The biological activity of<unk>  in the body depends upon dihydrofolate reductase action in the liver which converts<unk>  into tetrahydrofolate (THF). This action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized<unk> ic acid when consumption from dietary supplements and fortified foods nears or exceeds the U.S. Tolerable Upper Intake Level of 1,000 μg per day. Biosynthesis Animals, including humans, cannot synthesize<unk>  and therefore must obtain<unk>  from their diet. All plants and fungi and certain protozoa, bacteria, and archaea can synthesize<unk>  de novo through variations on the same biosynthetic pathway. The<unk>  molecule is synthesized from pterin pyrophosphate, para-aminobenzoic acid, and glutamate through the action of dihydropteroate synthase and dihydrofolate synthase. Pterin is in turn derived in a series of enzymatically catalyzed steps from guanosine triphosphate (GTP), while para-aminobenzoic acid is a product of the shikimate pathway. Bioactivation Biotransformation of<unk> ic acid into<unk> inic acids where R = para-aminobenzoate-glutamate. All of the biological functions of<unk> ic acid are performed by THF and its methylated derivatives. Hence<unk> ic acid must first be reduced to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, dihydrofolate reductase.<unk> ic acid is first reduced to dihydrofolate and then to tetrahydrofolate. Each step consumes one molecule of NADPH (biosynthetically derived from vitamin B3) and produces one molecule of NADP. Mechanistically, hydride is transferred from NADPH to the C6 position of the pteridine ring. A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of serine hydroxymethyltransferase (SHMT) to yield 5,10-methylenetetrahydrofolate (5,10-CH2-THF). This reaction also consumes serine and pyridoxal phosphate (PLP; vitamin B6) and produces glycine and pyridoxal. A second enzyme, methylenetetrahydrofolate dehydrogenase (MTHFD2) oxidizes 5,10-methylenetetrahydrofolate to an iminium cation which in turn is hydrolyzed to produce 5-formyl-THF and 10-formyl-THF. This series of reactions using the β-carbon atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell. Alternative carbon sources include formate which by the catalytic action of formate–tetrahydrofolate ligase add a 1C unit to THF to yield 10-formyl-THF. Glycine, histidine, and sarcosine can also directly contribute to the THF-bound 1C pool. Drug interference A number of drugs interfere with the biosynthesis of THF from<unk> ic acid. Among them are the antifolate dihydrofolate reductase inhibitors such as the antimicrobial, trimethoprim, the antiprotozoal, pyrimethamine and the chemotherapy drug methotrexate, and the sulfonamides (competitive inhibitors of 4-aminobenzoic acid in the reactions of dihydropteroate synthetase). Valproic acid, one of the most commonly prescribed epilepsy treatment drugs, also used to treat certain psychological conditions such as bipolar disorder, is a known inhibitor of<unk> ic acid, and as such, has been shown to cause birth defects, including neural tube defects, plus increased risk for children having cognitive impairment and autism. There is evidence that<unk>  consumption is protective.
Folate
Iron
Calamine
Zinc
Tocopherol
Pantothenic acid
Biotin
Riboflavin