Vitamin and cofactor acquisition in apicomplexans: Synthesis <i>versus</i> salvage

Krishnan, Aarti; Kloehn, Joachim; Lunghi, Matteo; Soldati‐Favre, Dominique

doi:10.1074/jbc.aw119.008150

Cited by 12 publications

(20 citation statements)

References 135 publications

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“…Apicomplexa and other parasites have evolved expert strategies to exploit the metabolism of their host, salvaging various nutrients including sugars, amino acids, nucleobases, lipids, fatty acids, vitamins, and cofactors [21,30,87,88]. Hence, many parasites have lost the capacity to synthesize certain metabolites and have developed scavenging mechanisms, allowing the pathogens to save energy by reducing their genome and metabolic capabilities [89].…”

Section: Availability and Uptake Of Exogeneous Heme In Apicomplexamentioning

confidence: 99%

“…CPOX is cytosolic in fungi and yeast; however, it localizes to the mitochondria in animals [103]. Curiously, coccidians and chromerids express a putative oxygen-independent bacterial-type coproporphyrinogen III dehydrogenase (CPDH), which is also predicted to catalyze the conversion of CPPgenIII to PPgenIX, via a radical s-adeonsyl-methionine (SAM) mechanism [88,101,102,110]. The final two enzymes of the pathway, PPOX and FECH, localize to the mitochondrion in Plasmodium spp.…”

Section: Heme Synthesis Enzymes In Apicomplexa: Conservation Localizmentioning

confidence: 99%

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Supply and demand—heme synthesis, salvage and utilization by Apicomplexa

2020

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The Apicomplexa phylum groups important human and animal pathogens that cause severe diseases, encompassing malaria, toxoplasmosis, and cryptosporidiosis. In common with most organisms, apicomplexans rely on heme as cofactor for several enzymes, including cytochromes of the electron transport chain. This heme derives from de novo synthesis and/or the development of uptake mechanisms to scavenge heme from their host. Recent studies have revealed that heme synthesis is essential for Toxoplasma gondii tachyzoites, as well as for the mosquito and liver stages of Plasmodium spp. In contrast, the erythrocytic stages of the malaria parasites rely on scavenging heme from the host red blood cell. The unusual heme synthesis pathway in Apicomplexa spans three cellular compartments and comprises enzymes of distinct ancestral origin, providing promising drug targets. Remarkably given the requirement for heme, T. gondii can tolerate the loss of several heme synthesis enzymes at a high fitness cost, while the ferrochelatase is essential for survival. These findings indicate that T. gondii is capable of salvaging heme precursors from its host. Furthermore, heme is implicated in the activation of the key antimalarial drug artemisinin. Recent findings established that a reduction in heme availability corresponds to decreased sensitivity to artemisinin in T. gondii and Plasmodium falciparum, providing insights into the possible development of combination therapies to tackle apicomplexan parasites. This review describes the microeconomics of heme in Apicomplexa, from supply, either from de novo synthesis or scavenging, to demand by metabolic pathways, including the electron transport chain.

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Section: Availability and Uptake Of Exogeneous Heme In Apicomplexamentioning

confidence: 99%

Section: Heme Synthesis Enzymes In Apicomplexa: Conservation Localizmentioning

confidence: 99%

Supply and demand—heme synthesis, salvage and utilization by Apicomplexa

2020

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“…The absence of the N-terminal DNA-binding helix-turnhelix domain required for the regulation of biotin-biosynthesis genes in LmBPL suggests that the enzyme belongs to the class I biotin protein ligases. As trypanosomatids lack the biotin-biosynthetic machinery, and salvage biotin exclusively from the host/environment, the regulatory domain is probably not required (Krishnan et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Leishmania major biotin protein ligase forms a unique cross-handshake dimer

Rajak¹,

Bhatnagar²,

Pandey³

et al. 2021

Acta Cryst Sect D Struct Biol

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Biotin protein ligase catalyses the post-translational modification of biotin carboxyl carrier protein (BCCP) domains, a modification that is crucial for the function of several carboxylases. It is a two-step process that results in the covalent attachment of biotin to the ɛ-amino group of a conserved lysine of the BCCP domain of a carboxylase in an ATP-dependent manner. In Leishmania, three mitochondrial enzymes, acetyl-CoA carboxylase, methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase, depend on biotinylation for activity. In view of the indispensable role of the biotinylating enzyme in the activation of these carboxylases, crystal structures of L. major biotin protein ligase complexed with biotin and with biotinyl-5′-AMP have been solved. L. major biotin protein ligase crystallizes as a unique dimer formed by cross-handshake interactions of the hinge region of the two monomers formed by partial unfolding of the C-terminal domain. Interestingly, the substrate (BCCP domain)-binding site of each monomer is occupied by its own C-terminal domain in the dimer structure. This was observed in all of the crystals that were obtained, suggesting a closed/inactive conformation of the enzyme. Size-exclusion chromatography studies carried out using high protein concentrations (0.5 mM) suggest the formation of a concentration-dependent dimer that exists in equilibrium with the monomer.

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“…Intracellular Plasmodium and Toxoplasma parasites have several ways to scavenge nutrients from the host, through the induction of new permeation pathways (NPPs) in Plasmodium -infected erythrocytes, the selectively permeable parasitophorous vacuole membrane, and by membrane transporter proteins [ 8 – 14 ]. Understanding the acquisition and de novo synthesis of metabolites and the characterization of metabolic pathways for the production of essential vitamins or cofactors is of significant therapeutic interest [ 15 ]. In this review, we focus on recent advances in our understanding of the biology of the pathways for the synthesis of pantothenate (Pan, vitamin B5) and coenzyme A (CoA) in the apicomplexan parasites T .…”

Section: Introductionmentioning

confidence: 99%

Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

et al. 2021

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The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

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Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Cited by 12 publications

References 135 publications

Supply and demand—heme synthesis, salvage and utilization by Apicomplexa

Supply and demand—heme synthesis, salvage and utilization by Apicomplexa

Leishmania major biotin protein ligase forms a unique cross-handshake dimer

Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

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