Understanding Folate and Vit B12 biological roles PDF

Preview

Summary

lecture notes final exam...

Description

UNDERSTANDING THE BIOLOGICAL ROLES OF FOLATE AND VITAMIN B12: Natural dietary folates have polyglutamate side chains. The side chains are removed in the small intestine during digestion. In contrast, folic acid is a monoglutamate structure and is readily absorbed “as is”. Inside the intestinal enterocytes, most folate and some folic acid are methylated to the N5methyl tetrahydrofolate (5-methyl THF) form and released into the blood stream. When taken up by cells, the N5-methyl group is removed by methionine synthase thanks to the Vitamin B12 (cobalamin) cofactor. The cobalamin temporarily becomes methyl-cobalamin. Consequently, the cell now has free tetrahydrofolate (THF), which is important in a wide variety of reactions. For the moment, let’s focus on the THF. THF can pick up a methyl group from an intracellular methyl donor (e.g. serine) to form N5N10-methylene THF. Two things can happen to N5N10-methylene THF: 1) The major outcome is that the N5N10-methylene THF passes the methyl group to dUMP, forming dTMP, which is required for DNA synthesis. The enzyme coordinating this is known as thymidylate synthase. Losing a methyl group allows THF to be reformed, which can then pick up another intracellular methyl group from another serine (for example), and the cycle continues. 2) An alternate minor outcome is that N5N10 undergoes an irreversible reduction reaction where it is converted to N5-methyl-THF. This secondary pathway is thought to exist as a means for the cell to funnel extra methyl groups back to the SAM cycle. During folate deficiency, DNA synthesis and cell division slow down, and this has a major impact in tissues which depend on rapid cell division, including; 1. bone marrow; leading to megaloblastic anaemia (few, large red blood cells, overstuffed with haemoglobin) 2. intestinal mucosa; decreased division of intestinal stem cells, disruption of epithelium, causing diarrhea 3. developing fetus; improper neural tube closure, defects such as spina bifida Let’s go back to Vit B12. The methyl-cobalamin transfers the methyl group into the SAM cycle. SAM is a very active methyl donor in metabolism, and folate arrives from the intestine as N5-methyl-THF as a way to fuel the SAM cycle. In addition, there is the irreversible reaction whereby N5N10methylene-THF is converted into N5-methyl-THF, which also fuels the SAM cycle. This is all well and good, as long as Vit B12 is present. With a Vit B12 deficiency, the incoming N5methyl THF (and any N5-methyl THF produced from N5N10-methylene THF) becomes “trapped” in the cell. In the absence of Vit B12, there is no way to free N5-methyl-THF for use by other cellular reactions. This is called the “methyl trap”, and it is the mechanism by which Vit B12 deficiency causes a functional folate deficiency. Vit B12 deficiency eventually leads to problems of neural degeneration and death, due to some functions of Vit B12 that are not well understood at present. Folate deficiency can occur, especially in young pregnant women. Folate deficiency may lead to improper fetal brain development very early in pregnancy (often before pregnancy is detected), and folate supplementation should be considered before conception. Folate fortification of flour and cereal products is now common, and this has helped to reduce the incidence of neural tube defects. Vit B12 is only made by bacteria, but animal products are good sources (because of very good storage in the body) and a little bacterial spoilage adds Vit B12 to the diet. To become deficient, you need to be an affluent vegetarian (who can discard any spoiled food). On becoming a vegan, Vit B12 deficiency may not set in for up to 7 years, due to excellent storage. Some people have a genetic defect in Vit B12 absorption, which causes the same pathologies, and it is called “pernicious anaemia”. This is treated with injections or dietary mega-doses of Vit B12. If megaloblastic anaemia due to Vit B12 deficiency is misdiagnosed as folate deficiency, the person may end up increasing folate intake. At a certain point, the folate intake will overcome the ability of the intestinal enterocytes for N5methylation and folate will go to the liver and be converted into THF. THF will flow to tissues to

overcome the methyl trap. Megaloblastic anaemia will be cured, but the patient will gradually develop signs of neural degeneration and death. This is why it is important to make the correct diagnosis, and not accidently treat a Vit B12 deficiency with folate....