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About the Authors:
Daniel E. Goldberg
* E-mail: [email protected] (DEG); [email protected] (PAS)
Affiliation: Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
ORCID http://orcid.org/0000-0003-3529-8399
Paul A. Sigala
* E-mail: [email protected] (DEG); [email protected] (PAS)
Affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
ORCID http://orcid.org/0000-0002-3464-3042Citation: Goldberg DE, Sigala PA (2017) Plasmodium heme biosynthesis: To be or not to be essential? PLoS Pathog13(9): e1006511. https://doi.org/10.1371/journal.ppat.1006511
Editor: Laura J. Knoll, University of Wisconsin Medical School, UNITED STATES
Published: September 28, 2017
Copyright: © 2017 Goldberg, Sigala. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by NIH grant AI110712 (DEG), a Burroughs Wellcome Fund Career Award at the Scientific Interface (PAS), and the Utah USTAR Initiative (PAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Sequencing of the Plasmodium falciparum genome in 2002 sparked hopes that metabolic pathway annotation could identify new parasite-specific targets for therapeutic intervention [1]. Cashing in on this potential has proved challenging because many pathways have unexpected properties and/or are only required in certain host environments. Heme biosynthesis has been considered as a possible antimalarial target. Our understanding of heme acquisition mechanisms and the role of heme biosynthesis in different stages of Plasmodium parasite development has evolved considerably in recent years. In this Pearl, we summarize recent major findings and highlight remaining questions.
Plasmodium parasites require heme as a metabolic cofactor
Eukaryotic malaria parasites have retained a mitochondrion and the heme-dependent cytochrome components of the electron transport chain (Fig 1), including cytochromes b and c1 of Complex III, soluble cytochrome c, and the CoxI subunit of Complex IV [2]. The antimalarial drug atovaquone kills parasites in blood, mosquito, and liver stages by binding to cytochrome b, where it inhibits ubiquinone association and blocks electron transport to Complex III, underscoring the critical role of heme-dependent electron transport throughout the parasite life cycle [3, 4]....