Agriculture Reference
In-Depth Information
intestinal mucosa, one of which is zinc dependent, to monoglutamyl, or “free” folate.
Thereafter, absorption seems to be an active process as it can be inhibited by anti-
folates (e.g., sulfasalazine, a drug commonly used in inflammatory bowel disease).
After absorption, it circulates as 5-methyl tetrahydrofolate (THF) monoglutamate
attached to albumin. This is reconjugated in tissues to 5-methyl THF polyglutamate
derivatives. These have one main role in all cells, that of picking up and depositing
one-carbon units. They act as such in two interrelated processes, the methylation
cycle and the DNA cycle.
The DNA cycle is relatively simple. By providing one-carbon units (viz. methyl
groups), both purines and pyrimidines are synthesized, which are then incorpo-
rated in DNA (and RNA). The major folate product is 5,10-methylene THF, which
is reduced by 5,10-methylene THF reductase (MTHFR) to 5-methyl THF, and the
cycle restarts (WHO 2004). Thus, the vitamin is essential for cell replication; hence,
its deficiency causes megaloblastic anemia, in which too few, large, immature red
cells circulate accompanied by too few white cells and too few platelets. The intes-
tinal mucosa's normally high turnover rate is reduced; malabsorption is another out-
come of folate deficiency. Although there is an association between low folate status
and many cancers, it is particularly strong for colorectal cancer. Recent research has
focused on the possible mechanisms. There are clear possibilities. In particular, a
common polymorphism of MTHFR seems to protect against colorectal cancer. Men
who were homozygous for the polymorphism and had adequate folate status had a
threefold lower risk compared with men whose genotype was heterozygous or wild
type. The polymorphism was not protective if they had low folate status. It appears
that the forms of folate within the cells affect the risk of disruption of DNA integrity
and hence cancer (Choi and Mason 2000).
However, in population studies of folic acid supplementation, although the results
have been described as “promising,” they are not clearly positive.
In the methylation cycle, 5-methyl THF is used by methionine synthase to remethylate
homocysteine to methionine. This requires vitamin B
12
(see vitamin B
12
discussion).
Excess methionine is degraded back to homocysteine. A raised plasma concentra-
tion of homocysteine is now considered to be a major independent risk factor for athero-
sclerosis and, indeed, an (imperfect) index of folate status. Homocysteine is normally
safely cleared by cystathionine synthase, with help from vitamin B
6
(pyridoxine).
Absence of the enzyme may be inherited, a consequence of an inborn error of metabo-
lism, homocystinuria. The characteristic features include early atherosclerosis.
Thus, these three vitamins (folate, B
12
, and B
6
) are essential for two major linked
metabolic cycles that involve numerous methylation reactions, including DNA and
RNA syntheses.
Neural tube defects (NTDs), in which the brain or spinal cord does not form
properly before day 27 of pregnancy, are six times more likely when folate status is
poor. In fact, they are also more likely when vitamin B
12
status is poor; this risk has
been exposed in populations receiving folate-fortified flour (Ray et al. 2007). Like
the causes of NTDs, the mechanisms underlying these findings are still unclear. It
may be presumed that they involve the DNA and methylation cycles, however. So
far, it appears that there are some genetic mutations associated with NTDs, and
there is no doubt that having one affected child increases the risk of having a second
