scholarly journals Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection

2020 ◽  
Vol 16 (5) ◽  
pp. e1008499
Author(s):  
Amy Bergmann ◽  
Katherine Floyd ◽  
Melanie Key ◽  
Carly Dameron ◽  
Kerrick C. Rees ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Heme Biosynthesis ◽  
Biosynthesis Pathway

scholarly journals Characterization of the apicoplast-localized enzyme TgUroD in Toxoplasma gondii reveals a key role of the apicoplast in heme biosynthesis

2019 ◽  
Vol 295 (6) ◽  
pp. 1539-1550 ◽  
Author(s):  
Edwin T. Tjhin ◽  
Jenni A. Hayward ◽  
Geoffrey I. McFadden ◽  
Giel G. van Dooren
Keyword(s):  
Oxygen Consumption ◽  
Toxoplasma Gondii ◽  
Heme Biosynthesis ◽  
Covalent Attachment ◽  
Biosynthesis Pathway ◽  
Extracellular Acidification ◽  
Mitochondrial Oxygen Consumption ◽  
Atp Levels ◽  
Free Heme

Apicomplexan parasites such as Toxoplasma gondii possess an unusual heme biosynthesis pathway whose enzymes localize to the mitochondrion, cytosol, or apicoplast, a nonphotosynthetic plastid present in most apicomplexans. To characterize the involvement of the apicoplast in the T. gondii heme biosynthesis pathway, we investigated the role of the apicoplast-localized enzyme uroporphyrinogen III decarboxylase (TgUroD). We found that TgUroD knockdown impaired parasite proliferation, decreased free heme levels in the parasite, and decreased the abundance of heme-containing c-type cytochrome proteins in the parasite mitochondrion. We validated the effects of heme loss on mitochondrial cytochromes by knocking down cytochrome c/c1 heme lyase 1 (TgCCHL1), a mitochondrial enzyme that catalyzes the covalent attachment of heme to c-type cytochromes. TgCCHL1 depletion reduced parasite proliferation and decreased the abundance of c-type cytochromes. We further sought to characterize the overall importance of TgUroD and TgCCHL1 for both mitochondrial and general parasite metabolism. TgUroD depletion decreased cellular ATP levels, mitochondrial oxygen consumption, and extracellular acidification rates. By contrast, depletion of TgCCHL1 neither diminished ATP levels in the parasite nor impaired extracellular acidification rate, but resulted in specific defects in mitochondrial oxygen consumption. Together, our results indicate that the apicoplast has a key role in heme biology in T. gondii and is important for both mitochondrial and general parasite metabolism. Our study highlights the importance of heme and its synthesis in these parasites.

scholarly journals Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection

2019 ◽  
Author(s):  
Amy Bergmann ◽  
Katherine Floyd ◽  
Melanie Key ◽  
Carly Dameron ◽  
Kerrick C. Rees ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
De Novo ◽  
Phylogenetic Analyses ◽  
Heme Biosynthesis ◽  
Microbial Pathogens ◽  
Biosynthesis Pathway ◽  
Prosthetic Group ◽  
Apicomplexan Parasites ◽  
Pathogenic Microbes ◽  
Living Organisms

Heme, an iron-enclosed organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic gas transport and detection to mitochondrial respiration to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates1,2. Intracellular pathogenic microbes switch routes for heme supply when heme availability in their replicative environment fluctuates through infections2. Here, we show that the Toxoplasma gondii, an obligate intracellular human pathogen, encodes a functional heme biosynthesis pathway. A chloroplast-derived organelle, termed apicoplast, is involved in the heme production. Genetic and chemical manipulation revealed that de novo heme production is essential for T. gondii intracellular growth and pathogenesis. Surprisingly, the herbicide oxadiazon significantly impaired Toxoplasma growth, consistent with phylogenetic analyses that show T. gondii protoporphyrinogen oxidase is more closely related to plants than mammals. We further improve upon this inhibition by 15-to 25-fold with two oxadiazon derivatives, providing therapeutic proof that Toxoplasma heme biosynthesis is a druggable target. As T. gondii has been used to model other apicomplexan parasites3, our study underscores the utility of targeting heme biosynthesis in other pathogenic apicomplexans.

scholarly journals NFE2 regulates transcription of multiple enzymes in the heme biosynthesis pathway

Haematologica ◽  
2014 ◽  
Vol 99 (10) ◽  
pp. e208-e210 ◽  
Author(s):  
L. Rheinemann ◽  
T. S. Seeger ◽  
J. Wehrle ◽  
H. L. Pahl
Keyword(s):  
Heme Biosynthesis ◽  
Biosynthesis Pathway

scholarly journals Laboratory Diagnosis of Porphyria

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1343
Author(s):  
Elena Di Pierro ◽  
Michele De Canio ◽  
Rosa Mercadante ◽  
Maria Savino ◽  
Francesca Granata ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Diagnostic Testing ◽  
Laboratory Diagnosis ◽  
Clinical Suspicion ◽  
Enzymatic Activities ◽  
Heme Biosynthesis ◽  
Present Review ◽  
Biosynthesis Pathway ◽  
Clinical Presentations

Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in the blood, urine, or feces, and these intermediates are responsible for specific clinical presentations. Porphyrias continue to be underdiagnosed, although laboratory diagnosis based on the measurement of metabolites could be utilized to support clinical suspicion in all symptomatic patients. Moreover, the measurement of enzymatic activities along with a molecular analysis may confirm the diagnosis and are, therefore, crucial for identifying pre-symptomatic carriers. The present review provides an overview of the laboratory assays used most commonly for establishing the diagnosis of porphyria. This would assist the clinicians in prescribing appropriate diagnostic testing and interpreting the testing results.

scholarly journals The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria

2019 ◽  
Vol 5 (9) ◽  
pp. eaaw6127 ◽  
Author(s):  
Pengcheng Wang ◽  
Madhav Sachar ◽  
Jie Lu ◽  
Amina I. Shehu ◽  
Junjie Zhu ◽  
...  
Keyword(s):  
Essential Role ◽  
Protoporphyrin Ix ◽  
Heme Biosynthesis ◽  
Biosynthesis Pathway ◽  
Efflux Transporter ◽  
Inherited Disease ◽  
Loss Of Function ◽  
Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.

Computational modeling of the catalytic mechanism of hydroxymethylbilane synthase

2019 ◽  
Vol 21 (15) ◽  
pp. 7932-7940 ◽  
Author(s):  
Navneet Bung ◽  
Arijit Roy ◽  
U. Deva Priyakumar ◽  
Gopalakrishnan Bulusu
Keyword(s):  
Computational Modeling ◽  
Catalytic Mechanism ◽  
Heme Biosynthesis ◽  
Biosynthesis Pathway ◽  
The Third

Hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthesis pathway, catalyzes the formation of 1-hydroxymethylbilane (HMB) by a stepwise polymerization of four molecules of porphobilinogen (PBG) using the dipyrromethane (DPM) cofactor.

Heme biosynthesis pathway regulation in a model of hepatocarcinogenesis pre-initiation

1992 ◽  
Vol 103 (1) ◽  
pp. 251-256 ◽  
Author(s):  
César F. Polo ◽  
Elba S. Vazquez ◽  
Fabiana Caballero ◽  
Esther Gerez ◽  
Alcira M.del C. Batlle
Keyword(s):  
Heme Biosynthesis ◽  
Biosynthesis Pathway ◽  
Pathway Regulation
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