Folate Biosynthesis, Reduction, and Polyglutamylation and the Interconversion of Folate Derivatives

Many microorganisms and plants possess the ability to synthesize folic acid derivatives de novo, initially forming dihydrofolate. All the folic acid derivatives that serve as recipients and donors of one-carbon units are derivatives of tetrahydrofolate, which is formed from dihydrofolate by an NADPH-dependent reduction catalyzed by dihydrofolate reductase (FolA). This review discusses the biosynthesis of dihydrofolate monoglutamate, its reduction to tetrahydrofolate monoglutamate, and the addition of glutamyl residues to form folylpolyglutamates. Escherichia coli and Salmonella, like many microorganisms that can synthesize folate de novo, appear to lack the ability to transport folate into the cell and are thus highly susceptible to inhibitors of folate biosynthesis. The review includes a brief discussion of the inhibition of folate biosynthesis by sulfa drugs. The folate biosynthetic pathway can be divided into two sections. First, the aromatic precursor chorismate is converted to paminobenzoic acid (PABA) by the action of three proteins. Second, the pteridine portion of folate is made from GTP and coupled to PABA to generate dihydropteroate, and the bifunctional protein specified by folC, dihydrofolate synthetase, or folylpolyglutamate synthetase, adds the initial glutamate molecule to form dihydrofolate (H2PteGlu1, or dihydropteroylmonoglutamate). Bacteriophage T4 infection of E. coli has been shown to cause alterations in the metabolism of folate derivatives. Infection is associated with an increase in the chain lengths in folylpolyglutamates and particularly the accumulation of hexaglutamate derivatives.