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Journal article
The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages
The Journal of biological chemistry, v 289(50), pp 34827-34837
12 Dec 2014
PMID: 25352601
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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-[13C4]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.
Background: Malaria parasites require heme for growth.
Results: Genetic disruption of the P. falciparum heme biosynthesis pathway ablated growth in mosquitoes but had no effect on blood-stage growth.
Conclusion: The heme biosynthesis pathway is only essential for exoerythrocytic parasite growth and transmission to mosquitoes.
Significance: Pathway inhibition is unlikely to be an effective antimalarial drug strategy. Heme salvage mechanisms likely exist in blood stages.
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Details
- Title
- The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages
- Creators
- Hangjun Ke - Drexel UniversityPaul A. Sigala - Howard Hughes Medical InstituteKazutoyo Miura - the Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852, and.Joanne M. Morrisey - Drexel UniversityMichael W. Mather - Drexel UniversityJan R. Crowley - Center for Infectious Disease Research and PolicyJeffrey P. Henderson - Washington University in St. LouisDaniel E. Goldberg - Howard Hughes Medical InstituteCarole A. Long - the Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852, and.Akhil B. Vaidya - Drexel University
- Publication Details
- The Journal of biological chemistry, v 289(50), pp 34827-34837
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000346260800034
- Scopus ID
- 2-s2.0-84918580707
- Other Identifier
- 991019168633804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology