FOLATE METABOLISM

Folate nutrition and metabolism and

influence on NTDs

Peri-conceptual folic acid reduces incidence of birth defects

Polymorphisms in folate genes and/or poor folate status are metabolic

and genetic risk factors for disease (cancer, vascular disease, birth
defects)

Daily recommended intakes (DRIs) for folate may be

influenced by individual genetic profiles

Metabolic roles of folate and factors that influence its requirement

 Folate transport and retention in the body

Dietary folates, primarily polyglutamates, are hydrolyzed by

a brush border hydrolase, prior to absorption in the gut.

Monoglutamate forms circulate in plasma and are transported

into tissues via a membrane carrier (RFC) and/or by a receptor-
mediated process (FBP).

Folate retention by tissues requires their conversion to long

chain length polyglutamate forms. Incomplete conversion to
polyglutamates by tissues such as intestinal mucosa and liver leads to
release of folate, mainly as methylfolate, into plasma.

Tissue folates turn over primarily by catabolism to pterins and

aminobenzoylpolyglutamates. The half life of whole body folate
is approximately 100-200 days, depending on folate intake.
 Folate transport and retention in the body:
effect of high folate intake

Plasma folate levels increase as folate intake increases while tissue folate
levels saturate at high folate intakes. Although folate absorption and tissue
uptake are not limited, a decreased ability to convert the entering folate in
tissues to retainable polyglutamate forms leads to release of much of the
transported folate back to the plasma.

At high folate doses, the capacity of the intestinal mucosa and liver to
metabolize the dose to methylfolate is exceeded and unmetabolized folate is
released into the circulation.

The half life of whole body folate decreases with increased

folate intake. At very high intakes, the initial loss is due to exceeding the
renal capacity for reabsorption.
Sources of Folate Fol ate RDAs A c r o ss th e Li fe Cy cl e
Fortifi ed cereals
g/day
Vege tables
Bread and bread produc ts Infants (AI) 65 - 80
Citr us fruit s and juices Childr en 150 300
Meat, poult ry and fish
Adolescents and Adults 400
Elderly Subjects 400
Pregnant Women * 600
Lactating Women 500

* Higher levels may be required to minimi ze the risk of birth defects. The
recommendation for women of child bearing age, who are capable of
becoming pregnant, is to take 400 g folic acid per day, derived from
supplements and/or fortifi ed food, in additional to their no rmal food folate
int ake. NB. 400 g folic acid is equivalent to almo st 700 g food folate.
The current level of fortification of the US food supply supplies a daily
average of about 200 g folic acid or the equivalent of 350 g food folate.
 remethylation transmethylation
serine
methionine
SHMT PLP MATII
cytosine
glycine THF
AdoMet X

MS B12
CH2-THF
AdoHcy CH3-X
MTHFR CH3-cytosine
homocysteine
FAD CH3-THF SAHH

adenosine

export
 remethylation transmethylation
serine
methionine
SHMT PLP MATI/III
glycine THF glycine
AdoMet
cytosine

GNMT
MS B12 BHMT
CH2-THF CH3-cytosine
AdoHcy sarcosine
MTHFR
homocysteine
FAD CH3-THF SAHH
CS PLP
adenosine
cystathionine

PLP

cysteine
transsulfuration
 Consequences of impaired folate status or
metabolism

Metabolic Biochemical Clinical

Disruption Markers Associations

Cancer
S-adenosylmethionine Hypomethylated DNA CVD
(MTHFR, MS, B12 Elevated homocysteine demyelination
deficiency) Reduced methylation NTDs

Increased uracil in DNA Cancer

Decreased DNA NTDs
Thymidylate
synthesis & reduced cell Anemia
division

Purines (A,G) Decreased DNA

Anemia
synthesis & reduced
cell division
 Neural tube defects (NTDs)
The most common congenital abnormality at birth in US

Neural tube closes during fourth week post conception

Embryo nutrition dependent on yolk sac during this period

Peri-conceptual folic acid decreases the incidence of NTDs

Disruption of some folate genes in mice produces a NTD

phenotype: in some cases preventable by additional folate
Relationship of early pregnancy maternal red cell
folate to risk of NTD
12

10

NTD Risk per 1000 Births

8

0
453 906 1360 1813
(200) (400) (600) (800)

Red Cell Folate, nmol/L (ng/mL)

Daly et al JAMA 1995; 274:1698-702

 Folate and the etiology of NTDs
Mechanism(s) for protective effect of folate not established

Etiology is both environmental and genetic

Not all NTDs are preventable by additional folate

Common polymorphisms in some folate genes influence NTD risk

MTHFR 677 C->T (case risk)

Folate fortification is the first nutritional intervention to expose the

entire population to target distinct genetic populations
A common polymorphism in the MTHFR gene
______________________________________________________

Normal allele
Gene sequence ..GCG GGA GCC GAT
Protein Sequence Ala Gly Ala Asp.

677 C->T allele

Gene Sequence ..GCG GGA GTC GAT.
Protein Sequence Ala Gly Val Asp .
______________________________________________________

Associated with elevated homocysteine when folate (and

riboflavin) status is poor, and decreased cancer risk.

Elevated homocysteine is a risk factor for vascular disease.

Common genetic variation may influence
the requirement for folate
Risk of inadequacy

EAR1 EAR2
UL

Risk of excess
0.5 0.5

RDA1 RDA2
Increasing intake