Metabolic functions of folate

Metabolic functions of folate
Domina Petric, MD

Coenzymes in single-carbon
metabolism
I.
April 20, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
2

Introduction
• The folates function as enzyme co-substrates in
many reactions of the metabolism of amino acids
and nucleotides, as well as the formation of the
primary donor for biological methylations,
S-adenosylmethionine (SAM).
• In each of these functions, the fully reduced
(tetrahydro-) form of each serves as an acceptor
or donor of a single-carbon unit.
• These reactions are referred to as single-carbon
metabolism.
April 20, 2018
3

Methionine and S-adenosylmethionine
(SAM) synthesis
• As 5-methyl-FH4, which is freely produced from
5,10-methenyl-FH4, folate provides labile methyl
groups for methionine synthesis from
homocysteine.
• Methionine is essential for the synthesis of
proteins and polyamines, and is the precursor of
SAM, which serves as a donor of labile methyl
groups for more than 100 enzymatic reactions
that have critical roles in metabolism.
April 20, 2018
4

Methionine and S-adenosylmethionine
(SAM) synthesis
S-adenosylmethionine also serves as a key
regulator of the transsulfuration and
remethylation pathways.
This metabolism is catalyzed by two enzymes:
methylenetetrahydrofolate reductase (MTHFR)
and methionine synthase.
Methylenetetrahydrofolate reductase is necessary
for the production of 5-methyl-FH4, the obligate
single-carbon donor for methionine synthesis.
April 20, 2018
5

Histidine catabolism
Cytosolic formiminotransferase
catalyzes the final reaction in the
catabolism of histidine by
transferring the formimino group
from formiminoglutamate
(FIGLU) to FH4.
April 20, 2018
6

Nucleotide metabolism
Folates are required for the synthesis of
thymidylate and for purine synthesis.
Both roles are necessary for de novo
synthesis of DNA and thus for DNA
replication and cell division.
Disruption of these functions impairs cell
division and results in the macrocytic
anemia of folate deficiency.
April 20, 2018
7

Thymidylate synthesis
• Folates transport formaldehyde (as 5,10-
methylene-FH4) for thymidylate synthesis.
• The enzyme thymidylate synthase catalyzes
the conversion of deoxyuridine
monophosphate (dUMP) to
deoxythymidine monophosphate (dTMP),
involving the transfer of formaldehyde
from 5,10-methylene-FH4 to dUMP.
April 20, 2018
8

Thymidylate synthesis
This step is rate limiting to DNA replication, thus
enabling the normal progression of the cell cycle.
Thymidylate synthase is expressed only in
replicating tissues.
The highest expression occurs during the S phase
of the cell cycle.
April 20, 2018
9

Purine synthesis
• Folates transport formate (as 10-formyl-
FH4, produced from 5,10-methylene-FH4) in
two steps in the synthesis of purines:
synthesis of adenine and guanine.
• In this way, formyl groups are used to
provide the C-2 and C-8 positions of the
purine ring, and FH4 is regenerated.
April 20, 2018
10

Purine synthesis
These reactions are catalyzed by
aminoimidazolecarboxamide
ribonucleotide tranformylase
and glycinamide ribonucleotide
tranformylase.
April 20, 2018
11

Regulation of single-carbon metabolism
The regulation of single-carbon metabolism
is effected by the interconversion of
oxidation states of the folate intermediates.
β-carbon of serine is the major source of
single-carbon units for these aspects of
metabolism.
April 20, 2018
12

That carbon fragment is accepted by FH4 to form 5,10-
methylene-FH4 (by serine hydroxymethyltransferase),
which has a central role in single-carbon metabolism.
The latter derivative can be used directly
for the synthesis of thymidylate (by
thymidylate synthetase).
It can be oxidized to 5,10-methenyl-FH4 (by 5,10-
methylene-FH4 dehydrogenase) for use in the de novo
synthesis of purines, or it can be reduced to 5-methyl-FH4
(by MTHFR) for use in the biosynthesis of methionine.
April 20, 2018
13

• The result is the channeling of single-carbon
units in several directions: to methionine, to
thymidylate (for DNA synthesis) or to purine
biosynthesis.
• Folyl polyglutamates have been found to inhibit a
number of the enzymes of single-carbon
metabolism.
• Variation in their polyglutamate chain lengths
may play a role in the regulation of single-carbon
metabolism.
April 20, 2018
14

The methyl-folate trap
April 20, 2018
15

• The committed step (5,10-methylene-FH4
reductase) is feedback inhibited by
S-adenosylmethionine and product inhibited by
5-methyl-FH4.
• Methionine synthetase depends on the transfer
of labile methyl groups from 5-methyl-FH4 to
vitamin B12.
• Methyl-B12 serves as the immediate methyl
donor for converting homocysteine to
methionine.
April 20, 2018
16

• Without adequate levels of vitamin B12 to accept
methyl groups from 5-methyl-FH4, homocysteine
accumulates at the expense of the other
metabolically active folate pools.
• This is known as the methyl-folate trap.
• The loss of FH4, that results from this blockage in
folate recycling, blocks transfer of the histidine-
formino group to folate (as 5-formimino-FH4)
during the catabolism of that amino acid.
April 20, 2018
17

This results in the accumulation of
the intermediate
formiminoglutamate (FIGLU).
Elevated urinary FIGLU levels after
an oral histidine load are diagnostic
of vitamin B12 deficiency.
April 20, 2018
18

Health effects
II.
April 20, 2018
19

Homocysteinemia
April 20, 2018
20

Homocysteinemia
Accumulation of homocysteine can occur through:
• elevated production of homocysteine from
methionine
• impaired disposal of homocysteine through
transsulfuration to cystathionine
This results in homocysteinemia and
homocysteinuria.
April 20, 2018
21

Homocysteinemia
• Homocysteine can be converted to homocysteine
thiolactone by methionyl tRNA synthetase, in an
error-editing reaction that prevents its incorporation
into the primary structure of proteins.
• At high levels the thiolactone can react with protein
lysyl residues.
• Protection against the damage to high-density
lipoproteins that results from homocysteinylation is
effected by a Ca2+-dependent homocysteine
thiolactonase associated with those particles.
April 20, 2018
22

Homocysteinemia
Homocysteinemia can have congenital
causes and can also be related to
nutritional status with respect to
vitamin B6, vitamin B12 and folate.
It causes displacement of protein-
bound cysteine, which results in
changes in redox thiol status, probably
via thiol-disulfide exchange and redox
reactions.
April 20, 2018
23

Homocysteinemia
Homocysteinemia can respond to
supplementation of folic acid.
The relationship is linear up to daily
folate intakes of about 0.4 mg.
April 20, 2018
24

Homocysteinemia
• The MTHFR genotype can also affect
plasma homocysteine levels.
• Individuals with the C677T T/T
genotype have slightly lower levels of
folate and slightly higher levels of
homocysteine in comparison to other
(C/C and C/T) genotypes.
April 20, 2018
25

Cardiovascular disease
Folate supplementation has been shown to
reverse endothelial dysfunction
independent of its effect in lowering
plasma homocysteine level, to reduce
arterial pressure and increase coronary
dilation.
These effects likely involve the stimulation
of nitric oxide production by 5-methylfolic
acid, and perhaps also inhibition of
lipoprotein oxidation by folic acid.
April 20, 2018
26

Neural tube defects (NTD)
Folate has an important role in normal
embryogenesis, apparently involving its
support of normal cell division.
Studies in the United States
demonstrated the efficacy of folate
supplements (400-4000 µg) in
preventing second NTDs in women with
prior NTD pregnancies.
April 20, 2018
27

Other serious pregnancy complications
Low-folate status has been associated with
other congenital defects, including cleft lip
and palate and defective development of
limbs and the heart.
Homocysteinemia has been associated with
increased risks of hypertension,
preeclampsia and placental abruption.
April 20, 2018
28

Erythropoiesis
Folate is required for the production of new
erythrocytes through its functions in:
• synthesis of purines and thymidylate
required for DNA synthesis as well as
through its function
• regenerating methionine, the methyl
donor for DNA methylation
April 20, 2018
29

Erythropoiesis
Folate deficiency causes:
• arrest of erythropoiesis prior to the
late stages of differentiation
• apoptotic reduction of cells surviving
to postmitotic, terminal stages
The condition is called megaloblastic
anemia.
April 20, 2018
30

Erythropoiesis
Addition of folate to
iron supplements can
improve the treatment
of anemia in pregnancy.
April 20, 2018
31

DNA methylation
Folate appears to have a role in the
methylation of DNA by virtue of its
function in single-carbon metabolism, as
the methylation of cytosine is important in
regulating gene transcription.
Folate deprivation has been found to
produce chromosomal breaks in
megaloblastic bone marrow, reflecting DNA
strand breaks and hypomethylation.
April 20, 2018
32

Cancer
Folate deprivation, by enhancing genomic
instability and dysregulated gene
transcription, appears to enhance
predisposition to neoplastic transformation.
Low-folate status has been associated with
increased risk of cancers of the colon, cervix,
lung, oral and pharyngeal, head and neck,
stomach and gastrointestinal tract, and brain.
April 20, 2018
33

Immune system
Folate supplementation can stimulate natural
killer (NK) cell cytotoxicity among subjects of
low-folate status.
Among subjects consuming a high-folate diet
the NK cytotoxicity was inversely related to the
plasma concentration of the non-metabolized
form of the vitamin, folic acid.
April 20, 2018
34

Cognitive function
• Folate is required to maintain
homocysteine at low levels in the central
nervous system.
• Hyperhomocysteinemia has been
associated with increased risks to
psychiactic and neurodegenerative
disorders including depression,
schizophrenia, Alzheimer’s disease and
Parkinson’s disease.
April 20, 2018
35

April 20, 2018
36
MTHFR polymorphisms

Vascular disease
The T/T C677T MTHFR
genotype has been identified
as a risk factor for carotid
intima-media thickening, a
risk factor to vascular disease.
April 20, 2018
37

Neural tube defects
The protective effect of folate
supplementation against NTD risk may
be limited to a subset of subjects with
defective folate metabolism
caused by MTHFR mutations.
The T/T C677T genotype is
associated with NTD risk, but the
effect appears to be dependent on
folate status.
April 20, 2018
38

Down syndrome
T/T C677T genotype
elevates risk in individuals
also carrying a mutation in
methionine synthase
reductase.
Such individuals have
also been found to
have elevated risks of
Down syndrome.
April 20, 2018
39

Cognitive disorders
Individuals of the T/T
C677T genotype have
increased risks of
depression and
schizophrenia.
April 20, 2018
40

Cancer
Homozygosity for
T/T C677T MTHFR
has consistently
been found to be
associated
with reduced risk
for colorectal
cancer.
The T/T genotype
does not appear
to affect risk for
colorectal
adenoma unless
folate status is
low, in which case
it is related to
increased risk.
April 20, 2018
41

Cancer
These risks
appear to be
even greater
in individuals
with the
combined
C677T/A1298C
heterozygous
genotype.
The T/T
genotype
has also
been
associated
with
increased
risk for
lymphocytic
leukemia.
April 20, 2018
42

Methotrexate therapy
April 20, 2018
43

Bone mineral density
One study found that women of the T/T C677T
genotype showed reduced bone mineral
density if they had relatively low intakes of
folate, vitamin B12 and riboflavin.
April 20, 2018
44

April 20, 2018
45
Masking vitamin B12 deficiency

Masking vitamin B12 deficiency
High-level intakes of folate can interfere with the
clinical diagnosis of vitamin B12 deficiency by
preventing the common presenting sign,
megaloblastic anemia.
Folate supplementation does not mask the
irreversible progression of neurological dysfunction
and cognitive decline of vitamin B12 deficiency.
Neurologic signs develop over a longer timeline than
does the anemia produced by the deficiency.
April 20, 2018
46

Literature
• Combs GF. The Vitamins. Fundamental Aspects in
April 20, 2018 47

Metabolic functions of folate

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