ABSTRACT
The treatment, cure and prevention of parasitic diseases has been hampered by a lack of knowledge about parasite metabolism and nutritional requirements. In large part, this can be attributed to the unavailability of suitable defined growth media in which to cultivate these organisms. One metabolic pathway that has been exploited for the chemotherapeutic manipulation of certain parasitic diseases is that for the synthesis of reduced folate co-enzymes. Folk acid is a vitamin that consists of a pterin ring, 2-amino-4-oxo-6-(hydroxymethyl)pterin, attached to the amino group of p-aminobenzoic acid (PABA), which in turn is attached through its carboxylate group to the a-amino group of glutamic acid. The vitamin is converted to its activated co-enzyme derivative, tetrahydrofolate (THF), by a two-step reduction process catalysed by the enzyme dihydrofolate reductase (DHFR). THF participates in a variety of one-carbon-atom transfer reactions in humans, including the synthesis of purine and thymidylate nucleotides, the reformation of methionine from homocysteine, and the interconversion of serine and glycine. Tetrahydrofolate is similar in structure to tetrahydrobiopterin, another reduced pteridine, which participates in a variety of mixed-function oxidase reactions, including the specific hydroxylations of the amino acids phenylalanine, tyrosine and tryptophan. However, unlike tetrahydrobiopterin, which humans can biosynthesize from guanosine triphosphate (GTP), THF cannot be manufactured de novo by humans since the enzymatic machinery of human cells is incapable of synthesizing the paminobenzoic acid moiety. However, plants and protists can synthesize THF by condensing 2-amino-4-oxo-6-(hydroxymethyl)dihydropterin with PABA to form dihydropteroate, a reaction catalysed by dihydropteroate synthetase, followed by conjugation of the dihydropteroate to glutamate (see Figure 51.1 in Chapter 51).
