Folic acid is an essential
vitamin for a wide spectrum of biochemical reactions; however, unlike bacteria and plants, mammals are devoid of
folate biosynthesis and thus must obtain this cofactor from exogenous sources. Therefore,
folate deficiency may impair the de novo biosynthesis of
purines and thymidylate and thereby disrupt
DNA and
RNA metabolism,
homocysteine remethylation,
methionine biosynthesis, and subsequent formation of
S-adenosylmethionine (the universal methyl donor) which in turn may lead to altered methylation reactions. This impaired
folate-dependent intracellular metabolism can lead to several key pathologies including, for example,
megaloblastic anemia,
homocysteinemia,
cardiovascular disease, embryonic defects, in particular
neural tube defects (NTDs),
congenital heart defects, and possibly
cancer. The current review presents and evaluates the up-to-date knowledge regarding the molecular mechanisms underlying cellular survival and/or adaptation to
folate deficiency or insufficiency. These mechanisms of adaptation to
folate deficiency generally associated with
folate uptake, intracellular
folate retention,
folate-dependent metabolism, and active
folate efflux specifically include: (a) Up- or downregulation of various
folate-dependent
enzymes like
dihydrofolate reductase (DHFR) and
thymidylate synthase (TS), (b) Cellular retention of folates via polyglutamylation by the
enzyme folylpoly-gamma-glutamate synthetase (FPGS), (c) Overexpression of
folate influx systems including the
reduced folate carrier (RFC),
folate receptor (FR) as well as the
proton-coupled folate transporter (PCFT), a recently identified intestinal
folate influx transporter optimally functioning at the acidic microclimate of the upper intestinal epithelium, (d) Downregulation of
ATP-driven
folate efflux transporters of the multidrug resistance
protein (MRP; ABCC) family and
breast cancer resistance
protein (BCRP; ABCG2) that belong to the multidrug resistance (MDR) efflux transporters of the
ATP-binding cassette (ABC) superfamily. Moreover, the intricate interplay between various components of the adaptive response to
folate deprivation is also discussed.