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microorganisms require selecting the strains most suitable for this application. Hence, the potential of folate
from bacterial origin will be discussed in this review.

HISTORY OF FOLATE INVOLVEMENT IN HOST HEALTH
Folate was first identified in the 1930s as a substance, named the “Willis factor” by Lucy Willis, that helped
[16]
prevent anemia during pregnancy . Folate was first described in 1941, when folic acid received its name
after being isolated from spinach (folium means leaf in Latin) by Mitchell et al., and showed its activity as a
[17]
growth factor for Streptococcus lactis R (now Lactococcus lactis) . In the 1960s-1970s, Brown et al. first
identified the folate pathway, the intermediates involved, and the enzymes catalyzing all reactions [18-21] .

CHEMICAL STRUCTURE AND BIOSYNTHETIC PATHWAY
Folate belongs to the group of pteridines and is also known as vitamin B vitamin M, folacin, pteroyl-L-
9,
glutamic acid, and pteroyl-glutamate. Its structure comprises three subunits: (i) a pterin moiety originating
from 6-hydroxymethyl-7,8-dihydro pterin pyrophosphate (DHPPP) and (ii) a para-aminobenzoic acid
(pABA) unit linked via a methylene bridge to form the pteroic acid, which is joined by a peptide linkage to
(iii) glutamic acid. The acyl group derived from the pteroic acid is a pteroyl group. Folic acid is also called
pteroylglutamate (pteroyl-L-glutamic acid) [Figure 1]. Shikimate and folate biosynthesis pathways and
relevant enzymes and genes involved are described in Figure 2.

While a group of bacteria possess all the enzymes to produce folate, mammals lack most of these enzymes,
which explains their dependence on exogenous sources of the vitamin [Figure 2]. This finding has been
supported by analysis with the software BRENDA (Braunschweiger Enzymdatenbank) (https://www.
brenda-enzymes.org/), which showed that mammals possess only guanosine triphosphate (GTP)
cyclohydrolase (3.5.4.16), tetrahydrofolate synthase (6.3.2.17), and dihydrofolate reductase (1.5.1.3)
[Figure 2 and Supplementary Table 1].

Folic acid is a synthetic folate analog with a fully oxidized pteridine ring. Natural folates exist in their
dihydro- (as in DHF) and tetrahydro- (as in THF) folate forms [Supplementary Figure 1]. Natural folates
are found in foods and are all conjugated to a polyglutamyl chain containing different numbers of glutamic
acids [Supplementary Figure 2] depending on the type of food; green vegetables and yeasts usually contain
[22]
the eptaglutamic folate form, whereas meat contains the pentaglutamic form .
The biological role of folates in metabolism is to donate one-carbon units in various biosynthetic pathways
within cells, such as the biosynthesis of purine and pyrimidine, the metabolic transformation of glycine into
serine, and the formation of glutamate from a histidine metabolite. Furthermore, folate plays an important
role in homocysteine methylation, converting it into methionine by the action of the 5-methyl-THF
(5-MTHF) cofactor. Owing to this reaction, the potentially cytotoxic effect of excess homocysteine levels is
alleviated, and methionine is produced . The latter is then activated to S-adenosyl methionine, the most
[23]
important methyl group donor in cell metabolism .
[24]
Dietary folates mainly exist as 5-methyl- and 10-formyl-THF in polyglutamate forms that cannot cross cell
membranes . The latter must be enzymatically hydrolyzed by folylpolyglutamate conjugase to the
[25]
monoglutamyl form to be absorbed. This process occurs in the small intestine, duodenum (main
absorption), distal jejunum (small absorption), distal ileum (virtually no absorption), and to a lesser extent,
also in the colon. In the brush border of mucosal cells, the polyglutamyl chain is removed by the enzyme
pteroyl-gamma-glutamyl carboxypeptidase (GCPII) associated with the mucous membranes of the cells and
folate monoglutamate is subsequently absorbed . The transport of folate monoglutamate inside human
[26]