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D’Aimmo et al. Microbiome Res Rep 2024;3:11 https://dx.doi.org/10.20517/mrr.2023.59 Page 5 of 22

be reduced to THF in a two-step process led by the enzyme dihydrofolate reductase (DHFR). First, folate is
[27]
reduced to dihydrofolate (DHF), which is further reduced to THF using NADPH as an electron donor .
After absorption, folate is transported to the liver, which is estimated to store 50% of the folate in the body.
The folate pool in the liver is partly secreted (intact or as inactive metabolites) into the bile [28,29] . Between
10%-20% of the absorbed folates are estimated to be retained in the liver . The remaining absorbed folates
[30]
are transported to other tissues via systemic circulation. In plasma, folates are partly protein-bound, mainly
to albumin (50% of bound folates) but also to soluble folate-binding proteins .
[31]

5-methyl-THF is the form in which folate moves out of the enterocyte cells to different tissues; it enters the
bloodstream through the solute carrier family 19 (folate transporter). Once in the bloodstream, the delivery
of 5-methyl-THF to the interior of cells is mediated by reduced folate carriers or folate receptors and
[32]
polyglutamated by folylpolyglutamate synthase . The latter converts intracellular folates into folate
polyglutamates, which are poor substrates for folate transport systems and hence restricted to intracellular
[33]
movement , and passive diffusion over intact membranes is negligible due to the negatively charged
carboxyl groups on each glutamate unit . Folate polyglutamates are also better substrates for enzymes
[34]
[35]
involved in one-carbon transfer .
In cells, 5-methyl-THF can be recycled to THF in a reaction forming methionine. The step is catalyzed by
methionine synthase/methionine synthase reductase (MTR/MTRR), which in humans also depends on
vitamin B (cobalamin); 5-methyl-THF donates its methyl group to B , which transfers it further to
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homocysteine resulting in methionine.
Mammals and other higher eukaryotes express only a B -dependent form of MTR, whereas plants, algae,
12
and fungi express a cobalamin-independent MTR (e.g., yeasts do not need B ). Other microorganisms
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express both the B -dependent and B -independent forms of MTR. Since B deficiency is also common in
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certain human groups, a gut colonizing strain able to synthesize both folate and B , as found in some
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bifidobacteria, may have positive health effects.
The THF formed in the MTR reaction will enter the so-called DNA cycle in which it may be converted to
10-formyl-THF or 5,10-methyleneTHF (a substrate of 5,10-methyleneTHF reductase; MTHFR) and used in
pyrimidine and purine synthesis, and thus DNA and RNA production. The folate form 5,10-methyleneTHF
will be recycled back to 5-methyl-THF through an amino acid synthesis reaction by accepting a one-carbon
[36]
group (-CH3) from the amino acid serine, which is subsequently converted into glycine [Figure 3].
Methionine can be used in the methionine cycle to produce S-adenosyl-methionine (SAM), S-adenosyl-
homocysteine (SAH), and homocysteine [Figure 3]. Accumulation of homocysteine in the cell is thereby
avoided, and synthesis of amino acids is maintained . The conversion of SAM to SAH requires betaine, a
[36]
product of the choline metabolism. SAM is the cellular methyl donor for DNA, RNA, protein, and
phospholipids, and hence also central for epigenetic labeling.

STABILITY AND INTERCONVERSION
Folates are chemically unstable reduced compounds and are particularly susceptible to being split apart by
oxidative cleavage at the C9-N10 bond. This often results in the production of inactive pteridine and
p-aminobenzoylglutamate molecules. However, folates with a substituent in the N5 or N10 position are
more resistant to cleavage .
[37]