The Use and Abuse of Heme in Apicomplexan Parasites

Dooren, Giel G. van; Kennedy, Alexander T.; McFadden, Geoffrey I.

doi:10.1089/ars.2012.4539

Cited by 68 publications

(113 citation statements)

References 186 publications

(188 reference statements)

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…In Plasmodium, chloroquine accumulates in the DV and interferes with the polymerization of heme released from hemoglobin (4,35). Heme in its free state is highly toxic to the parasite (36). Failure to polymerize heme results in swelling of the DV and rapid parasite death (37,38).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

et al. 2014

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

et al. 2014

Self Cite

View full text Add to dashboard Cite

“…Cryptosporidium is currently the only myzozoan where complete loss of these biosynthetic pathways is known to have taken place, and plastids have been lost outright (20). Interestingly, Cryptosporidium is predicted to have a very low requirement for heme (25) and has retained the fatty acid elongation pathway in the cytosol and endoplasmic reticulum (ER) (26). We hypothesize that another major factor in its plastid independence is the exploitation of a single host niche (gut epithelium) throughout its lifecycle.…”

Section: /Namentioning

confidence: 98%

Factors mediating plastid dependency and the origins of parasitism in apicomplexans and their close relatives

Janouškovec

Tikhonenkov

Burki

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

181

193

View full text Add to dashboard Cite

Apicomplexans are a major lineage of parasites, including causative agents of malaria and toxoplasmosis. How such highly adapted parasites evolved from free-living ancestors is poorly understood, particularly because they contain nonphotosynthetic plastids with which they have a complex metabolic dependency. Here, we examine the origin of apicomplexan parasitism by resolving the evolutionary distribution of several key characteristics in their closest free-living relatives, photosynthetic chromerids and predatory colpodellids. Using environmental sequence data, we describe the diversity of these apicomplexan-related lineages and select five species that represent this diversity for transcriptome sequencing. Phylogenomic analysis recovered a monophyletic lineage of chromerids and colpodellids as the sister group to apicomplexans, and a complex distribution of retention versus loss for photosynthesis, plastid genomes, and plastid organelles. Reconstructing the evolution of all plastid and cytosolic metabolic pathways related to apicomplexan plastid function revealed an ancient dependency on plastid isoprenoid biosynthesis, predating the divergence of apicomplexan and dinoflagellates. Similarly, plastid genome retention is strongly linked to the retention of two genes in the plastid genome, sufB and clpC, altogether suggesting a relatively simple model for plastid retention and loss. Lastly, we examine the broader distribution of a suite of molecular characteristics previously linked to the origins of apicomplexan parasitism and find that virtually all are present in their free-living relatives. The emergence of parasitism may not be driven by acquisition of novel components, but rather by loss and modification of the existing, conserved traits.A picomplexans are globally important parasites of humans and animals that include Plasmodium (malaria), Toxoplasma (toxoplasmosis), and Cryptosporidium (cryptosporidiosis). Their success as parasites rests on several highly specialized structures and systems that enable them to gain entry to and divide within cells or tissues of their hosts. These structures include the multimembrane pellicle, a relict nonphotosynthetic plastid (absent in Cryptosporidium), and the apical complex, which is made up of cytoskeletal and secretory elements (e.g., the conoid and rhoptries, respectively). Many specific characteristics of apicomplexans make attractive drug targets, and others may have played a key role in the origin of parasitism. Indeed, the question of apicomplexan origins has been of interest in general but is challenged by a paucity of comparable information from free-living relatives. Several apicomplexan relatives are known, some photosynthetic and others predatory (1, 2), but we lack a comprehensive understanding of their biology because they have either been discovered only recently, or are difficult to establish and maintain in culture. In general, photosynthetic apicomplexan relatives are referred to as chromerids (including Chromera and Vitrella) (1, 3) whereas predators...

show abstract

“…Plasmodium heme biosynthesis is unique to its phylum, since it extends to three cellular compartments, i.e., the cytoplasm, the mitochondrion, and the apicoplast (8). The apicoplast is a relict, nonphotosynthetic plastid found in most apicomplexan parasites and originates from a secondary endosymbiotic event (9).…”

mentioning

confidence: 99%

“…However, the biological significance of most of these proteins and their interaction with heme remains largely unknown. To date, heme is considered to be primarily required by cytochromes of the electron transport chain (ETC) for mitochondrial respiration (8,16). The Plasmodium ETC has long been recognized as a vulnerable target for antimalarial drugs (17,18).…”

mentioning

confidence: 99%

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

2016

View full text Add to dashboard Cite

Malarial parasites have evolved complex regulation of heme supply and disposal to adjust to heme-rich and -deprived host environments. In addition to its own pathway for heme biosynthesis, Plasmodium likely harbors mechanisms for heme scavenging from host erythrocytes. Elaborate compartmentalization of de novo heme synthesis into three subcellular locations, including the vestigial plastid organelle, indicates critical roles in life cycle progression. In this study, we systematically profile the essentiality of heme biosynthesis by targeted gene deletion of enzymes in early steps of this pathway. We show that disruption of endogenous heme biosynthesis leads to a first detectable defect in oocyst maturation and sporogony in the Anopheles vector, whereas blood stage propagation, colonization of mosquito midguts, or initiation of oocyst development occurs indistinguishably from that of wild-type parasites. Although sporozoites are produced by parasites lacking an intact pathway for heme biosynthesis, they are absent from mosquito salivary glands, indicative of a vital role for heme biosynthesis only in sporozoite maturation. Rescue of the first defect in sporogony permitted analysis of potential roles in liver stages. We show that liver stage parasites benefit from but do not strictly depend upon their own aminolevulinic acid synthase and that they can scavenge aminolevulinic acid from the host environment. Together, our experimental genetics analysis of Plasmodium enzymes for heme biosynthesis exemplifies remarkable shifts between the use of endogenous and host resources during life cycle progression. Heme is a ubiquitous iron-porphyrin complex that serves as a cofactor of hemoproteins, such as globins, catalases, and cytochromes (1). The iron component of heme permits the binding of diatomic gases, as well as unique enzymatic redox reactions based on its reduction potential from the oxidized ferric (Fe 3ϩ ) to the reduced ferrous (Fe 2ϩ ) state (1). Thus, heme mediates fundamental biological processes, including oxygen transport, antioxidant responses, and cellular respiration, and is, therefore, indispensable for virtually all living organisms. Exceptions, like the parasitic kinetoplastid flagellate Phytomonas serpens that can survive in the complete absence of heme (2), are rare. As a result of this nearly universal dependence on heme, two complementary strategies for heme acquisition have evolved; heme scavenging and de novo heme biosynthesis.Plasmodium parasites are the causative agents of malaria and have adapted to an intraerythrocytic lifestyle during blood infection, the exclusive pathogenic phase of the parasite life cycle. Erythrocytes make up the largest pool of heme in the human body, as they are rich in hemoglobin. In turn, hemoglobin constitutes the major source of amino acids for developing blood stage parasites, which import and digest almost all host hemoglobin, liberating large amounts of heme (3). Free heme acts as a biological Fenton reagent and can thus damage organic molecules by oxidation...

show abstract

The Use and Abuse of Heme in Apicomplexan Parasites

Abstract: Understanding heme requirements and regulation in apicomplexan parasites promises to reveal multiple targets for much-needed therapeutic intervention against these parasites.

Cited by 68 publications

References 186 publications

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

Factors mediating plastid dependency and the origins of parasitism in apicomplexans and their close relatives

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

Contact Info

Product

Resources

About