All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. The enzyme 7,8-dihydropteroate synthase (DHPS) catalyses the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7, 8-dihydropterin-pyrophosphate to form 7,8-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes, lower eukaryotes, and in plants, but is absent in mammals . By contrast, higher vertebrates possess an active transport system that enables them to use dietary folates. DHPS is the target of sulphonamides, which are substrate analogues that compete with pABA, but which do not affect vertebrates as they lack the DHPS enzyme. DHPS is a single domain protein that forms an eight-stranded TIM alpha/beta barrel, where the 7,8-dihydropterin pyrophosphate substrate binds in a deep cleft in the barrel . In the lower eukaryote Pneumocystis carinii, DHPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas) .
Other proteins contain a DHPS-like domain, including members of the methyltetrahydrofolate (corrinoid iron-sulphur protein methyltransferase (MeTr)) family. MeTr catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation . Other members of this family that contain a DHPS-like domain include methionine synthase and methanogenic enzymes that activate the methyl group of methyltetrahydromethano(or -sarcino)pterin.