive to it as the bacterial enzymes, so that there prevails almost little interference with folate metabolism in humans. 

Many factors affect folate metabolism, including dietary folate level, nutritional status of vitamins B6, B12, and riboflavin, zinc status, alcoholism, and physical states such as pregnancy and lactation. In many cases, the effects of these factors are seen in altered excretion rates of intact folates and metabolites, but the effects on tissue levels of the various folates and transfer rates between tissues are not well understood. Preliminary human and animal kinetic models are being devek ed in our laboratory based on studies conducted under controlled dietary conditions. These models will provide a base from which to study the effects of altered folate nutriture as well as the influence of other factors such as pregnancy and aging on folate metabolism. 

Gregory, J. F., Bailey, L. B., Thomas, E. A., Toth, J. P., Cerda, J. J., and Fisher, W.R. (1994). Stable-isoto M study of long-term folate metabolism in a human subject. FASEB J. 8, A920. 

Osborne, C. B., Lowe, K. E., and Shane, B. (1993). Regulation of folate and one carbon metabolism in mammalian cells. 1. Folate metabolism in Chinese hamster ovary cells expressing Escherichia coli or human folylpoly-y-glutamate synthetase activity. J. Biol. Chan. 268, 21657-21664. 

It is now recognized that genetic factors play an important role in folate metabolism and in determining folate status. However, many unknowns remain concerning the mechanisms and optimal human health. 

Recently a great deal of effort has been spent in studying the metabolism of leucovorin in vivo. This emphasis was prompted by the chemical stability of this folate and by the observation of a reduction in toxicity of methotrexate when it was given in conjunction with leucovorin. Fol-inic acid is found in human liver, but it is not the major circulating folate, which is 5-methyltetrahydrofolate. 

J. R. Bertino, P. F. Nixon, and A. Nahas, Mechanism of uptake of folate monoglutamates and their metabolism. In Folic Acid Biochemistry and Physiology in Relation to Human Nutrition Requirements, National Academy of Sciences, Washington, D. C. 1977, p. 178. 

Animal species show great variability in mean lethal doses of methanol. The special susceptibility of humans to methanol toxicity is probably due to folate-dependent metabolism to formate and not to methanol itself or to formaldehyde, the intermediate metabolite. 

The many diverse components of milk have demonstrable effects on human health. Perhaps, the most commonly associated component of dairy food is that of dietary calcium. Dairy products provide the most significant contribution to dietary calcium intake in the modem Western diet. It has been estimated that dairy products contribute to >72% of dietary calcium in the United States (Huth et al., 2006). Calcium is an important mineral for maintenance of optimal bone health (Bonjour et al., 2009) and is an integral component of key metabolic pathways relating to, for example, muscle contraction both in skeletal and smooth muscle (Cheng and Lederer, 2008). Further, dairy products contribute other essential nutrients in the diet, such as proteins, phosphorus, potassium, zinc, magnesium, selenium, folate, riboflavin, vitamin B12, and vitamin A (Haug et al., 2007 Huth et al., 2006). Low-fat milk alternatives are fortified with vitamin A and vitamin D which is added to milk and fermented milk in many countries making it an important source for vitamin D (Huth et al., 2006). 

Marasas, W. F., Riley, R. T., Hendricks, K. A., Stevens, V. L., Sadler, T. W., Gelineau-van Waes, J., Missmer, S. A., Cabrera, J., Torres, O., Gelderblom, W. C., Allegood, J., Martinez, C., et al. (2004). Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo A potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J. Nutr. 134(4), 711-716. 

Vitamin B12 is required by only two enzymes in human metabolism methionine synthetase and L-methylmalonyl-CoA mutase. Methionine synthetase has an absolute requirement for methylcobalamin and catalyzes the conversion of homocysteine to methionine (Fig. 28-5). 5-Methyltetrahydrofolate is converted to tetrahydrofolate (THF) in this reaction. This vitamin B12-catalyzed reaction is the only means by which THF can be regenerated from 5-methyltetrahydrofolate in humans. Therefore, in vitamin B12 deficiency, folic acid can become trapped in the 5-methyltetrahydrofolate form, and THF is then unavailable for conversion to other coenzyme forms required for purine, pyrimidine, and amino acid synthesis (Fig. 28-6). All folate-dependent reactions are impaired in vitamin B12 deficiency, resulting in indistinguishable hematological abnormalities in both folate and vitamin B12 deficiencies. 

The most widely known chemotherapeutic agent directed against TS is 5-fluorour-acil (5-FU). 5-FU was first used clinically almost 50 years ago, yet still remains a mainstay for the treatment of carcinoma of the breast and gastrointestinal tract. In cells, 5-FU is metabolized to 5-FdUMP, which forms a stable inhibitory ternary complex with the co-substrate N5N10-methylene-5,6,7,8-tetrahydrofolate (CH2H4-folate) and TS. In this complex, a covalent bond links the thiol of cysteine 195 of human TS to C6 of deoxyuracil monophosphate (dUMP) and the methylene carbon of the co-substrate is joined to C5 of the nucleotide [55]. The fluorine at C5, unlike the proton, cannot... 

The enzyme dihydrofolic acid (DHF) S5mthase (see below) converts p-aminobenzoic acid (PABA) to DHF which is subsequently converted to tetrahydric folic acid (THF), purines and DNA. The sulphonamides are structurally similar to PABA, successfully compete with it for DHF s)mthase and thus ultimately impair DNA formation. Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of sulphonamides. Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF. The drug is relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme. Both sulphonamides and trimethoprim are bacteriostatic. 

There are several vitamin Bg-responsive inborn errors of metabolism that include (1) cases of infantile convulsions in which the apoenzyme for glutamate decarboxylase has a poor affinity for the coenzyme (2) a type of chronic anemia in which the number but not morphological abnormality of erythrocytes is improved by pyridoxine supplementation (3) xanthurenic aciduria in which affinity of the mutant kynureninase for PLP is decreased (4) primary cystathion-inuria caused by similarly defective cystathionase and (5) homocystinuria in which there is less of the normal cystathionine synthetase. In these cases increased levels (200 to lOOOmg/day) of administered vitamin Bg are required for life. Low vitamin Bg status (together with low vitamin B12 and folate status) in humans has been linked to hyperho-mocysteinemia and as an independent risk factor for cardiovascular disease. ... 

---