Direct tests of enzymatic heme degradation by the malaria parasite Plasmodium falciparum
Open accessAbstract
Background: Malaria parasites detoxify copious amounts of heme during human infection, but enzyme involvement remains unclear.Results: Parasite-infected and uninfected erythrocytes contain indistinguishable low levels of heme catabolites, and a heme oxygenase-like parasite protein binds but does not degrade heme.Conclusion: P. falciparum parasites do not enzymatically degrade heme.Significance: This study comprehensively answers a long standing question regarding heme metabolism in this important parasite.Malaria parasites generate vast quantities of heme during blood stage infection via hemoglobin digestion and limited de novo biosynthesis, but it remains unclear if parasites metabolize heme for utilization or disposal.Recent in vitro experiments with a heme oxygenase (HO)-like protein from Plasmodium falciparum suggested that parasites may enzymatically degrade some heme to the canonical HO product, biliverdin (BV), or its downstream metabolite, bilirubin (BR).To directly test for BV and BR production by P. falciparum parasites, we DMSO-extracted equal numbers of infected and uninfected erythrocytes and developed a sensitive LC-MS/MS assay to quantify these tetrapyrroles.We found comparable low levels of BV and BR in both samples, suggesting the absence of HO activity in parasites.We further tested live parasites by targeted expression of a fluorescent BV-binding protein within the parasite cytosol, mitochondrion, and plant-like plastid.This probe could detect exogenously added BV but gave no signal indicative of endogenous BV production within parasites.Finally, we recombinantly expressed and tested the proposed heme degrading activity of the HO-like protein, PfHO.Although PfHO bound heme and protoporphyrin IX with modest affinity, it did not catalyze heme degradation in vivo within bacteria or in vitro in UV absorbance and HPLC assays.These observations are consistent with PfHO's lack of a heme-coordinating His residue and suggest an alternative function within parasites.We conclude that P. fal-ciparum parasites lack a canonical HO pathway for heme degradation and thus rely fully on alternative mechanisms for heme detoxification and iron acquisition during blood stage infection.
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Plasmodium may not use HB as an iron source, possibly because its P. falciparum heme oxygenase is unable to adequately metabolize heme.
“But paradoxically, Plasmodium may not use HB as iron source, possibly because its P. falciparum heme oxygenase (PfHO) is unable to adequately metabolize heme (Sigala et al., 2012).”
From Iron in infection and immunity (2020) · cites this paper as Sigala et al., 2012
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- Authors
- Sigala, P. A., Crowley, J. R., Hsieh, S., Henderson, J. P., & Goldberg, D. E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Washington University in St. Louis (US)
- Corresponding author
- Goldberg, Daniel E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 287
- Issue
- 45
- Pages
- 37793-37807
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3488054
- OpenAlex
- W1980079347
- Cited by
- 68
- References
- 79
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 1 · 2016: 6 · 2015: 1 · 2014: 8 · 2013: 12
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34)
- National Heart, Lung, and Blood Institute (P30HL101263, HL101263)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK20579, P50DK064540, DK064540, P60-DK-020579, P30DK056341, P30DK020579)
- National Center for Research Resources (P41-RR000954, P41 RR-00954)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD001459, HD001459)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- Plasmodium falciparum, heme degradation, heme oxygenase, biliverdin, bilirubin, heme detoxification, iron acquisition, blood-stage malaria, protoporphyrin IX
- MeSH terms
- Amino Acid Sequence, Bilirubin, Biliverdine, Chromatography, High Pressure Liquid, Erythrocytes, Heme, Heme Oxygenase (Decyclizing), Humans, Microscopy, Fluorescence, Molecular Sequence Data, Plasmodium falciparum, Protein Binding, Protoporphyrins, Spectrometry, Fluorescence, Protozoan Proteins, Mutagenesis, Site-Directed, Malaria, Falciparum, Sequence Homology, Amino Acid, Tandem Mass Spectrometry, Proteolysis
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