Folic Acid (Vitamin B9) Biochemistry and Nutrition

Vitamin B9, a water-soluble vitamin

Pteridine (2-amino-4-hydroxy-pteridine / pterin), PABA (para-aminobenzoic acid), and Glutamic Acid

2-amino-4-hydroxy-pteridine (pterin)

Green leafy vegetables (spinach, broccoli, lettuce), okra, asparagus, fruits (bananas, melons, lemons), yeast, mushrooms, meat and liver, and fortified foods

No, it must be obtained from dietary sources

In the small intestine, in the upper jejunum

400 µg/day DFE (dietary folate equivalent)

600 µg/day DFE

500 µg/day DFE

Supports cell growth and DNA synthesis, promotes healthy red blood cell production, is crucial for fetal development, and supports tissue and organ health

Folate is reduced to dihydrofolate (DHF) and then to tetrahydrofolate (THF) by dihydrofolate reductase using NADPH

Dihydrofolate reductase (DHFR)

NADPH + H+

By addition of four hydrogen atoms to the 5, 6, 7 and 8 positions in the pteridine ring

Tetrahydrofolate (THF)

It acts as a carrier of one-carbon residues in one-carbon metabolism

Formyl (-CHO), formimino (-CH=NH), methenyl (-CH=), methylene (-CH2-), hydroxymethyl (-CH2OH), and methyl (-CH3)

Serine, glycine, and histidine

Purine synthesis

Conversion of dUMP to dTMP (thymidine monophosphate) and serine-glycine interconversion

It donates a methyl group for conversion of homocysteine to methionine, a reaction that requires vitamin B12

Histidine metabolism

Synthesis of active methionine used in transmethylation reactions

Synthesis of choline, epinephrine, creatine, etc.

Inhibition of DNA synthesis during erythropoiesis, delaying nuclear maturation and cell division while cytoplasmic maturation continues normally, so haemopoietic precursor nuclei appear abnormally large and immature

Fatigue and weakness, pallor, glossitis, and megaloblastic / macrocytic anemia

N5-methyl-THF cannot donate its methyl group to convert homocysteine to methionine

Oxidative stress, endothelial damage, and enhanced thrombogenicity, increasing risk of myocardial infarction and stroke

Neural tube defects such as spina bifida due to improper closure of the neural tube

Elevated homocysteine and decreased folic acid levels in pregnant women

Periconceptual supplementation with folate reduces the risk

Humans cannot synthesize folic acid and must rely on dietary sources, while bacteria synthesize it; sulfonamides are PABA analogs and do not interfere with human purine synthesis

Because of structural similarity to PABA, they compete for bacterial dihydropteroate synthase, so THF cannot be converted to purines needed for bacterial DNA synthesis and the bacterial cell cannot divide

Dihydropteroate synthase (DHPS) in bacteria

It is a folic acid analogue that inhibits dihydrofolate reductase (DHFR), limiting THF available for purine synthesis and slowing DNA replication in mammalian cells

It is toxic to all dividing cells, not only cancer cells

Dihydropteroate synthase (DHPS), inhibited by sulfa drugs, and dihydrofolate reductase (DHFR), inhibited by pyrimethamine and trimethoprim

Combinations of inhibitors acting against different targets have a synergistic effect and help prevent drug resistance