PRIMARY STRUCTURE AND EXPRESSION OF THE DIHYDROPTEROATE SYNTHETASE GENE OF PLASMODIUM-FALCIPARUM

The enzyme dihydropteroate synthetase (DHPS) from Plasmodium falciparu m is involved in the mechanism of action of the sulfone/sulfonamide gr oup of drugs. We describe the cloning and sequencing of the gene encod ing the P. falciparum DHPS enzyme and show that it is a bifunctional e nzyme that includes dihydro-6-hydroxymethylpterin pyrophosphokinase (P PPK) at the N terminus of DHPS. The gene encodes a putative protein of 83 kDa that contains two domains that are homologous with the DHPS an d PPPK enzymes of other organisms. The PPPK-DHPS gene is encoded on ch romosome 8 and has two introns. An antibody raised to the PPPK region of the protein was found to recognize a 68-kDa protein that is express ed throughout the asexual life cycle of the parasite. We have determin ed the sequence of the DHPS portion of the gene from sulfadoxine-sensi tive and -resistant P. falciparum clones and identified sequence diffe rences that may have a role in sulfone/sulfonamide resistance.