Heme is an essential cofactor for aerobic organisms. Its redox chemistry is central to a variety of
biological functions mediated by hemoproteins. In blood stages,
malaria parasites consume most of the
hemoglobin inside the infected erythrocytes, forming nontoxic
hemozoin crystals from large quantities of
heme released during digestion. At the same time, the parasites possess a
heme de novo biosynthetic pathway. This pathway in the human
malaria parasite Plasmodium falciparum has been considered essential and is proposed as a potential
drug target. However, we successfully disrupted the first and last genes of the pathway, individually and in combination. These knock-out parasite lines, lacking 5-aminolevulinic
acid synthase and/or
ferrochelatase (FC), grew normally in blood-stage culture and exhibited no changes in sensitivity to
heme-related
antimalarial drugs. We developed a sensitive LC-MS/MS assay to monitor stable
isotope incorporation into
heme from its precursor 5-[(13)C4]
aminolevulinic acid, and this assay confirmed that de novo
heme synthesis was ablated in FC knock-out parasites. Disrupting the FC gene also caused no defects in gametocyte generation or maturation but resulted in a greater than 70% reduction in male gamete formation and completely prevented oocyst formation in female Anopheles stephensi mosquitoes. Our data demonstrate that the
heme biosynthesis pathway is not essential for asexual blood-stage growth of P. falciparum parasites but is required for mosquito transmission.
Drug inhibition of pathway activity is therefore unlikely to provide successful
antimalarial therapy. These data also suggest the existence of a parasite mechanism for scavenging host
heme to meet metabolic needs.